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PRINCIPLES  OF 
HUMAN    PHYSIOLOGY 


PRINCIPLES  OF 
HUMAN  PHYSIOLOGY 


BY 


ERNEST  H.  STARLING 

M.D.  (Lond.),  F.R.C.P.,  F.R.S.,   Hon.  M.D.  (Breslau) 
Hon.  Sc. D.  (Cambridge  and  Dublin) 

Jodrell  Professor  of  Physiology  in  University 
College,  London 


SECOND  EDITION 
With   566  Illustrations,   10  in  Colour 


PHILADELPHIA 
LEA    &    FEBIGER 

706  SANSOM  STREET 
1915 


Printed  in   Great  Britain 


PREFACE  TO  THE  SECOND  EDITION 

During  the  short  time  that  has  elapsed  since  the  pubhcation 
of  the  first  edition  of  this  work  physiology  has  made  some 
considerable  advances,  and  I  have  found  it  necessary  to  re-write 
much  of  the  sections  dealing  with  ^'oluntary  muscle  and  with 
the  circulation,  in  addition  to  making  many  modifications  in 
other  parts  of  the  work.  New  sections  have  also  been  intro- 
duced dealing  with,  the  nutrition  of  the  brain  and  Tvath  the 
innervation  of  the  bronchi. 

I  am  much  indebted  to  many  friends,  knowni  and  unkno\M^i, 
who  have  pointed  out  mistakes  and  omissions  in  the  first  edition. 
I  shall  be  glad  to  receive  any  suggestions  as  to  points  in  which 
this  text-book  may  be  made  more  useful  to  students. 

UxivERsnY  College,  Loxdon 


PREFACE  TO  THE  FIRST  EDITION 

Physiology,  though  deaUng  with  the  pheuomena  of  hving  organisms,  has 
to  use  the  same  tools,  whether  material  or  intellectual,  as  the  sciences  of 
physics  and  chemistry.  Any  advances  which  are  made  in  these  sciences 
not  only  increase  our  powers  of  attack  upon  physiological  problems  but  at 
the  same  time  alter  the  intellectual  standpoint  from  which  we  view  them. 
On  the  other  hand,  the  investigation  of  the  phenomena  of  hving  beings 
is  continually  attracting  our  attention  and  that  of  workers  in  the  other 
branches  of  science  to  unexplored  regions  in  physics  and  chemistry.  This 
mutual  stimulation  and  co-operation  among  the  different  sciences  have  as 
their  result  a  continual  modification  of  our  attitude  with  regard  to  the 
fundamental  problems  of  physiology.  The  present  time  has  seemed  to  me, 
therefore,  fitting  for  the  production  of  a  textbook  which,  while  not  neglecting 
the  data  of  physiolog}%  should  lay  special  stress  on  the  significance  of  these 
data,  and  attempt  to  weave  them  into  a  fabric  representing  the  principles 
which  are  guiding  physiologists  and  physicians  of  the  present  day  in  their 
endeavours  to  extend  the  bounds  of  the  known  and  to  increase  their 
powers  of  control  over  the  functions  of  living  organisms. 

In  a  science  such  as  physiology,  based  on  so  wide  a  discipline  and  with  so 
diverse  a  technique,  it  is  almost  impossible  for  any  one  man  to  attain  to  a 
personal  acquaintance  with  all  its  branches.  In  the  present  book  I  have 
therefore  not  hesitated  to  avail  myseK  of  the  work  of  masters  of  the  science 
in  fields  which  I  had  not  myself  explored.  Thus,  in  the  physiology  of  the 
nervous  system,  which  has  been  transformed  and  built  up  on  a  new  basis 
by  the  researches  of  Sherrington,  I  have  endeavoured  to  follow  this  author 
as  closely  as  possible.  I  am  also  deeply  sensible  of  my  obhgations  to 
the  writings  of  Tigerstedt,  Leathes,  and  Lusk  on  general  metabolism,  of 
Abderhalden  and  Plimmer  on  physiological  chemistry,  of  Bayliss  on  general 
physiology,  as  weU  as  to  various  authors  of  articles  in  the  "  Ergebnisse 
der  Physiologic,"  in  Nagel's  "  Handbuch  der  Physiologic,''  and  in  Dr.  L.  E. 
Hill's  "  Recent  and  Further  Advances  in  Physiology," 

Although  I  have  endeavom-ed  to  confine  my  demands  on  the  previous 
knowledge  of  the  student  within  the  narrowest  possible  hmits,  I  should 
recommend  him  in  every  case  to  read  some  primer  on  physiology  in  order  to 
obtain  a  bird's  eye  view  of  the  subject  before  beginning  the  study  of  this 
work.  He  will  then  be  able  to  vary  the  order  of  chapters  in  this  book 
according  to  the  part  of  physiology  which  he  is  hearing  about  in  his  lectures 
or  working  at  in  his  practical  classes.  Those  of  my  readers  who  are  entirely 
unacquainted  with  physiology  might  do  well  on  a  first  perusal  to  omit  Book  I., 
dealing  with  the  general  concepts  of  the  science. 


viii  PREFACE 

I  have  deemed  it  a  hopeless  and  indeed  a  useless  task  to  give  any  full 
account  of  the  multifarious  methods  employed  in  the  experimental  investiga- 
tion of  the  different  organs,  of  the  body.  In  most  cases  I  have  consigned  to 
small  type  a  description  of  one  or  two  typical  methods,  which  would  suffice 
to  show  how  the  questions  may  be  approached  from  the  experimental  side. 

Throughout  the  work  I  have  sought  to  show  that  the  only  foundation 
for  rational  therapeutics  is  the  proper  understanding  of  the  working  of  the 
healthy  body.  Until  we  know  more  about  the  physiology  of  nutrition, 
Cjuacks  will  thrive  and  food  faddists  abound.  Ignorance  of  physiology 
tends  to  make  a  medical  man  as  credulous  as  his  patients  and  almost  as 
easily  beguiled  by  the  specious  puffings  of  the  advertising  druggist.  I  trust, 
therefore,  that  the  following  pages  will  be  found  of  value  not  only  to  the 
candidate  for  a  university  degree  but  also  to  the  practitioner  of  medicine  in 
equipping  him  for  his  struggle  against  the  factors  of  disease. 

In  the  selection  of  diagrams  for  the  illustration  of  this  book  I  am  especi- 
ally indebted  to  Professor  Schafer  and  to  his  publishers,  Messrs.  Longmans, 
for  the  permission  to  make  use  of  a  large  number  from  Quain's  "  Anatomy  " 
and  from  Schafer's  "  Essentials  of  Histology."  I  must  also  express  my 
obligation  to  Professor  Wilson  for  the  use  of  certain  figures  from  his  admirable 
work  on  the  cell,  to  the  publishers  of  Cunningham's  "  Anatomy,"  and  to 
many  physiological  friends,  especially  to  Dr.  Mott  and  Dr.  Gordon  Holmes, 
for  the  use  of  original  diagrams.  The  index  was  kindly  made  for  me  by 
Mr.  Lovatt  Evans. 

ERNEST  H.  STARLING 

University  College,  London 
May  1912 


C  O  T^  T  E  N  T  S 


CHAPTER  I 

PAGK 

INTRODUCTION  1 


BOOK    I 
GENERAL  PHYSIOLOGY 

CHAPTER  II 
THE  STRUCTURAL  BASIS  OF  THE  BODY  ].3 

CHAPTER  III 
THE  MATERIAL  BASIS  OF  THE  BODY 

SKCTION 

I.  The  Elementary  Constituents  of  Living  Cells  3G 

II.  The  Proximate  Constituents  of  the  Animal  Body  45 

III.  The  Fats  53 

IV.  The  Carbohydrates  59 

V.  The  Proteins  7I 

VI.  The  Mechanism  of  Organic  Synthesis  109 

CHAPTER  IV 

THE  ENERGETIC  BASIS  OF  THE  BODY 

I.  The  Energy  OF  Molecules  IN  Solution  123 

11.  The  Passage  of  Water  and  Dissolved  Substances  across  Membranes  131 

III.  The  Properties  of  Colloids  I39 

IV.  The  Mechanism  of  Chemical  Changes  in  Living  Matter.     Ferments  153 
V.  Electrical  Changes  IN  Living  Tissues  170 

BOOK  II 
THE    MECHANISMS  OF  MOVEMENT  AND    SENSATION 

CHAPTER  V 

THE  CONTRACTILE  TISSUES 

I.  The  Structure  of  Voluntary  Muscle  1 77 
II.  The  Excitation  of  Muscle  185 
III.  The  Mechanical  Changes  that  a  Muscle  undergoes  when  it  Con- 
tracts 1  g.jt 

ix 


X  CONTENTS 

CHAPTER  V  (continued) 

SECTION  PAGE 

IV.  The  Conditions  affecting  the  Mechanical  Response  of  a  Muscle    205 

V.  The  Chemical  Chajstges  rsr  Mhscle  212 

VI.  The  Pkodtjction  of  Heat  in  Muscle  219 

VII.  Electrical  Changes  in  Muscle  224 

VIII,  The  Intimate  Natuke  op  Muscular  Contraction  234 

IX.  Voluntary  Contraction  239 

X.  Other  Forms  of  Contractile  Tissue  243 


CHAPTER  VI 

NERVE  FIBRES  (CONDUCTING  TISSUES) 

I.  The  Structure  of  Nerve  Fibres  250 

II.  Propagation  along  Nerve  Fibres  253 

III.  Events  accompanying  the  Passage  of  a  Nervous  Impulse  256 

IV.  Conditions  affecting  the  Passage  of  a  Nervous  Impulse  258 
V.  The  Excitation  of  Nerve  Fibres  262 

VI.  The  Conditions  which  Determine  Electrical  Stimulation  270 

VII.  The  Neuro-Muscular  Junction  275 

VIII.  Polarisation  Phenomena  in  Nerve  280 

IX.  The  Nature  of  the  Excitatory  Process  284 


CHAPTER  VII 

THE  CENTRAL  NERVOUS  SYSTEM 

I.  The  Evolution  and  Significance  of  the  Nervous  System  288 

11.  The  Nervous  System  op  Vertebrates  297 

III.  General  Characteristics  of  Reflex  Actions  303 

IV.  Nature  op  the  Connection  between  Neurons  307 
V.  Functions  of  the  Nerve-Cell  312 

THE  SPINAL  CORD 

VI.  Structure  of  the  Spinal  Cord  315 

VII.  The  Spinal  Cord  as  a  Reflex  Centre  322 

VIII.  The  Mechanism  of  Co-ordinated  Movements  338 

IX.  Trophic  Functions  of  the  Cord  359 

X.  The  Spinal  Cord  as  a  Conductor  351 

THE  BRAIN 

XL  The  Structure  of  the  Brain  Stem  361 

XIL  The  Functions  of  the  Brain  Stem  392 

XIII.  The  Functions  of  the  Cerebellum  397 

XIV.  Visual  Reflexes  406 
XV.  Summary  op  the  Connections  and  Functions  of  the  Cranial  Nerves    410 


CONTENTS 


XI 


THE  CEREBRAL  HEMISPHERES 

SEOTION  PAQB 

XVT.  General  Stkuctural  Arrangements  of  the  Cerebrum  416 

XVII.  The  Fitnctions  of  the  Cerebral  Hemispheres  434 
XVIII.  The  Nutritive  and    Vascular  Arrangements  of  the   Central 

Nervous  System  461 

THE  AUTONOMIC  SYSTEM 

XIX.  The  Visceral  or  Autonomic  Nervous  System  466 

CHAPTER  VIII 

THE  PHYSIOLOGY  OF  SENSATION 

I.  On  the  Relation  of  Sensation  to  Stimulus  478 

II.  Cutaneous  Sensations  486 

III.  Sensations  of  Smell  and  Taste  498 

IV.  Auditory  Sensations  505 
V.  Voice  and  Speech  520 

VISION 

VI.  Dioptric  Mechanisms  of  the  Eyeball  528 

VII.  The  Retinal  Changes  involved  in  Vision  558 

VIII.  Visual  Sensations  568 

IX.  Movements  of  the  Eyeballs  585 

X.  Visual  Judgments  589 

XL  The  Nutrition  of  the  Eyeball  694 

THE  ORGANIC  SENSATIONS 

XII.  Sensations  of  Movement  and  Position  598 

XIII.  The  Labymnthtne  Sensations  603 


BOOK  III 
THE  MECHANISMS  OF  NUTRITION 

CHAPTER  IX 

THE  EXCHANGES  OF  MATTER  AND  ENERGY  IN  THE  BODY 
(GENERAL  METABOLISM) 

I.  Methods  employed  in  Determining  the  Total  Exchanges  of  the 

Body  614 

II.  The  Metabolism  during  Starvation  624 

III.  The  Effect  of  Food  on  the  Metabolism  of  the  Body  631 

IV.  The  Effect  of  Muscular  Work  on  Metabolism  637 
V.  The  Significance  of  the  Food-stuffs  642 

VI.  The  Normal  Diet  of  Man  648 


Xll 


CONTENTS 


III.  The  Histoey  of  Fat  in  the  Body 

IV.  The  Metabolism  of  Carbohydrates 


CHAPTER  X 
THE  PHYSIOLOGY  OF  DIGESTION 

SECTION  PAGE 

Changes  undergone  by  the  Food-stuffs  in  the  Alimentary  Canal 

I.  Digestion  in  the  Mouth  661 

II.  The  Passage  of  Food  from  the  Mouth  to  the  Stomach  676 

in.  Digestion  in  the  Stomach  683 

rv.  The  Movements  of  the  Stomach                                   ^  697 

V.  The  Pancreatic  Juice  702 

VI.  The  Liver  and  Bile  "7 13 

VII.  The  Intestinal  Juice  718 

VIII.  Functions  of  the  Large  Intestine  722 

IX.  Movements  of  the  Intestines  725 

X.  The  Absorption  of  the  Food-stuffs  733 

XL  TheF^ces  '^^^ 


CHAPTER  XI 

THE  HISTORY  OF  THE  FOOD-STUFFS 

I.  Protein  Metabolism  756 

11.  NucLEiN  OR  Purine  Metabolism  774 

783 
796 


CHAPTER  XII 

THE  BLOOD 

General  Characters  of  the  Blood  810 

T.  The  White  Blood -Corpuscles  ^1"^ 

11.  The  Red  Blood-Corpuscles  ^1^ 

III.  The  Blood-Platelets 

IV.  The  Coagulation  of  the  Blood 
V.  The  Quantity  and  Composition  of  the  Blood  in  Man  854 


836 
839 


CHAPTER  XIII 

THE  PHYSIOLOGY  OF  THE  CIRCULATION 

I.  General  Features  of  the  Circulation 
11.  The  Blood-Pressure  at  Different  Parts  of  the  Vascular  Circuit    874 

III.  The  Velocity  of  the  Blood  at  Different  Parts  of  the  Vascular 

System 

IV.  The  Mechanism  of  the  Heart  Pump 


868 


88() 
891 


CONTENTS  xiii 

CHAPTER  XIT  {continued) 

SECTION  PAGE 

V.  The  Flow  OF  Blood  THROUGH  THE  Arteries  918 

VI.  The  Flow  of  Blood  in  the  Veins  932 

VII.  The  Pulmonary  Circulation  935 

VIII.  The  Causation  of  the  Heart-Beat  939 

IX.  The  Nervous  Regulation  op  the  Heart  969 

X.  The  Nervous  Control  of  the  Blood-Vessels  982 

XI.  The  Effect  of  Muscular  Exercise  on  the  Circulation  1006 

XII.  The  Influence   on  the  Circulation  op  Variations  in  the  Total 

Quantity  op  Blood  1009 

CHAPTER  XIV 

LYMPH  AND  TISSUE  FLUIDS  1012 


CHAPTER  XV 

THE  DEFENCE  OF  THE  ORGANISM  AGAINST  INFECTION 

I.  The  Cellular  Mechanisms  op  Defence  1021 

II.  The  Chemical  Mechanisms  op  Defence  1030 

CHAPTER    XVI 
RESPIRATION 

I.  The  Mechanics  of  the  Respiratory  Movements  1039 

II.  The  Chemistry  op  Respiration  1051 

III.  The  Regulation  of  the  Respiratory  Movements  1076 

The  Chemical  Regulation  op  the  Respiratory  Movements  1079 

The  Reflex  Nervous  Regulation  op  Respiration  1089 

IV.  The  Effects  on  Respiration  of  Changes  in  the  Air  Breathed  1098 
V,  The  Mechanisms  of  Oxidation  in  the  Tissues  1105 


CHAPTER  XVII 
RENAL  EXCRETION 

I.  The  Composition  and  Characters  op  the  Urine  1110 

IT.  The  Secretion  op  Urine  1131 

in.  The  Physiology  OF  Micturition  1152 


CHAPTER  XVI 11 
THE  SKIN  AND  THE  SKIN  GLANDS  1161 


XIV 


CONTENTS 


CHAPTER  XIX 

SECTION  PAGE 

THE  TEMPERATURE  OF  THE  BODY  AND  ITS  REGULATION  1167 


CHAPTER  XX 
THE  DUCTLESS  GLANDS  1178 


BOOK  rv 

REPRODUCTION 

CHAPTER  XXI 

THE  PHYSIOLOGY  OF  REPRODUCTION 

I.  The  Essential  Features  of  the  Sexual  Pkocess  1199 

11.  Development  and  Hebedity  1212 

III.  Repkoduction  in  Man  1217 

IV.  Peegnancy  and  Parturition  1230 
V.  The  Secretion  and  Properties  of  Milk  1137 

INDEX  1247 


CHAPTER  I 

INTRODUCTION 

Physiology  in  its  widest  sense  signifies  the  study  of  the  phenomena  pre- 
sented by  living  organisms,  the  classification  of  these  phenomena,  and  the 
recognition  of  their  sequence  and  relative  significance.  Such  a  range  would 
include  many  studies  which  are  not  generally  grouped  under  the  term 
physiology,  and  would  in  fact  correspond  to  the  comprehensive  science  of 
biology.  Thus  the  study  of  the  relations  of  living  beings  to  one  another  and 
to  their  surroundings  is  the  special  object  of  the  science  of  cecology.  The 
aims  of  physiology  in  its  restricted  sense  are  the  description,  analysis,  and 
classification  of  the  phenomena  presented  by  the  isolated  organism,  the 
allocation  of  every  function  to  its  appropriate  organ,  and  the  study  of  the 
conditions  and  mechanisms  which  determine  each  fmiction. 

The  fundamental  phenomena  of  life  are  essentially  identical  throughout 
the  whole  series  of  Hving  organisms.  This  continuity  of  function  is  the 
necessary  correlation  of  the  continuity  of  descent,  which  brings  into  relation 
all  members  of  the  animal  and  vegetable  kingdoms.  No  living  organism 
can  therefore  be  regarded  as  outside  the  sphere  of  our  investigations.  The 
interest  of  mankind  in  this  subject  was,  however,  naturally  awakened  in 
connection  with  his  o\^al  body,  and  the  science,  growing  up  as  ancillary  and 
preliminary  to  medical  studies,  has  always  taken  man  as  its  chief  tjrpe  of 
study.  In  the  present  work  the  elucidation  of  the  functions  of  man  will 
also  be  our  first  concern,  and  this  for  two  reasons.  In  the  first  place, 
in  physiology,  as  in  all  other  sciences,  the  motive  of  man's  activity  is  his 
social  instinct  to  increase  the  power  of  his  race  in  the  struggle  for  existence, 
by  the  acquisition  of  control,  either  over  the  external  forces  of  nature, 
which  may  be  turned  to  his  own  benefit,  or  over  the  factors,  intrinsic  and 
extrinsic,  which  tend  to  his  enfeeblement  or  extirpation  by  disease  and  death. 
Consciously  or  unconsciously,  all  our  researches  on  physiology,  whether  on 
the  higher  animals  or  on  the  lowest  protozoa,  have  the  welfare  of  man  as 
their  ultimate  object.  In  the  second  place,  the  choice  of  the  higher  animals 
as  our  chief  objects  of  study  receives  justification  from  the  fact  that  whereas 
morphology,  or  the  science  of  structure,  must  proceed  from  the  lowest  to 
the  highest  organisation,  the  science  of  function  presents  its  problems  in 
their  simplest  form  in  the  most  highly  dift'erentiated  organisms.  In  the 
unicellular  animal  all  the  essential  functions  which  we  associate  with  living 
beings  are  carried  out,  often  simultaneously,  in  one  little  speck  of  proto- 
plasm.    An  analysis  of  these  functions,  the  determination  of  their  conditions 

1  1 


2  PHYSIOLOGY 

and  mecliamsm,  is  obviously  impossible  under  such  circumstances.  It  is  only 
when,  as  in  the  higher  animals,  one  part  of  the  hving  body  is  difierentiated 
into  an  organ  which  has  one  function  and  one  function  only  as  the  outlet 
for  its  acti\dties,  that  it  becomes  possible  to  peer  into  the  details  of  the 
function  with  some  chance  of  discovering  its  ultimate  mechanism. 

Our  especial  preoccupation  with  the  physiology  of  man  will  not  prevent 
our  employment  of  examples  from  any  part  of  the  animal  or  vegetable 
kingdom,  when  light  can  be  thrown  by  their  study  on  fundamental  physio- 
logical phenomena  common  to  the  whole  of  the  living  world.  In  many 
cases  such  a  study  will  enable  us  to  separate  the  essential  features  in  a 
process  from  those  which  have  been  added  as  auxihary,  with  increasing 
complexity  of  the  structures  concerned. 

What  are  the  fundamental  phenomena  which  are  wrapt  up  in  our  con- 
ception of  living  beings  ?  When  deahng  mth  the  higher  animals,  we  are 
inclined  to  lay  greater  stress  on  the  phenomena  involving  a  discharge  of 
energy.  Thus  we  should  say  that  a  man  was  alive  if  his  body  were  warm 
and  if  he  were  presenting  spontaneous  movements,  such  as  those  of  respira- 
tion or  of  the  heart.  The  life  of  a  man  in  the  ordinary  sense  of  the  term  is 
made  up  of  those  movements  which  place  him  in  relationship  with  his  environ- 
ment. For  the  production  of  these  movements,  as  for  the  maintenance  of  a 
constant  body-temperature,  a  continual  expenditure  of  energy  is  necessary. 
Experience  teaches  us  that  these  movements  come  to  an  end  in  the  absence 
of  food  or  of  oxygen,  and  that  an  increased  call  on  the  energies  of  the  body 
must  always  be  met  by  a  corresponding  increase  in  the  air  and  in  the  food 
supplied.  Two  further  processes  must  therefore  be  included  among  those 
making  up  our  conception  of  life,  viz.  the  function  of  assimilation  (the 
taking  in  and  digestion  of  food),  and  the  function  of  respiration,  in  which 
oxygen  is  absorbed  and  carbon  dioxide  is  excreted  into  the  surrounding 
atmosphere. 

The  substances  which  make  up  our  food-stuffs  are  all  capable  of  oxidation. 
Composed  chiefly  of  carbon  and  hydrogen,  with  some  oxygen,  nitrogen,  and 
sulphur,  they  yield  on  complete  combustion  carbon  dioxide,  water  and 
small  amounts  of  ammonia  or  allied  bodies,  and  sulphates.  In  this  process 
of  oxidation  there  is  liberation  of  heat.  In  the  body  a  similar  oxidation 
occurs,  the  products  of  oxidation  being  discharged  into  the  surrounding 
medium.  An  amount  of  energy  is  thus  set  free  which  is  available  for  the 
activities  of  the  living  organism.  Before  we  can  make  any  accurate  in- 
vestigations of  the  conditions  which  determine  these  activities,  we  must 
know  whether  the  two  great  laws  of  chemistry  and  physics,  viz.  the  conser- 
vation of  mass  and  the  conservation  of  energy,  hold  good  for  the  processes 
within  the  living  body.  The  many  experiments  which  have  been  made  on 
this  point  have  decided  the  question  in  the  affirmative.  Thousands  of 
experiments  have  been  made,  both  on  man  and  on  animals,  in  which  the 
total  income  of  the  body,  viz.  food  and  oxygen,  has  been  weighed,  and 
compared  with  the  total  output,  viz.  carbon  dioxide,  water,  and  bodies 
allied  to  ammonia  (urea,  &c.).     In  every  case  complete  equality  has  been 


INTRODUCTION  3 

obtained,  and  we  can  be  certain  that  any  matter  found  in  the  body  must 
have  been  derived  from  without.  There  is  no  creation  or  destruction  of 
matter  in  the  body. 

The  determination  of  the  equation  in  the  case  of  the  total  energy  of  the 
body  is  rather  more  difficult.  We  have,  in  the  first  place,  to  measure  the 
total  income  and  output  of  the  body,  and  to  determine  the  total  heat  which 
would  be  evolved  by  the  oxidation  of  the  food-stufis  taken  into  the  carbon 
dioxide,  water,  &c.,  that  are  given  out.  We  must  then  compare  the  figure 
so  obtained  with  the  actual  output  of  energy  by  the  body.  The  latter  can 
be  measured  in  terms  of  heat  by  placing  the  animal  inside  a  calorimeter. 
Many  practical  difficulties  arise  in  the  performance  of  the  experiment,  in 
consequence  of  the  necessity  of  providing  the  animal  with  a  constant  supply 
of  air  to  breathe,  and  of  allowing  for  the  continual  loss  of  water  by  evapora- 
tion which  is  going  on  at  the  surface  of  the  animal.  The  first  accurate 
experiments  of  this  nature  were  made  by  Rubner.  This  observer  deter- 
mined by  means  of  the  calorimeter  the  total  heat  loss  of  dogs.  In  the  same 
animals  the  material  income  and  output  of  the  body  were  measured,  and  a 
calculation  was  made  as  to  the  amount  of  energy  which  would  be  set  free 
in  the  body  by  the  processes  of  oxidation  involved  in  the  change  of  material 
observed.     The  following  Table  represents  a  summary  of  Rubner's  results  : 


Calculated 

Heat  loss  deter- 

Duration 

Dog. 

Condition  of  dog. 

heat 

mined  calori- 

of 

production. 

mctricaliy. 

experiment. 

Cal. 

Cal. 

Days. 

1. 

Fasting     . 

259-3 

261-0 

5 

2. 

,,            .           .            . 

545-6 

528-3 

o 

3. 

Fed  with  meat  . 

329-9 

333-9 

1 

4. 

Fed  with  fat      . 

302-0 

299-1 

5 

5. 

Meat  and  fat 

332-1 

330-0 

12 

6. 

jj          jj           • 

311-6 

331-0 

8 

7. 

Fed  with  meat  . 

375-0 

379-5 

6 

8. 

"          »           •           • 

683-0 

681-3 

7 

It  will  be  seen  that  the  average  difference  between  the  calculated  and 
observed  results  amounts  only  to  1-01  per  cent. — an  amazing  agreement 
considering  the  extreme  difficulties  of  the  experimental  methods  involved. 
The  important  deduction  to  be  drawn  from  these  observations  is  that  the 
food-stuffs  which  are  oxidised  in  the  body  develop  in  this  process  exactly 
the  same  amount  of  energy  as  when  they  are  burnt  up  outside  the  body. 

From  one  aspect,  therefore,  the  animal  body  may  be  looked  upon  as  a 
machine  for  the  transformation  of  the  potential  energy  of  the  food-stuff's 
into  kinetic  energy,  represented  by  the  warmth  and  movements  of  the  body 
as  well  as  by  other  physical  changes  involved  in  vital  processes.  In  the  living 
organism  we  cannot,  however,  distinguish  between  the  source  of  energy  and 
the  machinery,  as  we  can  in  the  case  of  our  engines.  When  we  endeavour 
to  trace  the  food-stuffs  after  their  entry  into  the  body,  we  lose  sight  of 


4  PHYSIOLOGY 

them  at  the  point  where  they  are  built  up  to  form  apparently  an  integral 
part  of  the  living  framework.  During  activity  there  is  a  discharge  of  the 
products  of  oxidation  of  the  food-stuffs  from  this  living  matter,  which  there- 
fore becomes  reduced  in  mass.  This  reduction,  or  disintegration  of  the 
living  matter,  associated  with  activity,  is  always  followed  by  a  period  of 
increased  integration,  during  which  the  organism  grows  by  the  assimilation 
of  more  food.  Om'  conception  of  life  must  therefore  involve  the  idea  of  a 
constantly  recurring  cycle  of  processes,  one  of  building  up,  repair,  or  inte- 
gration, and  the  other,  associated  with  activity,  of  destruction  or  disinte- 
gration. If  the  former  process  predominates,  we  obtain  a  steady  increase 
in  the  mass  of  the  organism,  an  increase  which  we  speak  of  as  growth,  and 
in  many  cases,  as  in  that  of  plants,  it  is  this  power  of  growth  which  we  take 
as  our  criterion  of  the  existence  of  life.  In  fact,  the  possession  by  the  green 
parts  of  plants  of  the  power  of  utiHsing  the  energies  of  the  sun's  rays  for  the 
integration  of  food-stuffs,  such  as  starch,  with  a  high  potential  energy,  is 
the  necessary  condition  for  the  existence  of  all  higher  forms  of  hfe  on  this 
earth. 

Closely  associated  with  the  property  of  growth  is  the  power  possessed 
by  all  living  organisms  of  repair,  i.e.  the  replacement  by  newly  formed 
healthy  Uving  material  of  parts  which  have  been  damaged  by  external 
events. 

The  process  of  growth  does  not,  in  the  individual,  proceed  indefinitely. 
At  a  certain  stage  in  its  life  every  organism  divides,  and  a  part  or  parts  of 
its  substance  are  thrown  off  to  form  new  individuals,  each  of  them  endowed 
with  the  same  properties  as  the  parent  organism,  and  destined  to  grow  until 
they  are  indistinguishable  from  the  organism  whence  they  were  derived. 
In  the  lowest  forms  of  Hfe,  the  unicellular  organisms,  these  processes  of  growth 
and  division  may  go  on  until  brought  to  an  end  by  some  change  in  the 
environment  which  will  not  allow  the  necessary  conditions  of  life,  viz. 
assimilation  and  disintegration,  to  proceed.  In  all  the  higher  forms,  how- 
ever, after  the  process  of  reproduction  has  been  completed,  the  parent 
organism  begins  to  undergo  decay,  and  the  processes  of  assimilation  and 
repair  no  longer  keep  pace  with  those  of  destruction,  however  favourable 
the  environment,  until  finally  death  of  the  organism  takes  place. 

All  these  phenomena,  viz.  assimilation,  respiration,  activity  associated 
with  the  discharge  of  energy,  growth,  reproduction,  and  death  itself,  are 
bound  up  in  our  conception  of  life.  All  have  one  feature  in  connnon,  viz. 
they  are  subject  to  the  statement  that  every  living  organism  is  endowed 
with  the  power  of  adaptation.  Adaptation  may  indeed  receive  the  definition 
which  Herbert  Spencer  has  applied  to  life — "  the  continuous  adjustment 
of  internal  relations  to  external  relations."  A  living  organism  may  be 
regarded  as  a  highly  unstable  chemical  system  which  tends  to  increase  itself 
continuously  under  the  average  of  the  conditions  to  which  it  is  subject, 
but  undergoes  disintegration  as  a  result  of  any  variation  from  this  average. 
It  is  evident  that  the  sole  condition  for  the  survival  of  the  organism  is  that 
any  such  act  of  disintegration  shall  result  in  so  modifying  the  relation  of  the 


INTRODUCTION  5 

system  to  the  environment  that  it  is  once  more  restored  to  the  average  in 
which  assimilation  can  be  resumed.  Every  phase  of  activity  in  a  hving 
being  must  be  not  only  a  necessary  sequence  of  some  antecedent  change  in 
Its  environment,  but  must  be  so  adapted  to  this  change  as  to  tend  to  its 
neutralisation,  and  so  to  the  survival  of  the  organism.  This  is  what  is  meant 
by  '  adaptation.'  Not  only  does  it  involve  the  teleological  conception  that 
every  normal  activity  must  be  for  the  good  of  the  organism,  but  it  mui^t 
also  apply  to  all  the  relations  of  living  beings.  It  must  therefore  be  the 
guiding  principle,  not  only  in  physiology  with  its  special  preoccupation  with 
the  internal  relations  of  the  parts  of  the  organism,  but  also  in  the  other 
branches  of  biology,  which  treat  of  the  relations  of  the  living  animal  to  its 
environment,  and  of  the  factors  which  determine  its  survival  in  the  struggle 
for  existence.  The  origin  of  new  species  and  the  succession  of  the  different 
forms  of  life  upon  this  earth  depend  on  the  varying  perfection  of  the 
mechanisms  of  adaptation. 

We  may  imagine  that  the  first  step  in  the  evolution  of  life  was  taken 
during  the  chaotic  chemical  interchanges  which  accompanied  the  cooling 
down  of  the  molten  mass  forming  the  earth,  when  some  compound  was 
formed,  probably  with  absorption  of  heat,  endowed  with  the  property  of 
continuous  polymerisation  and  growth  at  the  expense  of  surrounding 
material.  Such  a  substance  could  continue  to  exist  only  at  the  expense  of 
the  energy  derived  from  the  surrounding  medium,  and  would  undergo 
destruction  with  any  stormy  change  in  its  environment.  Out  of  the  many 
such  compounds  which  might  have  come  into  being,  only  such  would  survive 
in  which  the  process  of  exothermic  disintegration  tended  towards  a  condition 
of  greater  stability,  so  that  the  process  would  come  to  an  end  spontaneously, 
and  the  organism  or  compound  be  enabled  to  await  the  more  favourable 
conditions  necessary  for  the  continuance  of  its  growth.  With  the  con- 
tinued cooling  of  the  earth,  the  new  production  of  endothermic  compounds 
would  become  rarer  and  rarer  ;  and  in  all  probability  the  beginning  of  life, 
as  we  know  it,  was  the  formation  of  some  complex  substance,  analogous 
to  the  present  chlorophyll  corpuscles,  with  the  power  of  absorbing  the 
newly  penetrating  sun's  rays  and  utilising  them  for  the  endothermic  forma- 
tion of  further  unstable  compoimds.  Once  given  an  unstable  system, 
such  as  we  have  imagined,  the  great  principle  laid  down  by  Darwin,  viz. 
survival  of  the  fittest,  will  suffice  to  account  for  the  production  from  it  by 
evolution  of  the  ever-increasing  variety  of  living  beings  which  have  appeared 
in  the  later  history  of  this  globe.  The  '  adaptation,'  i.e.  the  reactions  of 
the  primitive  living  material  to  changes  in  its  environment,  must  become 
ever  more  and  more  complex,  since  only  by  means  of  increasing  variety  of 
reaction  is  it  possible  to  provide  for  the  stability  of  the  system  within  greater 
and  greater  range  of  external  conditions.  The  difference  between  higher 
and  lower  forms  is  therefore  one  of  complexity  of  reaction,  or  of  range  of 
adaptation. 

In  all  the  physiological  processes  which  we  shall  study  in  the  course  of 
this  work,  adaptation  will  be  found  the  constant  and  guiding  quality.     The 


6  PHYSIOLOGY 

naked  protoplasm  of  the  plasmodium  of  Myxomycetes,  if  placed  on  a  piece 
of  wet  blotting-paper,  will  crawl  towards  an  infusion  of  dead  leaves,  or 
away  from  a  solution  of  quinine.  It  is  the  same  property  of  adaptation, 
the  deciding  factor  in  the  struggle  for  existence,  which  impels  the  greatest 
thinkers  of  our  time  to  spend  long  years  of  toil  in  the  invention  of  the  means 
for  the  offence  and  defence  of  their  community,  or  for  the  protection  of  man- 
kind against  disease  and  death.  The  same  law  which  determines  the  down- 
ward growth  of  the  root  in  plants  is  responsible  for  the  existence  to-day  of 
all  the  sciences  of  which  mankind  is  proud. 

This  "  adjustment  of  internal  to  external  relations  "  is  possible,  however, 
only  within  strictly  defined  limits,  limits  which  increase  in  extent  with  rise 
in  the  type  of  organism,  and  in  the  complexity  of  its  powers  of  reaction. 
Some  of  these  limiting  conditions  we  shall  have  to  study  in  the  next  chapter. 
Among  the  chief  of  them  are  temperature,  and  the  presence  of  food  material 
and  of  oxygen.  At  the  present  time  the  limits  of  temperature  may  be 
placed  between  0°  and  50°  C,  Many  organisms,  however,  are  killed  by  the 
alteration  of  only  a  few  degrees  in  the  temperature  of  their  environment. 
Every  shifting  of  a  cold  or  warm  current  in  the  Atlantic,  in  consequence  of 
storms  on  the  surface,  leads  to  the  destruction  of  myriads  of  fish  and  other 
denizens  of  the  sea.  In  the  higher  animals  a  greater  stability  in  face  of  such 
changes  has  been  accomplished  by  the  development  of  a  heat-regulating 
mechanism,  so  that,  provided  sufficient  food  is  available,  the  temperature 
of  the  body  is  maintained  at  a  constant  level,  which  represents  the  optimum 
for  the  discharge  of  the  normal  functions  of  the  constituent  parts  of  the 
body.  The  presence  of  food  material  in  the  environment  of  the  living 
organism  is  a  necessary  condition  for  its  continued  existence.  In  some  cases, 
and  this  we  must  assume  to  be  the  primitive  condition,  the  food  material 
must  be  of  a  given  character  and  form  a  constant  constituent  of  the  sur- 
rounding medium.  In  the  higher  forms,  the  development  of  a  complex 
digestive  system  has  enabled  the  organism  to  utilise  many  different  kinds  of 
food,  while  the  storage  of  any  excess  of  food  as  reserve  material,  either  in 
the  form  of  fats  or  carbohydrates,  provides  for  a  constant  supply  of  food 
to  the  constituent  cells  of  the  body,  even  when  it  is  quite  wanting  in  the 
environment.  Since  plants  depend  for  their  food  in  the  first  place  on  the 
carbohydrates  produced  within  the  chlorophyll  corpuscles  out  of  the 
atmospheric  carbon  dioxide  by  the  energy  of  the  sun's  rays,  necessary 
conditions  for  their  existence  will  be  sunlight  and  the  presence  of  this 
gas  in  the  surrounding  atmosphere. 

One  other  necessary  condition  for  the  existence  of  life  is  the  presence  of 
water.  Although  this  substance  cannot  furnish  any  energy  to  the  complex 
molecules  of  which  the  living  matter  is  composed,  it  is  an  essential  con- 
stituent of  all  living  matter,  and  takes  part  in  all  the  changes  which  deter- 
mine the  transformations  of  matter  and  energy  in  the  organism. 

This  short  summary  of  the  chief  characteristics  of  living  beings  would 
be  incomplete  without  the  mention  of  what  is  perhaps  their  distinctive 
feature,  namely,  organisation.     Although  little  marked  in  the  lowest  members 


INTRODUCTION  7 

of  the  living  kingdom,  where  we  can  detect  only  a  speck  of  structureless 
material  containing  a  few  granules,  of  which  one  or  more,  in  consequence  of 
its  reaction  to  stains,  is  distinguished  by  the  name  of  a  nucleus,  in  the 
higher  members  this  organisation  becomes  more  and  more  marked.  This 
increased  complexity  of  organisation,  which  we  often  speak  of  as  histological 
differentiation,  runs  parallel  with  increasing  range  of  power  of  adaptation, 
and  with  increasing  efficiency  of  adaptive  reactions  attained  by  the  setting 
apart  of  special  structures  (organs)  for  the  performance  of  definite  functions. 
This  parallelism  between  the  development  of  function  and  structure  justifies 
us  in  the  assumption  generally,  though  often  only  tacitly,  made  by  physio- 
logists, that  the  structure  is  the  determining  factor  for  the  fimction.  We 
might  regard  the  histological  differentiation  as  representing  merely  a  con- 
tinuation of  the  increasing  molecular  complexity,  which  we  assumed  nmst 
accompany  and  determine  every  widening  in  the  range  of  the  adaptive 
power  of  the  organism. 

To  sum  up  : — our  objects  in  the  study  of  physiology  include  the  descrip- 
tion of  the  chief  reactions  of  the  body  to  changes  in  its  environment,  the 
analysis  of  these  reactions  into  the  simpler  reactions  of  which  they  are  made 
up,  and  the  assignment  to  each  differentiated  structure  of  the  organism  its 
part  in  every  reaction.  We  must  determine  the  conditions  under  which 
each  reaction  takes  place,  so  that  we  may  learn  to  evoke  any  part  of  it  at 
will  by  application  of  the  appropriate  stimulus,  i.e.  by  effective  change  of 
environment. 

A  reaction  involves  expenditure  of  energy,  and  this  can  be  derived  only 
from  chemical  change  in  the  reacting  organ,  and  ultimately  from  the  dis- 
integration or  oxidation  of  the  food-stuffs.  Our  next  task  must  be,  there- 
fore, the  analysis  of  the  energetic  and  material  changes,  with  a  view  to 
determining  the  whole  sequence  of  events,  from  the  occurrence  of  the 
external  exciting  change  to  the  finished  reaction,  which  will  alter  in  the 
direction  of  protection  the  relation  of  the  organism  to  its  environment. 
In  short,  it  is  the  office  of  physiology  to  discover  the  routine  sequence  of 
events  in  the  living  organism  under  all  manner  of  conditions.  In  attacking 
this  problem  our  methods  cannot  differ  fundamentally  from  those  of  the 
physicist  and  chemist.  In  every  case  our  experiments  will  consist  in  the 
observation  and  measurement  of  movements  of  one  kind  or  another  which 
we  shall  interpret  in  terms  of  mass  or  energy.  Physiology,  if  it  could  be 
completed,  would  therefore  describe  the  how  of  every  process  in  the  body. 
It  would  state  the  sequence  of  events  and  would  summarise  these  as  so-called 
'  laws.'  These  laws  would,  however,  no  more  explain  the  phenomena 
of  life  than  does  the  '  law  of  gravitation  '  explain  the  fact  that  two  masses 
tend  to  move  towards  one  another  with  uniform  acceleration.  Nor  can  we 
hope  to  explain  physiological  phenomena  by  reference  to  the  laws  of  physics 
and  chemistry,  since  these  themselves  are  only  expressions  of  sequences, 
and  not  explanations.  With  every  growth  in  science,  however,  its  generalisa- 
tions become  wider  and  its  laws  summarise  ever  more  extensive  groups  of 
phenomena.     We  have  no  reason  for  asserting  that,  in  the  course  of  research, 


8  PHYSIOLOGY 

we  may  not  finally  succeed  in  describing  vital  phenomena  in  the  ''  conceptual 
shorthand  "  *  used  by  the  physicist,  involving  his  ideal  world  of  ether,  atom, 
and  molecule.  At  present  we  are  far  from  such  a  consurmnation.  The 
principle  of  adaptation  is  the  only  formula  which  will  include  all  the  pheno- 
mena of  Hving  beings,  and  it  is  difficult  to  see  how  this  principle  can  be 
expressed  by  means  of  the  concepts  of  the  physicist. 

This  diflB.culty,  which  must  be  felt  with  greater  force  the  more  deeply  the 
physiologist  endeavours  to  peer  into  the  processes  within  the  living  cells, 
has  led  some,  even  at  the  present  day,  to  the  assumption  of  some  special 
quality  in  hving  organisms  which  is  designated  as  '  vital  force  '  or  '  vital 
activity.'  Such  views  are  classified  together  under  the  term  vitalism. 
From  his  beginning  man  has  been  accustomed  to  draw  a  sharp  line  of  dis- 
tinction between  those  phenomena  which  by  their  constant  occurrence  seemed 
to  him  natural,  and  therefore  explicable,  and  those  phenomena  of  which  he 
could  not  see  the  determining  antecedent,  and  which  were  to  him,  therefore, 
anomic  and  capricious.  To  the  latter  he  set  up  graven  images,  and  not 
perceiving  his  own  springs  of  action,  endowed  them  with  a  self-determining 
personahty  such  as  he  imagined  himself  to  possess.  This  procedure,  though 
possessing  certain  advantages  in  allowing  him  to  perform  his  common  duties 
free  from  the  ever-lurking  fear  of  supernatural  interference,  suffered  from 
the  great  drawback  that  it  fenced  off  unknown  phenomena  as  unknowable 
and  not  to  be  known.  It  has  therefore  acted  as  a  continual  check  on  the 
growth  of  man's  knowledge  and  control  of  his  environment.  Such  a  graven 
image  is  vitalism.  As  a  working  hypothesis  it  must  be  sterile.  Just  as  the 
hypothesis  of  special  creation  would  impede  all  research  into  the  relationships 
of  animals  and  plants,  so  vitalism  would  stay  the  hand  of  the  physiologist 
in  his  endeavours  to  determine  the  changes  which  occur  within  the  living 
organism.  In  many  cases,  however,  the  terms  '  vitalism  '  and  its  antithesis 
'  mechanism '  are  used  unjustifiably.  The  production  of  energy  within 
the  body  is  due  to  the  oxidation  of  Mie  food-stuffs.  In  certain  functions  it  is 
not  yet  fully  established  whether  the  changes  involved  take  place  at  the 
expense  of  the  energy,  hydrostatic  pressure  or  otherwise,  of  the  fluids  outside 
the  cells,  or  whether  energy  is  supplied  to  the  process  by  the  cells  themselves 
at  the  expense  of  oxidative  or  other  changes  occurring  in  their  living  sub- 
stance. Both  views  are  possible,  but  the  adoption  of  either  by  a  physiologist 
does  not  justify  the  statement  that  he  is  a  '  vitaHst,'  '  neo-vitalist,'  or 
'  mechanist.'  The  office  of  the  physiologist  is  the  determination  of  the  changes 
which  occur  in  the  living  body  and  the  establishment  of  the  causal  nexus 
{i.e.  the  routine  of  sequences)  between  them.  For  such  a  man  to  describe 
himself  as  a  vitalist  or  mechanist  is  as  germane  to  the  subject  as  if  he  were 
to  call  himself  a  Trinitarian  or  a  Plymouth  Brother. 

Throughout  this  chapter  we  have  assumed  no  necessary  dividing  line 

between  the  different  classes  of  phenomena  in  the  conceptual  universe, 

although  in  the  present  state  of  our  knowledge  we  are  far  from  being  able 

to  include  the  whole  of  them  under  the  same  general  laws.     It  might  be 

*  Karl  Pearson,  "Grammar  of  Science,"  p.  328  et  seq.  (2nd  ed.) 


INTRODUCTION  9 

objected  that  in  taking  up  this  attitude  we  had  left  out  of  account  one 
supreme  fact,  viz.  the  existence  of  consciousness  in  ourselves.  As  a  com- 
parative and  objective  study,  however,  physiology  is  concerned,  not  with 
the  study  of  consciousness,  but  with  the  conceptions  in  consciousness  of  the 
fhenomena  presented  by  living  beings.  Consciousness,  in  fact,  we  know  only 
in  ourselves.  From  the  actions  of  other  living  beings  similarly  organised,  we 
infer  in  them  the  existence  of  a  similar  consciousness.  Again,  from  the  fact 
that  the  reactions  of  the  higher  mammals  are  evidently  determined,  not  by 
immediate  impressions,  but  largely  by  stored-up  impressions  of  past  stimuli 
we  credit  them  also  with  a  certain  but  lower  degree  of  consciousness.  As 
we  descend  the  scale  of  animal  Hfe,  evidence  of  the  existence  of  consciousness, 
as  we  know  it,  rapidly  diminishes  and  finally  disappears,  though  it  is  im- 
possible to  draw  a  sharp  line  between  those  animals  which  possess  conscious- 
ness and  those  in  which  it  is  absent.  That  it  is  a  necessary  accompaniment 
of  life  is  certainly  not  the  case.  A  man  is  living  though  he  is  asleep,  anaes- 
thetised, or  stunned,  and  it  would  be  absurd  to  speak  of  the  consciousness 
of  a  cabbage.  Consciousness  is,  in  fact,  comiected  with  the  possession  of  a 
highly  developed  central  nervous  system,  and  its  activity  is  in  proportion  to 
the  complexity  of  this  system.  Since  the  brain  with  all  the  other  organs 
of  the  body  is  derived  from  a  simple  cell,  the  fertilised  ovum,  similar  in  its 
absence  of  differentiation  to  the  lowest  organisms,  it  might  be  argued  that  all 
types  of  life  are  endowed  with  something  which  is  not  consciousness,  but 
which  has  the  potentiality  of  developing  into  consciousness.  To  such  a 
hypothetical  property  Lloyd  Morgan  has  given  the  name  '  metakinesis.'  We 
have,  however,  no  means  of  judging  of  the  presence  or  absence  of  this  hypo- 
thetical quality  and  still  less  of  determining  whether  it  is  a  property  only  of 
living  substance,  or  is  shared  also  by  the  atoms  of  so-called  dead  material. 


BOOK  I 
GENERAL  PHYSIOLOGY 


CHAPTER  II 
THE  STRUCTURAL  BASIS  OF  THE  BODY 

THE  CELL 

All  the  liigher  animals  and  plants,  when  submitted  to  microscopic  examina- 
tion, are  seen  to  consist  of  structural  units  which  are  spoken  of  as  cells. 
In  each  organ  we  find  a  mass  of  these  cells  closely  resembhng  one  another 
in  all  respects,  and  we  may  therefore  regard  the  function  of  any  organ  as 
the  sum  of  the  functions  of  its  constituent  cells.  Indeed,  any  given  reaction 
of  the  whole  body  is  the  resultant  of  the  reactions  of  the  unlike  cells  of  which 
the  body  is  composed.  The  cell  is  therefore  the  physiological  as  well  as  the 
structural  unit,  and  it  is  necessary  to  commence  our  study  of  the  functions  of 
the  animal  body  with  some  consideration  of  the  functions  and  reactions  which 
are  common  to  all  the  structural  units. 

This  composite  structure  is  pecuUar  to  the  higher  forms  of  life.  Amongst 
the  lower  forms,  both  animal  and  vegetable,  an  immense  number  of  organisms 
consist  only  of  a  single  cell.  In  this  cell  are  represented  all  the  phenomena 
of  life,  all  the  adapted  reactions  which  we  associate  with  the  life  of  the  higher 
organisms.  That  the  unicellular  condition  represents  the  more  primitive 
stage  from  which  the  higher  organisms  have  been  evolved  in  the  course  of 
ages  is  indicated  by  the  fact  that  every  one  of  these  higher  organisms  in 
the  course  of  its  development  passes  through  a  unicellular  stage,  namely, 
the  fertilised  ovum.  We  may  assume  that  the  series  of  changes  attending 
the  development  of  the  higher  organism  from  the  egg  is  a  repetition  in  sum- 
mary of  the  changes  which  have  determined  the  evolution  of  the  species  from 
the  primitive  unicellidar  type.* 

The  general  characteristics  of  the  cell  present  important  similarities, 
whether  we  are  considering  a  cell  which  forms  the  whole  of  an  organism  or  a 
cell  which  is  but  an  infinitesimal  part  of  a  highly  developed  animal. 

The  name  '  cell '  was  first  applied  by  botanists  to  the  structural  units 
found  by  them  in  plant  tissues,  and  involved  therefore  the  idea  of  certain 
qualities  which  do  not  enter  into  our  present  conception  of  the  term.  A 
section  through  the  stem  of  a  growing  plant  shows  it  to  be  made  up  of  an 
aggregation  of  cells  in  the  etymological  sense  of  the  word,  i.e.  small  sacs 
bounded  by  a  wall  of  cellulose  and  containing  cell  sap.  Immediately  inside 
the  cellulose  wall  is  a  thin  layer,  the  primordial  utricle,  which  encloses  at  one 
point  a  spherical  or  oval  structure  known  as  the  nucleus.     If  the  section  be 

*  This  assumption  is  often  spoken  of  as  the  '  law  of  rc-cai)itulation.' 

13 


14  PHYSIOLOGY 

taken  from  the  growing  tip  of  a  plant  (Fig.  1),  the  cell  sap  is  found  to  be 
wanting  and  the  cells  consist  only  of  the  substance  known  as  protoplasm, 
which  later  on  will  form  the  primordial  utricle.  This  with  a  nucleus  is 
enclosed  in  a  dehcate  cellulose  wall.  The  wall  is  not  an  essential  constituent, 
since  it  is  absent  from  many  vegetable  cells  at  some  period  of  their  hfe 
and  from  animal  cells  generally. 

A  better  conception  of  the  essentials  of  a  cell  can  be  obtained  by  the  study 


Fig.  1.     General  view  of  cells  in  the  growing  root-tip  of  the  onion,  from  a  longitudinal 
section,  enlarged  800  diameters.     (Wilson.) 
a,   non-dividing    cells,    with  chromatin-network  and  deeply  stained  nucleoli ; 
h,  nuclei  preparing  for  division  (spireme-stage)  ;    c,  dividing  cells  showing  mitotic 
figures  ;   e,  pair  of  daughter-cells  shortly  after  division. 

of  a  unicellular  animal  such  as  an  amoeba  (Fig.  2).  This  is  an  organism 
frequenting  stagnant  pools,  of  varying  size  (from  0-1  to  0-3  mm.  in  diameter), 
apparently  of  a  semi-fluid  consistence.  When  first  examined  it  is  generally 
spherical,  but  in  a  short  time  begins  to  change  its  form,  putting  out  processes 
known  as  pseudopodia.  By  shifting  the  distribution  of  its  material  among 
these  processes,  it  is  able  to  move  about  and  also  to  ingest  particles  of  food  or 
pigment  with  which  it  may  come  in  contact.  Near  its  centre  a  differentiated 
portion  can  be  distinguished  which  is  known  as  the  nucleus.  The  rest  of  the 
amoeba,  the  protoplasm  or  cytoplasm,  often  presents  further  differentiation 
into  an  outer  clear  layer  and  an  inner  finely  granular  substance.  The  latter 
may  contain  coarser  granules,  some  of  food  material,  others  apparently 
formed  in  situ  by  the  surrounding  protoplasm,  and  often  small  vacuoles 
('  contractile  vacuoles  ')  which  are  continually  altering  their  size  and  serve 
to  keep  up  a  circulation  of  fluid  in  the  interstices  of  the  cytoplasm.  In  all 
cells,  whether  animal  or  vegetable,   with  which  we  are  acquainted,  this 


THE  STRUCTURAL  BASLS  OF  THE  BODY  15 

twofold  structure  is  also  found.     So  we  may  define  a  cell  as  a  small  mass  of 
protoplasm  containing  a  nucleus. 

Doubt  has  often  been  expressed  whether  a  nucleus  is  to  be  regarded  as  essential 
to  our  conception  of  a  cell.  In  many  of  the  lowest  forms  of  animals  and  plants,  such 
as  the  Flagellata  among  the  former  and  the  Cyanophycete  and  Bacteria  among  the 
latter,  no  distinct  nucleus  can  be  demonstrated.  In  many  of  these  forms  the  dimen- 
sions of  the  whole  organism  are  too  minute  to  allow  of  any  definite  statement  being 


■''"^■-'■-^'^•'•''v'^'^.o^'i-;  ",> 


Fig.  2.     Amoeba  proteus,  an  animal  consisting  of  a  single  naked  cell,   X  280      (From  Sedg- 
wick and  Wilson's  Biology.) 
n,  the  nucleus  ;    ivv,  water- vacuoles  ;    cv,  contractile  vacuole  ;  fv,  food-vacuolc. 

made  as  to  the  presence  or  absence  of  nuclear  material.  In  the  larger  of  them,  how- 
ever, the  cytoplasm  of  the  cell  contains  numerous  scattered  granules  which  stain  with 
dyes  in  the  same  way  as  do  the  nuclei  of  the  cells  of  higher  animals,  and  these  granules 
possess  the  resistance  to  the  action  of  certain  digestive  fluids  which  is  typical  of  nuclei. 
They  may  therefore  be  taken  as  representing  the  nucleus  in  the  higher  forms.  Even 
in  the  latter,  at  certain  stages,  namely,  during  the  divisicn  of  the  cell,  the  nucleus 
breaks  up  into  discrete  parts,  and  there  is  no  reason  for  believing  that  such  a  scattered 
condition  of  the  nuclear  material  may  not  last  throughout  the  whole  life  of  the  cell. 

We  have  defined  a  cell  as  a  small  mass  of  protoplasm  containing  a  nucleus. 
Since  we  shall  have  to  use  the  term  '  protoplasm  '  on  many  occasions  in  the 
course  of  this  work,  we  must  have  a  definite  conception  of  what  we  mean 
by  it.  The  term  is  often  used  by  histologists  as  implying  a  substance  of 
certain  definite  chemical  and  staining  characters.  When  employed  by 
physiologists  it  general!/ implies  any  material  which  we  can,  on  a  study  of  its 
behaviour  to  changes  in  its  environment,  regard  as  endowed  with  life. 
Huxley  has  defined  it  as  "  the  physical  basis  of  life."  Though  it  may  be  con- 
venient to  have  a  word  such  as  protoplasm  signifying  simply  'living  material,' 
it  is  important  to  remember  that  there  is  no  such  thing  as  a  single  substance 
— protoplasm.  The  reactions  of  every  cell  as  well  as  its  organisation  are  the 
resultant  of  the  molecular  structure  of  the  matter  of  which  it  is  built  up. 
The  gross  methods  of  the  chemist  show  him  that  the  composition  of  the 


16 


PHYSIOLOGY 


'  protoplasm  '  of  the  muscle  cell  is  entirely  different  from  that  of  a  leucocyte 
or  white  blood  corpuscle.  The  finer  methods  of  the  physiologist  show  him 
that  every  sort  of  cell  in  the  body  has  its  own  manner  of  fife,  its  own  pecu- 
Harities  of  reaction  to  uniform  changes  in  its  surroundings.  No  individual 
will  react  in  exactly  the  same  manner  as  another  individual,  even  of  the 
same  species,  and  the  reactions  of  the  whole  organism  are  but  the  sum  of  the 

Attraction-sphere  enclosing  two  centrosomes 


/' Plasmosome 

or  true 
nucleolus 

Chromatin- 

network 

Nucleus  <  Linin-network 


Karyosome 
net-knot,  or 
chromatin- 
nucleolus 


Plastids  lying  in  the 
cytoplasm 


Vacuole 


Passive  bodies  (metaplasm 
or  paraplasm)  suspended 
in  the  cytoplasmic  mesli- 
work 


Fig.  3.     Diagram  of  a  cell.     Its  basis  consists  of  a  meshwork  containing  numerous  minute 
granules  [microsomes)  and  traversing  a  transparent  ground-substance.     (Wilson.) 

reactions  of  its  constituent  cells.  There  is  not  one  protoplasm,  therefore,  but 
an  infinity  of  protoplasms,  and  the  use  of  the  term  can  be  justified  only  if  we 
keep  this  fact  in  mind  and  use  the  word  merely  as  a  convenient  abbreviation 
for  any  material  endowed  with  life.  Even  in  a  single  cell  there  is  more  than 
one  kind  of  protoplasm.  In  its  chemical  characters,  in  its  mode  of  life, 
and  in  its  reactions,  the  nucleus  differs  widely  from  the  cytoplasm.  Both 
are  necessary  for  the  life  of  the  cell  and  both  must  be  considered,  according  to 
our  present  ideas,  as  '  living.'  In  the  cytoplasm  itself  we  find  structures  or 
substances  which  we  must  regard  as  on  their  way  to  protoplasm  or  as  products 
of  the  breakdown  of  protoplasm  ;  but  in  many  cases  it  is  impossible  to  say 
whether  a  given  material  is  to  be  regarded  as  lifeless  or  as  reactive  living 
matter.  Even  in  a  single  cell  we  may  have  differenttation  among  its  different 
parts,  one  part  serving  for  the  process  of  digestion  while  others  are 
employed  for  the  purpose  of  locomotion.  Here  again  there  must  be  chemical 
differences,  and  therefore  different  protoplasms.  In  this  work  the  term 
protoplasm  will  be  used  in  its  broadest  sense,  namely,  as  the  physical  basis 
of  living  organisms. 

STRUCTURE  OF  THE  CELL.     In  every  cell  can  be  distinguished  the 
two  parts — nucleus  and  cytoplasm.     The  nucleus  is  generally  an  oval  or 


THE  STRUCTUEAL  BASIS  OF  THE  BODY  17 

spherical  body  lying  near  the  centre  of  the  cell  and  bounded  by  a  definite 
contour  or  nuclear  membrane.  In  its  interior  it  contains  masses  or  filaments 
of  a  material  known  as  chromatin,  which  are  strung,  so  to  speak,  on  a  fine 
network  of  material  kno^vn  as  linin.  Besides  the  granules  of  chromatin, 
other  masses  are  sometimes  found  which  stain  in  a  different  manner  and  are 
called  nucleoli.  The  material  filling  up  the  meshes  of  the  network  is  the 
nuclear  sap  or  nucleoplasm.  The  cytoplasm,  which  varies  greatly  in  extent 
in  different  cells,  varies  also  in  its  appearance,  being  sometimes  homogeneous, 
sometimes  alveolar,  sometimes  granular  in  structure.  In  it  can  be  often 
distinguished  differentiated  parts  which  may  be  regarded  as  organs  of  the 
cell.  Thus  in  the  amoeba  we  have  the  contractile  vacuoles  already  men- 
tioned. In  the  green  parts  of  plants  the  cytoplasm  contains  green  gi-anules, 
the  cliloroplasts,  whose  special  function  it  is  to  assimilate  carbon  dioxide  from 
the  atmosphere,  and  by  means  of  the  energy  of  the  sun's  rays  to  convert  this 
into  starch  with  the  evolution  of  oxygen.  Other  parts  of  the  plant  have 
similar  granules,  the  leucoplasts,  whose  office  it  is  to  build  up  sugar  into 
starch,  and  it  is  possible  that  other  kinds  of  these  '  plastids  '  with  special 
chemical  functions  are  present  in  the  cytoplasm  of  many  cells.  In  addition 
to  these  cell  organs,  the  cytoplasm  may  contain  granules  which  represent 
stages  in  the  metabolism  of  the  ceU  and  are  either  food  material  which  is 
being  assimilated  or  products  of  the  disintegration  of  the  protoplasm, 
formed  either  for  the  service  of  the  cell  itself  or,  in  the  case  of  the  multi- 
cellular animals,  for  the  service  of  other  cells  of  the  organism.  Others 
of  these  granules  may  represent  reserve  material,  i.e.  excess  of  noimshment 
which  has  been  put  aside  by  the  cell  in  an  insoluble  form,  to  serve  for  its 
subsequent  needs  in  times  of  scarcity. 

THE  PHYSICAL  STRUCTURE  OF  PROTOPLASM.  Owing  to  the  close 
similarities  which  exist  between  the  fundamental  properties  of  all  living 
organisms,  histologists  have  sought  to  discover  some  corresponding  uniform 
morphological  organisation  of  the  physical  basis  of  these  phenomena,  namely, 
protoplasm. 

It  is  often  impossible,  even  under  the  highest  powers  of  the  microscope, 
t(i  make  out  any  structure  whatsoever  in  the  cytoplasm,  which  is  spoken  of 
then  as  hyaline.  In  most  cases  examination  of  a  cell,  even  unstained,  shows 
some  differentiation  between  a  more  or  less  regular  framework  or  meshwdik 
and  a  more  fluid  portion  filling  up  its  interstices,  and  these  appearances  arc 
still  more  manifest  when  the  cells  have  been  fixed  by  various  hardening 
fluids.  All  the  results  obtained  in  this  manner  must  be  regarded  with  some 
suspicion,  since,  as  has  been  shown  by  Fischer  and  by  Hardy,  it  is  possible  to 
imitate  artiticially  the  various  structures,  which  have  been  assigned  as 
characteristic  of  protoplasm,  by  hardening  a  homogeneous  colloidal  solution 
such  as  egg-white  by  difl'erent  methods  and  with  different  agents.  The 
theories  of  protoplasmic  structure  can  be  classified  under  three  heads  : 

1 .  The  Granular  Theory  of  Altmann.  By  the  use  of  certain  hardening 
reagents,  a  dense  mass  of  spherical  or  rod-shaped  gi-annles  may  be  demon- 
strated in  almost  all  cells  of  the  body  (Fig.  4).     These  granules  have  been 


18 


PHYSIOLOGY 


regarded  by  Altmami  as  the  elementary  particles  of  life,  and  he  locates  in 
them  the  various  vital  functions,  the  sum  of  which  make  up  the  life  of  the 
cell.  According  to  Altmann  these  granules  can  only  arise  from  the  division  of 
pre-existing  granules,  and  he  has  formulated  the  phrase  omne  granulum  e 
granulo,  which  is  a  further  extension  of  Virchow's  sentence  omnis  cellula  e 
cellula.  It  is  probable  that  a  number  of  different  kinds  of  structures  of  vary- 
ing importance  are  included  among  Altmann's  granules.     In  some  cases  they 


Fig.  4.     Section  of  liver  stained  to  show  granules.     (Altmann. 


are  the  products  of  the  activity  of  the  cytoplasm  and,  as  in  secreting  cells, 
will  be  later  on  cast  out  with  water  and  salts  as  the  specific  secretion.  In 
other  cases  they  may  be  cell  organs  or  plastids  with  the  special  metabohc 
functions  assigned  to  all  granules  by  Altmann.  In  some  cases  no  treatment 
whatever  will  display  the  existence  of  granules. 

2.  The  Fibrillar  Theory.  By  the  employment  of  appropriate  methods 
of  hardening,  it  is  easy  in  most  cells  to  demonstrate  a  network  or  clusters 
of  fibrils  which  form,  so  to  speak,  a  denser  part  of  the  cell.  This  fibrillar 
network  has  been  named  the  '  spongioplasm '  in  contra-distinction  to  the 
structureless  material  filling  its  meshes  known  as  '  hyaloplasm.'  A  network 
is,  however,  one  of  the  commonest  pseudostructures  produced  in  the  coagu- 
lation of  an  albuminous  fluid  by  any  means  whatever,  and  it  is  probable 
that  in  most  cases  the  network  which  is  seen  in  hardened  cells  is  simply  an 
artefact.  Sometimes  a  large  portion  of  the  protaplasm  may  take  a  fibrillar 
form  which  can  be  detected  even  in  the  unstained  and  unfixed  cell,  and  there 
is  no  doubt  that,  in  certain  phases  at  any  rate,  the  fibrillar  structure  of  the 
protoplasm  is  really  present. 

3.  The  Alveolar  Theory  op  Bijtschli.  This  theory  may  be  looked 
upon  as  corresponding  morphologically  to  the  granular  theory  of  Altmann. 
If  we  imagine  a  hyaline  protoplasm  which  is  continually  manufacturing 
metaplasmic  products  and  storing  them  up  in  its  protoplasm,  these  products 
will  be  deposited  as  spherules  gradually  increasing  in  size,  so  that  the  proto- 


THE  STRUCTURAL  BASIS  OF  THE  BODY 


19 


Fig.  5.  Diagram  of  a  cell, 
highly  magnified.  (Schafer.) 
p,  protoplasm,  consisting  of 
hyalo])lasm  and  a  network  of 
spongioplasm  ;  ex,  cxoplasm  ; 
end,  endoplasm,  with  distinct 
granules  and  vacuoles; 
c,  double  centrosome;  n,  nu- 
cleus ;  n',  nucleolus. 


plasm  between  them  will  be  converted  into  alveolar  partitions  between  the 
droplets.  In  many  an  egg  cell,  where  there  is  a  growth  of  protoplasm  from 
this  building  up  of  food  into  reserve  materials,  the  development  of  such 

an  alveolar  structure  can  be  followed  in  the 
living  protoplasm,  and  such  cells  when  mature 
show  a  marked  alveolar  structure  whether  ex- 
amined fresh  or  in  the  hardened  and  stained 
condition.  Such  a  protoplasm  would  be  prac- 
tically an  emulsion  of  one  fluid  in  another  and 
according  to  Biitschli  artificial  emulsions,  made 
by  mixing  rancid  oil  with  sodium  carbonate 
solutions,  may  show  under  the  microscope  a 
very  close  resemblance  to  cell  protoplasm 
(Fig.  6),  and  may  even  exhibit  amoeboid 
changes  of  form  in  consequence  of  the  diffusion 
currents  set  up  at  the  surface  of  the  drop 
between  its  contents  and  the  surrounding 
water.  Most  histologists  are  in  accord  that 
none  of  the  above  theories  can  be  regarded  as  applicable  to  all  forms  of 
protoplasm,  but  that  during  the  life  of  a  cell  its  protoplasm,  as  observed  under 
the  microscope,  may  be  either 
hyaline  and  structureless  or  may 
present  any  of  the  structural  modi- 
fications described  above,  according 
to  its  state  of  nutrition  and  the  form 
in  which  its  metabolic  products  are 
laid  down  in  the  cell.  Of  course 
it  is  possible  that,  even  in  the 
apparently  hyaline  protoplasm,  a 
structural  differentiation  is  still  pre- 
sent, but  is  invisible  owing  to  the 
minute  size  of  its  constituent  parts 
or  an  identity  of  refractive  index 
between  the  alveolar  walls  and  their 
contents.  The  fact  that  every 
chemical  dift'ereutiation  occurring 
within  the  colloidal  mass  will  tend 
to  cause  differences  of  surface  ten- 
sion, and  therefore  formation  of 
droplets,  shows  that  an  alveolar 
structure,  i.e.  one  in  which  there  is 
a  large  number  of  surfaces  separat- 
ing heterogeneous  mixtures  inside 
the  cells,  must  be  of  very  common 
occurrence,  even  in  cases  where  it  is  not  detectable  under  the  microscope. 
Such  a  structure  must  be  present,  at  any  rate,  in  those  cases  where,  apart 


Fio.  6.  A,  protoplasm  of  an  epidermal  cell  of 
the  crayfish ;  B,  foam-like  appearance 
of  an  emulsion  of  olive  oil.     (BiJTSCHLi.) 


20  PHYSIOLOGY 

from  the  existence  of  a  solid  cell  wall,  the  cell  presents  a  certain  degree 
of  rigidity  and  resistance  to  deforming  stress. 

ULTRAMICROSCOPIC  STRUCTURE  OF  PROTOPLASM.  Since  the  study  of 
the  behaviour  of  the  cell  shows  that  it  must  possess  a  much  moi"e  complex  structure 
or  organisation  than  that  which  is  revealed  by  the  microscope,  one,  that  is  to  say, 
which  permits  of  the  spatial  differentiation  of  the  different  chemical  processes  that 
may  occur  at  one  and  the  same  time  in  the  protoplasm,  many  theories  have  been  put 
forward  of  an  ultramicroscopic  cell  structure.  Though  Spencer  in  1864  spoke  of 
physiological  units  out  of  which  protoplasm  could  be  regarded  as  made  up,  and  Darwin 
(1868)  conceived  ultramicroscopic  particles — gemmules — which  might  be  discharged 
from  every  cell  in  the  body  and,  passing  into  the  reproductive  organs,  serve  as  the 
material  basis  of  heredity,  the  first  elaborate  conception  of  such  a  structure  was  worked 
out  by  Nageli  (1884).  According  to  Nageli  all  organised  structures  are  made  up  of 
miccllEe,  minute  particles  arranged  in  definite  order  and  surrounded  with  water.  For 
growth  to  take  place  it  was  necessary  that  the  system  should  be  in  a  condition  of 
'  turgor,'  which  was  determined  by  the  amount  of  water  between  the  micellae.  These 
micellae  arose  in  every  case  from  the  division  of  pre-existing  micellae,  and  the  vital 
properties  of  the  protoplasm  were  to  be  regarded  as  the  sum  of  the  changes  taking 
place  in  the  individual  micellae.  Similar  conceptions  have  been  put  forward  by  numerous 
other  observers,  each  of  whom  has  applied  a  different  name  to  the  elementary  living 
particle,  such  as  '  pangene,'  '  plasome,'  '  biophor,'  '  biogen-molecule,'  and  many  others. 
The  resemblance  of  these  theories  to  that  of  Altmann  is  obvious,  though  the  latter 
regarded  the  elementary  particle  as  in  many  cases  of  microscopic  size  and  capable  of 
demonstration  by  appropriate  methods  of  staining.  That  the  cell  possesses  organs 
of  smaller  dimensions  than  itself,  which  may  give  rise  to  like  organs  by  division,  is 
shown  by  Schimper's  observations  on  the  plastids  of  plant  cells.  These  apparently 
are  not  formed  by  a  process  of  differentiation  of  the  protoplasm,  but  are  continuous 
from  one  generation  to  another  and  are  reproduced  by  division.  There  is  no  doubt, 
however,  that  most  of  the  granules  to  be  observed  in  the  cytoplasm  are  not  of  this 
character,  but  are  elaborated  by  the  general  cytoplasm  out  of  the  foodstuffs  which  are 
supplied  to  it ;  and  though  conceptions  such  as  those  of  De  Vries  and  Verworn  are 
"  often  of  value  as  a  means  of  describing  certain  phenomena  in  the  life  of  the  cell  and  have 
played  a  great  part  in  the  description  of  the  phenomena  of  heredity,  they  cannot  be 
regarded  as  having  any  serious  justification  in  fact.  At  the  present  time  our  know- 
ledge of  the  properties  of  the  colloidal  and  capillary  systems,  which  must  play  so  great 
a  part  in  the  organisation  and  reactions  of  living  protoplasm,  is  much  too  meagre  to 
justify  weight  being  laid  on  any  theory  of  the  ultramicroscopic  structure  of  protoplasm 
that  can  at  present  be  put  forward. 

One  question  which  has  been  much  discussed  relates  to  the  physical 
condition  of  protoplasm.  Is  it  to  be  regarded  as  a  viscous  fluid  or  as  a  soft 
sohd  ?  The  perfect  potential  mobility  of  the  protoplasm  of  many  cells,  as 
instanced  by  the  flow  of  a  substance  of  an  amoeba  into  its  pseudopodia,  or  the 
occurrence  of  rapid  streaming  movements  in  the  threads  of  protoplasm 
found  in  many  plants,  e.^.  the  root  hairs  of  tradescantia,  indicates  a  fluid 
character  for  the  protoplasm.  Against  such  a  character  has  been  urged  the 
fact  that  in  protoplasm  we  may  have  shape,  organisation,  and  power  of 
resistance  to  deformation — qualities  which  are  generally  associated  with  the 
possession  of  solidity.  It  must  be  remembered,  however,  that  the  absence  of 
resistance  to  deformation,  which  is  characteristic  of  a  liquid,  applies  only  to 
the  internal  molecules,  and  that  the  surface  of  any  liquid  is  in  a  condition 
of  tension  which  not  only  limits  deformation,  but  presents  considerable 
resistance  to   any  enlargement  of  the  surface.     Small  water  animals  take 


THE  STRUCTURAL  BASIS  OF  THE  BODY  21 

advantage  of  this  resistance  to  run  freely  over  the  surface  of  water,  although 
their  specific  gravity  may  be  greater  than  that  of  water.  The  continued 
existence  of  protoplasm  in  a  watery  environment  shows  that  not  only  must 
its  composition  be  different  from  that  of  its  environment,  but  that  there  must 
bo  a  distinct  surface  separating  the  two.  The  superficial  layers  of  the  proto- 
plasm must  therefore  be  in  a  condition  of  tension,  and  exercise  pressure  on  the 
internal  portions  of  the  cell,  which  will  tend  to  diminish  the  surface  of  the  cell 
to  the  smallest  possible  extent,  i.e.  to  bring  it  into  the  spherical  form. 

This  form  is  characteristic  of  free  cells  in  their  conditions  of  inactivity, 
and  the  smaller  the  mass  of  protoplasm,  supposing  it  to  be  homogeneous, 
the  greater  will  be  the  pressure  exerted  by  its  surface  layer  on  its  contents 
and  the  greater  resistance  will  it  present  to  deformation  of  the  spherical  form. 
A  fluid  drop,  if  suspended  in  a  fluid  with  which  it  is  immiscible,  will  present 
greater  rigidity  the  smaller  its  dimensions.  Almost  any  degree  of  rigiditv 
can  also  be  imparted  to  larger  masses  of  fluid  protoplasm  if  their  interior  has 
undergone  chemical  differentiation  so  as  to  be  made  up  of  two  or  more  im- 
miscible fluids  arranged  as  droplets  within  alveoU,  as  in  Biitschh's  theory. 
In  such  a  case  every  droplet  will  present  resistance  to  deformation  and 
every  surface  will  resist  penetration  or  extension.  The  resistance  of  the 
surface  in  colloidal  fluids  is  still  further  increased  by  a  property  common  to 
all  these  fluids,  namely,  the  aggregation  in  the  surface  of  a  greater  concentra- 
tion of  the  dissolved  substance  than  is  present  in  the  underlying  fluid.  If, 
foi'  instance,  we  take  a  beaker  containing  egg-white  diluted  100  times,  and 
drop  a  steel  magnetised  needle  on  to  the  surface,  it  will  float  although  it  is 
much  heavier  than  the  fluid,  in  consequence  of  the  resistance  of  the  surface. 
If  the  needle  be  greasy  the  same  thing  will  occur  on  a  glass  of  water.  In  this 
case  the  needle  will  lie  N.  and  S.  On  the  albumen  solution,  however,  the 
needle  will  lie  in  the  position  in  which  it  has  been  dropped.  The  aggregation 
of  the  albumen  molecules  on  the  surface  of  the  fluid  is  such  that  it  is  practi- 
cally solid  and  resists  any  turning  of  the  needle.  In  consequence  of  the  sur- 
face aggregation  and  solidification  of  the  colloidal  molecules,  it  is  possible 
to  throw  out  the  greater  part  of  the  albumen  in  a  sohd  form  from  a  solution 
of  this  substance,  if  it  be  shaken  up  in  a  bottle  with  a  httle  air  so  as  to  make 
a  surface.  As  the  fluid  is  shaken  fresh  surfaces  are  always  being  formed,  and 
the  albumen  aggregating  in  each  of  these  surfaces  has  not  time  to  redissolve 
before  a  fresh  aggregation  occurs  on  a  new  surface,  and  the  films  thus  pro- 
duced gradually  collect  to  form  a  solid  mass  of  insoluble  protein.  Proto- 
plasm may  be  regarded  as  essentially  fluid  in  character,  the  form  and  rigiditv 
which  are  acquired  by  most  cells  being  due  to  chemical  and  physical  differen- 
tiation occurring  in  the  fluid. 

THE  SURFACE  LAYER  OF  CELLS.  Since  it  is  by  means  of  its  surface 
layer  that  the  organism  enters  into  relation  with  its  emnronment,  this 
layer  acquires  a  prime  importance  for  the  hfe  of  the  cell,  and  we  may  there- 
fore consider  here  at  greater  length  some  of  the  properties  of  this  layer,  the 
PlasmaJiauf,  as  it  has  been  called. 

The  superficial  layer  of  the  protoplasm  is  not  to  be  confounded  with  the 


22  PHYSIOLOGY 

cell  wall.  The  latter,  which  plays  a  great  part  in  the  building  up  of  vegetable 
tissues,  is  formed  by  a  process  of  secretion  from  the  hving  protoplasm  and 
is  situated  altogether  outside  the  superficial  Plasmahaut.  The  cell  wall 
differs  considerably  in  its  chemical  composition  from  the  protoplasm  out  of 
which  it  has  been  formed.  In  most  plants  it  consists  of  cellulose,  a  substance 
belonging  to  the  carbohydrate  group,  and  with  a  composition  represented 
by  some  multiple  of  the  formula  CgHioOg.  In  other  cells  the  wall  may  be 
built  up  from  calcium  carbonate  or  other  Hme  salts,  from  silica,  fromchitin. 
In  many  cases  it  is  perforated  to  allow  the  passage  of  communicating  strands 
of  protoplasm  between  adjacent  cells.  It  is  generally  freely  permeable  to 
all  kinds  of  solutions,  and  in  this  case  plays  no  part  in  regulating  the  inter- 
changes of  the  cell  with  the  environment. 

The  superficial  layer  of  protoplasm  represents  that  part  of  the  hving 
substance  which  stands  in  immediate  relationship  to  the  environment. 
Every  change  in  the  latter  can  only  influence  the  living  cell  through  this 
layer,  and  it  is  through  this  layer  that  substances  must  pass  on  their  way  into 
the  cell  for  assimilation,  or  out  of  the  cell  for  excretion.  The  retention  of  an 
individuality  by  the  cell  must  be  determined  by  chemical  and  physical 
differences  between  this  layer  and  the  surrounding  fluid.  Since  it  differs  from 
the  rest  of  the  protoplasm  in  the  changes  to  which  it  is  subject,  it  must  also 
differ  in  its  chemical  composition,  apart  altogether  from  the  factors  which, 
as  we  saw  above,  determine  molecular  differences  between  the  surface  and  the 
interior  of  any  colloidal  solution.  On  this  account  one  must  assume  the 
existence  of  a  definite  boundary  layer  of  the  protoplasm,  even  where  it  is 
impossible  to  see  any  differentiation  between  this  layer  and  the  deeper 
parts  under  the  highest  powers  of  the  microscope. 

A  (living)  cell,  which  leads  its  life  in  a  liquid  environment,  must  take  up 
the  greater  part  of  its  food  material  in  the  form  of  solution,  and  it  is  the 
permeability  of  the  superficial  protoplasm  which  will  determine  the  passage 
of  food  substances  from  the  surrounding  medium  into  the  body  of  the  cell. 
The  immiscibility  of  the  protoplasm  with  the  surrounding  fluid  shows  that 
the  permeability  of  the  membrane  must  be  a  limited  one.  The  qualitative 
permeabihty  can  be  easily  studied  in  vegetable  cells.  These  present  within 
a  cellulose  wall  a  thin  layer  of  protoplasm  (the  primordial  utricle),  enclosing 
a  cell  sap.  If  the  root  hairs  of  tradescantia  be  immersed  in  a  10  per  cent, 
solution  of  glucose  or  in  a  2  to  3  per  cent,  solution  of  salt,  a  process  of 
plasmolysis  takes  place.  The  cell  sap  diminishes  in  amount  by  the  diffusion 
of  water  outwards  so  that  the  primordial  utricle  shrinks  (Fig.  7).  On  im- 
mersing the  cells  in  distilled  water,  water  passes  into  the  cell  sap  until  the 
further  expansion  of  the  protoplasmic  layer  is  prevented  by  the  tension  of 
the  surrounding  cell  walls.  This  behaviour  can  be  explained  only  on  the 
assumption  that  the  protoplasm  is  impermeable  both  to  sugar  and  to  salt, 
but  is  freely  permeable  to  molecules  of  water,  i.e.  it  behaves  as  a  semi- 
permeable membrane.  Similar  experiments  can  be  made  on  animal  cells. 
The  most  convenient  for  this  purpose  are  the  red  blood  corpuscles.  These 
also  shrink  when  immersed  in  salt  solutions  with  a  greater  molecular 


THE  STRUCTUEAL  BASIS  OF  THE  BODY 


23 


concentration  than  would  correspond  to  the  plasma  of  the  blood  from  which  the 
corpuscles  were  derived,  whereas  if  placed  in  weak  salt  solutions  or  distilled 
water  they  swell  up  and  burst,  discharging  their  haemoglobin  in  solution  into 
the  surrounding  fluid.  By  comparison  of  various  salts  it  is  found  that  the 
strength  of  each  salt  solution  which  is  just  necessary  to  cause  plasmolysis 
or  haemolysis,  as  the  case  may  be,  is  determined  entirely  by  its  molecular 
concentration,  i.e.  a  decinormal  solution  of  sodium  chloride  will  be  equivalent 


12  3  4 

Fig.  7.     Vegetable  cells,  showing  varying  degrees  of  plasmolysis.     (De  Vrtes.) 

in  its  effect  on  the  cells  to  a  decinormal  solution  of  potassium  nitrate  or  of 
potassium  chloride.  The  impermeability  of  the  plasma  skin  does  not  apply 
to  all  dissolved  substances.  Overton  has  found  that,  whereas  this  layer  is 
practically  impermeable  to  salts,  sugars,  and  amino-acids,  it  permits  the 
easy  passage  of  monatomic  alcohols,  aldehydes,  alkaloids,  &c.  All  these 
substances  are  more  soluble  in  ether,  oil,  and  similar  media  than  they  are  in 
water.  The  passage  of  dissolved  substances  through  a  membrane  wetted 
by  the  solvent  depends  on  the  solubility  of  these  substances  in  the  membrane, 
and  Overton  therefore  concludes  that  the  superficial  layer  of  protoplasmic 
cells  must  itself  partake  of  a  '  lipoid  '  character,  and  that  cholesterin  and 
lecithin  probably  enter  largely  into  its  composition.  Thus  only  those  aniline 
dyes  which  are  soluble  in  a  mixture  of  melted  lecithin  and  cholesterin  have 
the  property  of  penetrating  the  living  cell,  and  only  these  dyes,  such  as 
methylene  blue,  neutral  red,  can  be  used  for  intra  vitam  staining.  For  the 
same  reason  substances  which  have  the  power  of  dissolving  lecithin  and 
cholesterin,  such  as  ether  or  bile  salts,  also  act  as  hsemolytic  agents,  i.e.  they 
cause  a  destruction  of  the  red  blood  cells  by  dissolving  the  superficial  layer 
which  is  necessary  for  their  preservation  from  the  solvent  effects  of  the  sur- 
rounding fluid. 

The  semi-permeability  of  the  plasma  skin  can  be  altered  by  changes  in 
the  saline  concentration  or  other  factors  of  the  surrounding  medium.  Over- 
ton has  sho^vn  that,  whereas  a  7  per  cent,  solution  of  saccharose  produces 
plasmolysis  in  living  cells,  no  plasmolysis  is  observed  if  they  are  treated  with 
a  solution  containing  3  per  cent,  methyl  alcohol  phis  7  per  cent,  cane  sugar. 
The  superficial  layer,  therefore,  is  able  to  dissolve  a  mixture  of  methyl 
alcohol  and  cane  sugar,  although  it  has  no  solvent  power  on  cane  sugar  in 


24  PHYSIOLOGY 

pure  watery  solutions.  It  is  possible  that,  in  order  to  serve  the  nutrient 
needs  of  the  cells,  more  extensive  changes  may  take  place  in  the  permeabihty 
of  the  surface  layer  under  hmited  conditions  of  time  and  space.  There  is  no 
doubt,  for  instance,  that  dextrose,  to  which  the  surface  layer  is  apparently 
impermeable,  can  yet  serve  as  a  very  efficient  food  for  the  ceU,  and  one 
might  ascribe  the  fact  that  the  cell  assimilates  only  the  food  which  it  requires 
and  no  more,  to  such  hmited  changes  in  permeabihty.  An  important  factor 
in  the  process  of  assimilation,  at  any  rate  by  lowly  organised  cells,  must  be  the 
relative  solubihty  of  the  absorbed  substances  in  the  cell  and  its  surrounding 
medium  respectively.  When  a  watery  solution  of  iodine  is  shaken  up  with 
chloroform,  the  latter  sinks  to  the  bottom,  carrying  with  it  the  greater  part 
of  the  iodine.  If  a  watery  solution  of  organic  acid  be  shaken  with  ether,  the 
latter  fluid  will  extract  the  greater  quantity  of  the  acid.  In  no  case  will  the 
extraction  be  complete,  but  there  wiU  be  a  definite  ration  between  the 
amount  dissolved  by  the  ether  and  the  amount  dissolved  by  the  water,  the 
so-called  '  coefficient  of  partage,'  depending  on  the  different  solubihties  of 
the  dissolved  substance  in  the  two  menstrua.  In  the  same  way  a  mass  of 
protoplasm  will  tend  to  absorb  from  the  surrounding  medium  and  to  con- 
centrate in  itseK  aU  those  substances  which  are  more  soluble  in  the  colloidal 
system  of  the  protoplasm  than  in  the  surrounding  fluid,  and  this  process  of 
absorption  may  be  carried  to  a  very  large  extent,  if  the  dissolved  substances 
meet  in  the  cell  with  any  products  of  protoplasmic  activity  with  which  they 
form  insoluble  compounds  so  that  they  are  removed  from  the  sphere  of 
action.  It  is  probably  by  such  a  process  as  this  that  we  may  account  for 
the  accumulation  of  calcium  or  sihcon  in  such  large  quantities  in  connection 
with  the  bodies  of  various  minute  organisms. 

Whereas  assimilation  by  a  living  cell  is  ultimately  conditioned  by  the 
permeabihty  of  the  surface  protoplasm,  its  form  is  determined  by  the  tension 
of  this  layer.  If  the  tension  is  uniform  at  all  parts  of  the  surface  the  form  of 
the  cell  will  be  spherical.  Any  diminution  of  the  surface  tension  at  one 
point  must  tend  to  cause  a  bulging  of  the  fluid  contents  at  this  point,  just  as 
on  distending  a  rubber  tube  with  one  weak  spot  in  its  wall  this  suddenly 
gives  way  with  the  production  of  a  large  balloon,  which  rapidly  extends  in 
size  and  ruptures  unless  the  pressure  be  diminished.  Diminution  of  the  sur- 
face tension  at  one  point  of  the  cell  wiU  be  attended  by  a  contraction  of  all  the 
rest  of  the  surface  and  a  driving  out  of  the  contents  through  the  weak  part. 
This  process  will  not  as  a  rule  result  in  destruction  of  the  cell ;  the  resulting 
protrusion  wiU  be  hmited  by  the  distortion  of  the  internal  alveolar  structure 
of  the  protoplasm  caused  by  any  alteration  of  the  spherical  form  of  the  cell. 
Change  of  form  in  hving  structures  thus  depends  ultimately  on  alterations 
in  surface  tension,  return  to  normal  being  affected  by  the  elastic  reaction  of 
the  structural  arrangement  of  the  protoplasm.  This  point  we  shall  have  to 
consider  more  fully  when  deahng  with  muscular  contraction.  At  present 
it  is  sufficient  to  see  how  any  shght  alteration  in  the  chemical  environment, 
such  as  might  be  due  to  the  presence  of  a  particle  of  food-stuff,  may 
cause   local   variations  in   the  surface  tension   of  the  plasma  skin  and 


THE  STRUCTURAL  BASIS  OF  THE  BODY  25 

thus  result  in  the  protrusion  of  pseudopodia  and  the  ingestion  of  the  food 
particle. 

VITAL  PHENOMENA  OF  CELLS.  A.  Assimikition.  The  activity  of 
every  living  being,  whether  uni-  or  multicellular,  can  be  regarded  as  com- 
pounded of  two  phases,  assimikition  and  dissimilation.  By  assimilation  we 
mean  the  building  up  of  the  living  substance  at  the  expense  of  material 
obtained  from  the  external  world.  In  this  process  substances  are  formed  of 
high  potential  energy,  and  this  energy  can  be  obtained  only  at  the  expense 
either  of  energy  imparted  to  the  system  at  the  moment  of  assimilation,  as, 
e.g.  in  the  assimilation  of  carbon  from  carbon  dioxide  under  the  influence 
of  the  sun's  rays,  or  of  energy  contained  in  the  food-stuffs  themselves.  In  all 
living  organisms,  except  those  provided  with  chlorophyll  corpuscles,  it  is 
the  latter  method  which  is  adopted,  and  a  food-stuff  therefore  connotes  some 
substance  which  can  be  taken  in  by  the  cell  and  can  serve  to  it  as  a  source 
of  chemical  energy.  The  evolution  of  energy,  which  is  required  for  the 
movements  and  other  vital  activities  of  the  cell,  is  derived  from  a  disintegra- 
tion or  dissimilation  of  the  protoplasm  and  is  generally  associated  with  the 
process  of  oxidation.  In  assimilation,  besides  the  building  up  of  living 
protoplasm,  there  may  also  be  a  synthesis  of  more  complex  from  less  complex 
compounds,  without  their  necessary  entry  into  the  structure  of  the  living 
molecule.  In  the  absence  of  any  definite  criteria  by  which  we  may  judge 
as  to  the  living  or  non-Hving  condition  of  parts  of  the  cell,  it  is  a  little 
dangerous  to  draw  any  hard-and-fast  distinction  between  these  two  sets  of 
processes.  Assimilation  requires  the  ingestion  of  food  into  the  organism,  and 
in  the  second  place  its  digestion,  i.e.  its  solution  in  the  juices  of  the  cells. 
These  two  processes  are  succeeded,  through  stages  which  we  cannot  trace, 
by  an  actual  growth  in  the  living  material.  In  naked  cells  ingestion  may 
occur  either  at  any  part  of  the  surface,  as  in  the  amoeba,  or  at  a  specialised 
portion,  so-called  '  mouth,'  as  in  many  of  the  infusoria.  Digestion  is 
apparently  effected  in  most  cases  by  the  production  and  secretion  around  the 
ingested  food  particle  of  solutions  containing  ferments,  i.e.  agents  which  have 
the  power  of  hydrolysing  the  different  food-stuffs  and  rendering  them  soluble. 

In  the  vast  majority  of  living  organisms  the  energy  for  their  activities 
is  derived  from  the  oxidation,  ultimately  of  the  food-stuff's,  but  immediately 
of  molecules  attached  to  the  living  pTotoplasm.  A  necessary  condition, 
therefore,  for  the  life  of  these  cells  is  the  presence  of  oxygen  in  the  surromiding 
medium,  from  which  it  is  taken  up  in  the  molecular  form.  We  may  there- 
fore speak  of  an  assimilation  of  oxygen ;  but  it  is  still  a  matter  of  dispute 
whether  the  oxygen  is  built  up  as  such  in  the  living  molecule  (so-called  intra- 
molecular oxygen)  to  be  utiUsed  for  the  formation  of  carbon  dioxide  when  a 
discharge  of  energy  is  necessary,  or  whether  it  is  only  taken  in  at  the  moment 
when  the  combustion  of  the  carbon  and  hydrogen  constituents  of  the  food 
or  protoplasm  is  necessary  for  the  supply  of  energy.  However  this  may  be, 
products  are  formed  as  a  result  of  this  oxidation  which  are  of  no  further 
value  to  the  cell  and  are  therefore  excreted,  i.e.  turned  out  of  the  cell.  The 
chief  of  these  are  the  products  of  oxidation  of  carbon  and  hydrogen,  namely, 


26  PHYSIOLOGY 

carbon  dioxide  and  water.  There  are  also  many  substances  resulting  from 
the  oxidation  of  the  nitrogenous  portions  of  the  protoplasm,  which  have  to 
be  excreted  in  the  solid  or  dissolved  form. 

Although  the  assimilation  of  oxygen  is  so  general  a  quality  of  living  protoplasm, 
the  presence  of  this  gas,  at  any  rate  in  the  free  form,  does  not  seem  to  be  necessary 
for  all  kinds  of  life.  Thus  a  number  of  the  bacteria  are  known  which  are  anaerobic, 
i.e.  exist  only  in  the  absence  of  oxygen.  Examples  of  such  are  bacillus  tetanus,  and 
the  bacillus  of  malignant  oedema.  In  order  to  cultivate  them  it  is  necessary  to  dis- 
place all  the  air  in  the  cultivating  vessels  by  means  of  a  current  of  hych-ogen.  It  has 
been  supposed  that  the  ultimate  source  of  the  energy  of  these  organisms  is  also  derived 
from  a  process  of  oxidation,  and  that  they  differ  from  other  organisms  in  being  able 
to  utilise  for  this  purpose  oxygen  which  is  built  up  into  the  structure  of  their  food  sub- 
stances. It  is  possible,  however,  that  these  organisms  derive  the  energy  for  the  building 
up  of  their  protoplasm,  for  their  movements,  &c.,  not  from  a  process  of  oxidation  at 
all,  but  from  processes  of  disintegration  of  the  substances  which  they  utilise  as  food. 
It  is  by  such  means  that  in  all  probability  the  intestinal  worms,  fairly  highly  organised 
animals,  are  able  to  exist  in  the  intestine  in  a  medium  containing  no  oxygen,  but  rich 
in  carbon  dioxide.  Here  they  are  plentifully  supplied  with  food-stuffs  and  can  afford 
to  adopt  a  wasteful  method  of  nutrition,  in  A^hich  only  a  small  fraction  of  the  energy 
is  obtained  which  would  be  produced  by  a  total  oxidation  of  the  food. 

B.  The  Phenomena  of  Dissimilation.  The  activities  of  a  living  cell 
or  organism  can  be  regarded  in  every  case  as  dependent  originally  on  en- 
vironmental change,  and  are  adapted  to  this  change,  i.e.  are  of  such  a  nature 
that  they  tend  to  preserve  the  organism  intact,  to  favour  its  groM^th,  or  pre- 
vent its  destruction.  The  property  of  reacting  in  such  a  manner  to  changes 
in  the  environment  is  fundamental  to  all  protoplasm  and  is  spoken  of  as 
excitahility,  and  the  change  which  will  influence  an  organism  and  cause  a 
corresponding  adaptive  change  in  it  is  known  as  a  stimulus.  Stimuli  may  be 
of  various  kinds.  Thus  mechanical,  thermal,  chemical,  electrical  changes, 
light,  and  so  on,  may  act  as  stimuli.  The  reactions  which  they  evoke  involve 
in  every  case  chemical  changes  in  the  protoplasm,  i.e.  changes  in  the  metabol- 
ism of  the  cell.  Sometimes  this  change  may  be  assimilatory  in  character, 
leading  to  an  increased  growth  of  the  protoplasm,  or  at  any  rate  to  a  cessation 
of  dissimilation.  In  such  a  case  the  stimulus  is  spoken  of  as  inhibitory, 
because  it  diminishes  or  prevents  the  output  of  energy  by  the  organism. 
The  frequent  result  of  a  stimulus  is  an  increased  output  of  energy,  which  may 
appear  in  the  form  of  movement,  in  the  form  of  heat,  or  as  chemical  change. 

A  common  feature  of  all  dissimilatory  changes  evoked  by  the  appUcation 
of  a  stimulus  is  that  the  energy  of  the  reaction  is  always  many  times  greater 
than  the  energy  represented  by  the  stimulus,  the  excess,  of  course,  being 
suppUed  at  the  expense  of  the  potential  energy  of  the  food  material  which 
has  been  stored  up  in  or  built  up  into  the  hving  protoplasm.  This  dispropor- 
tion between  stimulus  and  reaction  can  be  well  illustrated  on  an  excitatory 
tissue  such  as  muscle.  Thus  in  one  experiment  the  gastrocnemius  muscle  of  a 
frog  was  loaded  with  a  weight  of  48  gms.  The  nerve  running  to  the  muscle 
was  placed  on  a  hard  surface  and  a  weight  of  half  a  gramme  was  allowed  to 
fall  upon  it  from  a  height  of  10  mm.  The  muscle  contracted  in  response  to 
this  mechanical  stimulus  applied  to  the  nerve  and  raised  the  weight  3-8  mm. 


THE  STRUCTURAL  BASIS  OF  THE  BODY  27 

In  this  case  the  work  performed  by  the  muscle  was  48  x  3-8  =  1824 
grm.  mm.,  while  the  potential  energy  of  the  stimulus  represented  only 
0-5  X  10-0  =  5-0  grm.  mm.  Thus  the  work  performed  by  the  muscle 
was  thirty-six  times  larger  than  the  energy  of  the  stimulus  applied  to  the 
nerve. 

In  the  case  of  unicellular  organisms,  definite  classes  of  motor  reaction  to  stimulus 
ha%'c  been  described.  The  ordinary  retraction  of  a  imicellular  organism,  such  as  the 
vorticella,  in  response  to  a  touch  is  called  thigmotaxis.  Certain  cells  are  influenced 
by  gravity,  tending  to  rise  or  fall  in  the  surroimding  medium  according  to  the  conditions 
which  favour  their  existence.  A  similar  sensitiveness  to  gravity  is  observed  in  the 
growing  parts  of  plants,  where  the  root  always  grows  downwards  and  the  stem  up- 
wards. This  reaction  to  gravity  is  known  as  qeotaxis,  which  is  distinguished  as  '  nega- 
tive '  or  '  positive  '  respectively,  according  as  the  plant  grows  in  opposition  or  in 
obedience  to  the  gravitational  attraction.  If  growing  plants  be  placed  on  the  rim  of  a 
wheel  and  rotated  so  that  the  centrifugal  force  is  greater  than  that  of  gravity,  the 
stems  all  grow  towards  the  centre  of  the  wheel  while  the  rootlets  grow  outwards.  In 
the  same  way  the  reaction  of  micro-organisms  to  light  is  laio^\Ti  as  pJiototaxis,  some 
organisms  seeking  the  light  while  others  shun  it.  Among  the  primitive  reactions  of 
cells  pcrhajjs  the  most  important  in  the  life  of  higher  animals  are  those  grouped  mider 
the  term  chemiotaxis.  The  fertilisation  of  the  ovum  in  the  prothallus  of  ferns  is  effected 
by  the  penetration  of  the  antherozoids  produced  in  the  male  organs  at  some  little 
distance  from  the  female  organs.  It  was  shown  by  Pfeffer  that  the  movement  of 
the  antherozoids  towards  the  ova  is  effected  in  response  to  a  chemical  stimulus,  probably 
malic  acid,  since  he  fomid  that  antherozoids  suspended  in  a  fluid  will  always  swim 
towards  any  locality  where  there  is  a  greater  concentration  of  this  acid.  In  the  same 
way  aerobic  bacteria  are  attracted  by  the  presence  of  oxygen.  If  such  bacteria  are 
present  in  a  solution  with  an  alga,  on  exposure  of  the  fluid  to  light  there  is  an  evolution 
of  oxygen  by  the  green  alga,  and  a  consequent  congregation  of  the  bacteria  round  the 
seat  of  production  of  the  oxygen.  The  movements  of  the  white  corpuscles  of  the  blood 
of  the  higher  animals  are  also  largely  determined  by  their  chemical  sensibility,  and 
various  substances  can  be  divided  into  (a)  those  which  exercise  positive  and  (h)  those 
which  exercise  negative  chemiotactic  influence  on  the  leucocytes.  Thus  the  intro- 
duction under  the  skin  of  an  animal  of  a  capillary  tube  containing  a  solution  of  sub- 
stances of  the  first  class,  such  as  peptone,  tissue  extracts,  or  the  chemical  products 
of  certain  bacteria,  leads  to  an  accumulation  within  the  tube  of  leucocytes  which  pass 
to  it  from  all  the  surrovmding  tissues.  Other  substances,  such  as  quinine,  exert  a  nega- 
tive chemiotaxis.  Tubes  filled  with  these,  after  introduction  into  the  subcutaneous 
tissue  of  a  mammal,  ^ill  be  foimd  many  hours  later  to  contain  no  leucocytes  at  all. 

THE  RELATIONS  OF  THE  NUCLEUS  TO  THE  CYTOPLASM.  The 
universal  existence  in  living  cells  of  a  differentiated  nucleus  indicates  that 
the  life  cycle  of  assimilation  and  dissimilation  must  depend  on  an  interaction 
between  the  nucleus  and  cytoplasm,  and  that  each  plays  a  distinct  part  in  the 
sum  of  the  changes  Avhich  make  up  the  life  of  the  cell.  The  different  staining 
reactions  of  nucleus  and  cytoplasm  suggest  a  corresponding  difference  in  their 
chemical  composition,  a  suggestion  which  is  confirmed  by  analysis.  In  the 
building  up  of  protoplasm  proteins  play  an  important  part.  They  are  not 
present,  however,  as  simple  proteins,  but  built  up  with  other  complex  bodies 
to  form  conjugated  proteins.  Whereas  in  the  cytoplasm  these  conjugated 
proteins  consist  chiefly  of  compounds  of  protein  and  lecithin,  in  the  nucleus 
the  chief  constituents  belong  to  the  class  of  nucleo-proteins.  The  nucleo- 
proteins  are  of  varying  composition,  and  are  distinguished  chiefly  by  the 


28  PHYSIOLOGY 

large  amount  of  phosphorus  in  their  molecule.  A  nucleo-protein  can  be 
broken  down  into  nuclein  and  protein.  Nuclein  can  be  broken  down  into 
nucleic  acid  and  a  protein-hke  substance,  protamine.  Nuclei  differ  among 
each  other  and  at  different  periods  of  their  existence  or  in  different  conditions 
of  activity  according  to  the  greater  or  less  amount  of  protein  which  is  com- 


'^;j 


Fig.  8.     Nucleated  and  non-nucleated  fragments  of  Amaba.     (Wilson  after  Hofeb.) 
A,  B.  An  Aync^a  divided  into  nucleated  and  non-nucleated  halves,  five  minutes 
after  the  operation.     C,  D.  The  two  halves  after  eight  days,  each  containing  a  eon- 
tractile  vacuole. 

bined  with  the  nuclein.  The  latter  seems  to  be  the  essential  constituent  of 
cell  nuclei  and  to  be  present  in  only  small  quantities  in  the  cytoplasm.  The 
properties  and  reactions  of  these  bodies  will  be  dealt  with  at  greater  length 
in  the  next  chapter. 

In  order  to  appreciate  the  part  played  by  the  nucleus  in  the  ordinary 
cell  processes,  we  must  study  the  behaviour  of  cells  or  parts  of  cells  deprived 
of  a  nucleus  and  compare  it  with  that  of  similar  cells  or  parts  of  cells  still 
containing  a  nucleus.  By  means  of  a  fine  needle  it  is  possible  to  divide  the 
larger  protozoa  into  two  pieces,  one  with  and  one  without  a  nucleus.  Hofer, 
experimenting  on  the  amoeba,  found  that  the  fragment  containing  the  nucleus 
quickly  regenerated  the  missing  part  and  pursued  a  normal  existence.  On 
the  other  hand,  the  non-nucleated  fragments  showed  no  signs  of  regeneration. 
They  might,  indeed,  live  as  long  as  fourteen  days  after  the  operation  (Fig.  8). 


THE  STRUCTURAL  BASIS  OF  THE  BODY 


29 


Their  movements  continued  for  a  short  time  and  then  ceased,  though  the 
pulsations  of  the  contractile  vesicle  were  but  little  affected.  The  power 
of  digestion  of  food  was  completely  lost.  Other  observers  have  shown 
that  Stentor,  an  infusorium  which  possesses  a  fragmented  nucleus,  may  be 
broken  up  into  fragments  of  all  sizes.  Nucleated  fragments  as  small  as 
one-twenty-seventh  the  volume  of  the  entire  animal  are  still  capable  of 


Fiu.  9.     Kcgcneration  in  the  unicellular  animal  Stentor.     (From  Grubbk  after  Balblvni.) 
A.  Animal  divided  into  three  pieces,  each  containing  a  fragment  of  the  nucleus. 
B.  The  three  fragments  shortly  afterwards.      C.  The  three  fragments  after  twenty-four 
hours,  each  regenerated  to  a  perfect  animal. 


regeneration.  The  wound  quickly  heals  and  the  special  organs — the  mouth, 
with  its  surrounding  cilia,  and  the  contractile  vacuole — are  regenerated,  but 
all  non-nucleated  fragments  C[uickly  perish  (Fig.  9). 

Many  similar  observations  have  shown  that  the  non-nucleated  cytoplasm, 
though  it  may  survive  for  some  time  and  perform  normal  movements  in 
response  to  stimuli,  such  as  those  of  ingestion  of  food  particles,  loses  entirely 
the  power  of  digestion,  secretion,  and  growth.  In  animals  possessing  a  shell, 
a  small  secretion  of  the  Ume  salts  may  occur  on  the  surface,  but  this  process 
rapidly  comes  to  an  end  as  the  store  of  material  in  the  cytoplasm  is  exhausted. 
In  vegetable  cells  it  is  possible  to  break  up  the  protoplasm  by  means  of 
plasmolysis  into  nucleated  and  non-nucleated  parts.  The  nucleated  part 
quickly  forms  a  new  cell  wall.  The  non-nucleated  part  is  unable  to  effect 
this  formation,  and  soon  dies  unless  it  is  in  connection  with  an  adjacent 
cell  containing  a  nucleus  by  means  of  j&ne  threads  of  protoplasm  which 
pass  through  pores  in  the  intercellular  septa  (Fig.  10).     In  the  higher  animals 


30 


PHYSIOLOGY 


we  have,  in  the  case  of  the  nerve-cell,  an  example  of  the  necessity  of  the 
nucleus  for  growth.  Here  division  of  the  nerve  fibre  causes  degeneration  of 
the  whole  fibre  separated  from  the  cell  containing  the  nucleus,  and  regenera- 
tion of  the  fibre,  when  it  occurs,  is  eft'ected  by  a  down-growth  of  that  part  of 
the  fibre  which  is  still  in  connection  -svith  the  nucleus.     All  these  facts  show 

W J 


A 


C 


D 


Fig.  10.  Formation  of  membranes  by  protoplasmic  fragments  of  jilasmolysed  cells. 
(Wilson  after  Townsend.) 
A.  Plasmolysed  cell,  leaf -hair  of  Cucurhita,  showing  protoplasmic  balls  connected 
by  strands.  B,  Calyx-hair  of  Oaillurdia  ;  nucleated  fragment  with  membrane,  non- 
nucleated  one  naked.  C.  Root-hair  of  Murchantia  ;  all  the  fragments,  connected  by 
protoplasmic  strands,  have  formed  membranes.  D.  Leaf-hair  of  Cucurhita ;  non- 
nucleated  fragment,  with  membrane,  connected  with  nucleated  fragment  of  adjoining 
cell.  :f 

that  the  power  of  morphological  as  well  as  of  chemical  synthesis  depends  on 
the  presence  of  a  nucleus.  On  this  account  the  nucleus,  as  we  shall  learn 
later  on,  must  be  regarded  as  the  especial  organ  of  inheritance.  The  trans- 
mission of  the  paternal  quahties  from  one  generation  to  the  next  is  eft'ected  by 
the  entrance  simply  of  the  nuclear  material  of  the  male  cell,  the  spermatozoon, 
into  the  ovum.  In  the  words  of  Claude  Bernard,  "  the  functional  phenomena 
in  which  there  is  expenditure  of  energy  have  their  seat  in  the  protoplasm  of 
the  cell  {i.e.  the  cytoplasm).  The  nucleus  is  an  apparatus  for  organic  syn- 
thesis, an  instrument  of  production,  the  germ  of  the  cell." 

Similar  conclusions  may  be  drawn  from  a  study  of  the  changes  in  the 
nucleus  which  accompany  different  phases  in  the  activity  of  the  whole  cell. 


THE  STRUCTURAL  BASIS  OF  THE  BODY  31 

Thus  in  growing  plant  cells  the  nucleus  is  always  situated  at  the  point  of 
most  rapid  growth.  In  the  formation  of  epidermal  cells  the  nucleus  moves 
towards  the  outer  wall  and  remains  closely  apphed  to  it  so  long  as  it  is  growing 
in  thickness.  When  this  growth  is  finished  the  nucleus  moves  to  another 
part  of  the  cell.  In  the  formation  of  root  hairs  the  outgrowth  always  takes 
place  in  the  immediate  neighbourhood  of  the  nucleus,  which  is  carried  forward 
and  remains  near  the  tip  of  the  growing  hair.  The  active'growth  of  cyto- 
plasm, which  accompanies  the  activity  of 
secreting  cells,  is  always  associated  with 
changes  in  the  position  and  in  the  size  of 
the  nucleus.  Where  the  nutritive  activi1\ 
of  the  cell  is  very  intense,  as  in  the  silk 
glands  of  various  lepidopterous  larvae,  the 
nucleus  is  found  to  be  very  large  and  much 
branched  (Fig.  11)  so  as  to  present  the 
greatest  possible  extent  of  surface  through  fig.    il.     Branched  nucleus  from 

which    interchanges    can    go    on    between         *^«  ^P/^^^.g  §1*°^  ^^  butterfly 

^  ^  larva  {Pteris).     (Koeschelt.) 

nucleus  and  cytoplasm. 

The  important  changes  which  the  nucleus  undergoes  in  the  process 
of  cell  division  we  shall  have  to  consider  more  fully  in  the  later  chapters 
of  this  work.  In  the  function  of  assimilation  it  is  natural  to  assume  that 
it  is  those  constituents  of  the  nucleus  which  are  pecuhar  to  it  both  morpho- 
logically and  chemically,  namely,  the  chromatin  filaments,  which  are  most 
directly  concerned.  This  assumption  receives  support  from  the  changes 
which  have  been  observed  to  occur  in  these  filaments  during  various  phases 
of  nutritive  activity  of  the  cell.  The  staining  powers  of  chromatin  are  in 
direct  proportion  to  the  amount  of  nuclein  it  contains.  In  the  eggs  of  the 
shark  it  has  been  shown  that  the  chromosomes  undergo  characteristic  changes 
during  the  entire  growing  period  of  the  egg.  At  first  they  are  small  and  stain 
deeply  with  ordinary  nuclear  dyes,  but  during  the  period  of  growth  they 
undergo  a  great  increase  in  size  and  at  the  same  time  lose  their  staining 
capacity,*  their  surface  being  increased  by  the  development  of  long  threads 
which  grow  out  in  every  direction  from  the  central  axis.  As  the  egg  ap- 
proaches its  full  size,  the  chromosomes  diminish  in  size  and  are  finally 
reduced  to  minute  intensely  staining  bodies  which  take  part  in  the  first 
division  of  the  egg  preparatory  to  its  fertilisation  (Fig.  12).  We  must 
conclude  that  whereas  the  processes  of  destructive  metabolism  or  dissimila- 
tion, which  determine  the  activity  of  the  cell,  have  their  immediate  seat  in 
the  cytoplasm,  the  processes  of  constructive  metabolism  which  lead  to  the 
formation  of  new  material,  to  the  chemical  and  morphological  building  up  of 
the  cell,  are  carried  out  in  or  by  the  intermediation  of  the  nucleus. 

HISTOLOGICAL  DIFFERENTIATION  OF  CELLS.  Even  within  the 
limits  of  a  single  cell,  differentiation  of  structure  can  take  place  by  the 
setting  apart  of  distinct  portions  of  the  cell  for  isolated  functions.  Thus 
in  an  organism  such  as  vorticella  the  cell  is  shaped  somewhat  like  a  wine-glass, 

*  Piiickert,  cited  by  Wilson. 


32 


PHYSIOLOGY 


the  stem  being  composed  of  a  spiral  contractile  fibre  which  has  the  function 
of  withdrawing  the  rest  of  the  organism  when  necessary  towards  its  point  of 
attachment.  The  main  portion  of  the  cell  presents  at  its  free  extremity  a 
part  which  is  the  seat  of  ingestion  of  food,  and  is  therefore  spoken  of  as  the 
'  mouth.'  This  is  surrounded  by  a  circle  of  cilia  whose  function  it  is  to  set 
up  currents  in  the  surrounding  fluid  and  so  favour  the  passage  of  food  particles 
towards  the  mouth.     Food  when  ingested  at  this  end  passes  only  a  short 


^^x'X^I. 


'^»»s»iw«^^^,-as#^ 


Fig.  12.     Chromosomes  of  the  germinal  vesicle  in  the  shark  Pristiurus,  at  different  periods, 
drawn  to  the  same  scale.     (Rtjckbrt.) 
A.  At  the  period  of  maximal  size  and  minimal  staining-capacity  (egg  3  mm.   in 
diameter).     B.  Later  period  (egg  13  mm.  in  diameter).     C.  At  the  close  of  ovarian  life, 
of  minimal  size  and  maximal  staining-power. 


distance  into  the  body  of  the  vorticella.  Here  fluid  is  secreted  around  it 
which  serves  for  its  digestion.  This  portion  of  the  cell  may  therefore  be 
regarded  as  the  alimentary  canal  or  stomach.  The  indigestible  residue  of  the 
food  is  excreted  in  close  proximity  to  the  mouth.  In  addition  to  these  organs 
we  have  the  usual  differentiation  of  the  protoplasm  into  an  external  and 
internal  layer,  and  the  development  within  the  protoplasm  of  contractile 
vacuoles  which  serve  to  keep  up  a  circulation  of  fluid  and  therefore  to  pass 
the  products  of  digestion  through  all  parts  of  the  cell  body.  Within  the 
limits  of  the  single  cell  which  forms  the  vorticella  we  may  therefore  speak 
of  organs  for  contraction,  for  digestion,  for  circulation,  and  so  on. 

The  organs  which  are  thus  formed  in  unicellular  animals  or  plants  can  be 
divided  into  two  classes,  namely  (1)  temporary  organs,  which  are  formed  out 


THE  STRUCTUEAL  BASIS  OF  THE  BODY  33 

of  a  common  structural  basis  and  can  therefore  be  replaced  at  any  time  by 
the  cytoplasm  if  destroyed.  Examples  of  such  organs  are  the  ciha,  the 
commonest  motor  apparatus  of  unicellular  organisms  ;  the  pseudopodia, 
which,  as  we  have  seen,  can  be  made  and  destroyed  at  will ;  the  mouth  of 
animals  such  as  Volvox  or  Vorticella  ;  and  the  stinging  cells  or  nectocysts, 
which  surround  the  mouth  of  many  of  these  animals  and  serve  to  paralyse  or 
kill  the  smaller  hving  organisms  which  are  brought  by  the  ciha  within  reach 
in  order  that  they  may  serve  as  food.  In  contradistinction  to  these  organs 
are  (2)  a  number  of  others  which  must  be  regarded  as  permanent.  These 
cannot  be  formed  by  differentiation  from  the  cytoplasm  of  the  cell,  but  are 
derived  by  the  division  of  pre-existing  organs  of  the  same  character,  and 
are  therefore  transmitted  from  one  generation  to  another.  As  examples  of 
such  cell  organs  may  perhaps  be  mentioned  the  nucleus,  \Ndth  its  chromo- 
somes, and  the  plastids,  of  which  the  chloroplasts  of  vegetable  cells  are  the 
most  conspicuous.  Certain  cell  organs  may  fall  into  either  class.  Thus, 
the  contractile  vacuoles  are  sometimes  derived  by  the  division  of  the  pre- 
existing vacuoles  in  a  previous  generation,  at  other  times  are  certainly  formed 
out  of  the  common  cytoplasm.  The  centrosome,  a  small  particle  generally 
situated  in  the  C}i:oplasm,  which  plays  an  important  part  in  cell  division, 
is  generally  derived  by  the  division  of  a  pre-existing  centrosome,  but  under 
certain  conditions  and  in  some  organisms  can  be  developed  in  situ  in  the 
cytoplasm  itself. 

The  possibiUty  of  histological  differentiation  and  of  the  adaptation  of 
structure  to  definite  fmictions  becomes  much  more  pronounced  as  we  pass 
from  the  unicellular  to  the  multicellular  organisms  or  metazoa.  The  lowest 
of  the  metazoa,  such  as  the  sponges,  consist  of  Uttle  more  than  an  aggregation 
or  colony  of  cells.  All  the  cells  are  still  bathed  with  the  outer  fluid,  and  any 
differentiation  of  structure  or  function  seems  to  be  entirely  conditioned  by 
the  position  of  the  cell.  In  the  coelenterata  the  differentiation  is  already 
much  more  marked.  The  hydra,  one  of  the  simplest  of  the  group,  consists 
of  a  sac  formed  of  two  layers  of  cells  and  attached  by  a  stalk  to  some  firm 
basis.  Round  the  mouth  of  the  sac  is  a  circle  of  tentacles.  The  inner  layer, 
or  hypoblast,  represents  the  digestive  and  assimilatory  layer,  while  the 
epiblast,  or  outer  layer,  is  modified  for  the  purposes  of  protection,  of  reception 
of  stimuh,  and  of  motor  reaction.  In  the  jelly-fish  the  differentiation  of  the 
outer  layers  leads  to  the  formation  of  the  first  trace  of  a  nervous  system,  i.e. 
a  system  fitted  especially  for  the  reception  of  stimuli  and  for  their  trans- 
mission to  the  reactive  tissues,  namely,  the  muscles. 

In  all  these  classes  of  animals  the  external  medium  of  every  cell  forming 
the  organism  is  the  sea- water  or  other  medium  in  which  they  live.  This  can 
penetrate  through  the  interstices  between  the  cells,  and  every  cell  is  there- 
fore exposed  to  all  the  possible  variations  which  may  occur  in  the  composition 
of  the  surrounding  medium.  A  great  step  in  evolution  was  accomplished 
with  the  formation  of  the  ccelomata,  the  class  to  which  all  the  higher  animals 
belong.  In  these,  by  the  formation  of  a  body  cavity  containing  fluid,  an 
internal  medium  is  provided  for  all  the  working  cells  of  the  body.     The  com 

2 


34  PHYSIOLOGY 

position  of  this  internal  medium  is  maintained  constant  by  the  activity  of  the 
cells  in  contact  with  it,  and  the  stress  of  sudden  changes  in  the  chemical  com- 
position of  the  surrounding  medium  is  borne  entirely  by  the  outer  protective 
layer  of  epiblast  cells.  These  are  rendered  more  or  less  impermeable  by  the 
secretion  on  their  surfaces  of  a  cuticular  layer,  and  only  such  of  the  con- 
stituents of  the  surrounding  medium  are  allowed  to  enter  the  organism  as  can 
be  utihsed  by  it  for  building  up  its  hving  protoplasm.  Out  of  the  coelom 
is  later  on  formed  a  circulatory  system  which,  by  the  circulation  of  the  coelo- 
mic  fluid  or  of  blood  throught  the  whole  body,  can  procure  a  still  more  perfect 
uniformity  in  the  chemical  conditions  to  which  every  cell  is  exposed.  It  is 
not  till  much  later  that  the  organism  achieves  an  independence  of  external 
conditions  of  temperature.  In  the  mammalia,  by  means  of  the  reactive 
nervous  system,  the  heat  produced  in  every  vital  activity  by  the  chemical 
changes  of  combustion  and  disintegration  is  so  balanced  against  the  heat 
lost  through  the  external  surface  to  the  environment  that  the  temperature  of 
the  internal  fluid  is  maintained  practically  constant.  One  of  the  main  results 
of  the  differentiation  of  function  and  structure  is  therefore  a  gradual  setting 
free  of  the  majority  of  the  cells  of  the  body  from  the  influence  of  variations  in 
the  environment ;  and  in  the  highest  type  of  all  animals,  in  man,  this  inde- 
pendence of  external  conditions  is  carried  to  a  much  further  extent  by 
.  conscious  adaptations,  such  as  the  use  of  clothes,  dwellings,  artificial  heating, 
and  so  on. 

The  differentiation  of  the  cells  which  compose  the  organs  of  the  body  is 
determined  in  the  first  place  by  the  different  conditions  to  which  they  are 
exposed  in  virtue  of  their  positions  in  the  course  of  development.  All  the 
higher  animals  may  be  considered  as  built  in  the  form  of  a  tube,  the  external 
surface  of  which  is  modified  for  the  purpose  of  defence  and  for  adaptation  to 
changes  in  the  environment.  From  this  layer  there  are  developed  not  only 
the  protective  cuticle,  but  also  the  organs  of  motor  reaction,  namely,  the 
special  senses  and  the  nervous  system.  The  internal  surface  of  the  tube 
is  modified  for  purposes  of  ahmentation.  From  it  are  developed  all  those 
structures  which  serve  for  the  digestion  of  the  food-stuffs,  for  their  absorption 
into  the  common  circulating  fluid,  for  their  elaboration  after  absorption,  and 
their  preparation  for  utihsation  by  other  cells  of  the  body.  Between  these 
two  surfaces  are  situated  the  supporting  tissues  of  the  body  as  well  as  the 
organs  for  the  conversion  of  the  potential  energy  of  the  body  into  motion  and 
work,  namely,  the  muscles.  Here  also  is  the  coelom  or  body  cavity,  repre- 
sented in  the  higher  animals  by  the  pleural  and  peritoneal  cavities.  The 
alimentary  canal  projects  for  a  considerable  part  of  its  course  into  this  coelom, 
being  attached  to  the  body  wall  only  by  one  side.  From  the  ccelom  is  also 
developed  the  blood  vascular  system,  surrounded  by  contractile  and  con- 
nective cells  which  maintain  a  constant  circulation  of  the  blood  throughout 
the  body.  By  this  differentiation  the  body  becomes  divided  into  a  number 
of  organs,  each  of  which  is  composed  of  like  cells,  modified  for  a  common 
function  and  bound  together  by  connective  tissue,  the  latter  serving  also  to 
carry  the  blood-vessels  which  convey  the  common  medium  for  the  working 


THE  STRUCTURAL  BASIS  OF  THE  BODY  35 

cells.  In  the  study  of  physiology  our  task  consists,  firstly,  in  the  description 
of  the  special  part  taken  by  each  organ  in  the  general  functions  of  the  body, 
and,  secondly,  in  the  determination  of  the  hmiting  conditions  of  such  func- 
tions and  of  the  physical  and  chemical  factors  which  determine  them. 
Finally,  we  have  to  endeavour  to  form  a  complete  conception  of  the  chain  of 
events  concerned  in  the  discharge  of  each  function  and  of  their  causal 
nexus. 

We  have  compared  the  higher  animal  in  the  foregoing  hues  to  a  colony 
of  cells,  and  we  often  speak  of  an  isolated  cell  of  the  body  as  if  it  were  an 
independent  elementary  organism.  A  better  term  for  such  an  aggregation  of 
cells  as  presented  by  the  higher  animals  is  not  however  '  cell  colony,'  but 
'  cell  state,'  since,  just  as  in  the  state  pohtic,  no  cell  is  independent  of  the 
activities  of  the  others,  but  the  autonomy  of  each  is  merged  into  the  Hf e  of  the 
whole.  With  increasing  differentiation  there  is  increasing  division  of  func- 
tion among  the  various  members  of  the  state,  and  each  therefore  becomes 
less  and  less  fitted  for  an  independent  existence  or  for  the  discharge  of  all  its 
vital  functions.  The  more  highly  civiHsed  a  man  becomes  and  the  greater 
his  speciahsation  in  the  work  of  the  community,  the  smaller  chance  would  he 
have  of  existing  on  a  desert  island.  Thus  the  Hfe  of  the  organism  is  essentially 
composed  of  and  determined  by  the  reciprocal  actions  of  the  single  elementary 
parts.  It  is  evident  that,  if  the  process  of  speciahsation  has  gone  far  enough, 
a  discussion  whether  each  unit  has  or  has  not  an  independent  life  is  beside  the 
mark,  since  it  cannot  possibly  exist  apart  from  the  activities  of  the  other 
cells.  Of  late  years  histologists  have  brought  forward  evidence  which  seems 
to  imply  that  an  actual  structural  interaction  exists,  in  addition  to  the 
functional  dependence  which  is  a  necessary  resultant  of  speciahsation. 
Even  in  the  case  of  plant  cells  with  their  thick  cellulose  walls,  fine  bridges  of 
protoplasm  can  be  made  out  passing  from  one  cell  to  another  through  pores 
in  the  cellulose  wall.  In  animals  protoplasmic  bridges  are  known  to  exist 
joining  up  adjacent  cells  in  unstriated  muscle,  epithehum  and  cartilage 
cells,  and  in  some  nerve-cells.  The  conclusion  has  therefore  been  drawn 
that  the  morphological  unit  is  not  the  cell,  but  the  whole  organism,  and  that 
the  division  of  the  common  cytoplasm  into  cells  is  merely  a  question  of  size 
and  convenience.  There  can  be  no  doubt  that  the  determining  factor  in  the 
division  of  cells  is  their  growth ;  the  cell  divides  because  it  grows.  With 
increased  mass  of  living  substance  it  is  necessary  to  provide  for  increase  of 
surface  both  of  cytoplasm  and  of  nucleus.  Whether  all  the  tissues  of  the 
higher  animals  remain  in  structural  continuity  by  protoplasmic  bridges,  &c., 
must  be  to  us  a  matter  of  indifierence,  since  all  that  is  necessary  for  the 
interdependent  working  of  the  different  cells  of  the  body  is  a  functional 
continuity,  and  this  in  the  higher  animals  is  effected  by  the  presence  of  a 
common  circulating  fluid  and  a  reactive  nervous  system  connected  by  con- 
ducting strands  with  all  the  cells  of  the  body. 


CHAPTEE  III 
THE   MATERIAL   BASIS   OF  THE   BODY 

SECTION  I 

THE  ELEMENTARY  CONSTITUENTS   OF 
PROTOPLASM 

The  material  basis  of  whicli  living  organisms  are  built  up  is  derived  from 
the  surrounding  medium,  and  the  elements  which  compose  the  framework 
of  the  body  must  therefore  be  identical  with  those  found  in  the  earth's  crust. 
Not  all  the  elements  are  so  utihsed  in  the  formation  of  hving  matter.  Every 
hving  organism  without  exception  contains  the  following  elements  :  carbon, 
hydrogen,  oxygen,  nitrogen,  sulphur,  phosphorus,  chlorine,  potassium, 
sodium,  calcium,  magnesium,  and  iron.  In  addition  to  these  twelve  elements 
others  are  found  in  certain  organisms,  sometimes  to  a  large  extent,  but  it  is 
not  known  how  far  they  are  necessary  to  the  proper  development  of  these 
organisms,  and  it  is  certain  that  they  do  not  form  an  integral  constituent 
of  all  organisms.  Of  these  elements  we  may  mention  especially  sihcon, 
iodine,  fluorine,  bromine,  aluminium,  manganese,  and  copper.  Deahng  with 
the  first  class,  i.e.  those  which  are  essential  to  all  forms  of  life,  we  find  that 
their  relative  proportions  in  hving  organisms  have  httle  or  no  relation  to 
their  proportions  in  the  environment  of  the  organisms.  Their  presence, 
however,  in  the  latter  is  a  necessary  condition  of  life.  In  the  case  of  plants 
which  have  a  fixed  habitat  and  cannot  move  in  search  of  food,  the  growth 
of  the  plant  is  hmited  by  the  amount  of  the  necessary  element  which  is 
present  in  smallest  quantities  in  the  surrounding  medium.  This  is  what  is 
meant  by  the  agriculturist's  '  Law  of  the  Minimum.'  Of  the  elements  derived 
from  the  earth's  crust,  those  present  in  the  smallest  amounts  in  most  soils 
are  potassium,  nitrogen,  and  phosphorus.  The  growth  of  a  crop  in  any  given 
soil  is  determined  by  the  amount  of  that  one  of  these  three  substances  which 
is  present  in  smallest  quantities,  and  the  aim  of  agriculture  is  to  supply  to 
every  soil  the  ingredient  which  is  present  in  minimal  amount. 

Carbon  forms  the  greater  part  by  weight  of  the  solid  constituents  of 
living  protoplasm.  The  proximate  constituents  of  living  organisms  are 
piactically  all  carbon  compounds,  so  that  organic  chemistry,  which  was 
originally  the  chemistry  of  substances  produced  by  the  agency  of  hving 
organisms,  has  come  to  be  synonymous  with  the  chemistry  of  carbon  com- 

36 


THE  ELEMENTARY  CONSTITUENTS  OF  PROTOPLASM       37 

pounds.  The  carbon  compounds  which  make  up  the  living  cell  are  com- 
bustible, i.e.  they  can  unite  with  oxygen  to  form  carbon  dioxide  with  the 
evolution  of  heat.  Li  the  inorganic  world  practically  all  the  carbon  occurs 
in  a  completely  oxidised  form,  namely,  carbon  dioxide.  A  small  amount, 
4  parts  in  10,000,  is  present  in  the  atmosphere,  while  vast  quantities  are 
buried  in  the  crust  of  the  earth  as  carbonates  of  the  alkaline  earths,  &c.,  in 
the  form  of  chalk  and  limestone.  In  this  condition  the  carbon  dioxide  is 
practically  removed  from  the  life  cycle,  the  whole  of  the  carbon  contained  in 
the  tissue  of  Uving  beings,  whether  plant  or  animal,  being  derived  from 
the  minute  proportion  of  carbon  dioxide  present  in  the  atmosphere.  The 
energy  for  the  conversion  of  carbon  dioxide  into  the  oxidisable  forms  with 
high  potential  energy,  which  make  up  the  tissues  of  plants  and  animals,  is 
furnished  by  the  sun's  rays.  The  machine  for  the  conversion  of  the  radiant 
energy  into  the  potential  chemical  energy  of  the  carbon  compounds  is 
represented  by  the  chlorophyll  corpuscles  in  the  green  parts  of  plants.  In 
these  corpuscles,  under  the  influence  of  the  sun's  rays,  the  carbon  dioxide  of 
the  atmosphere,  together  with  water,  is  converted  into  carbohydrates,  viz. 
starch  (CgHioOs),  and  the  oxygen  liberated  in  the  process  is  set  free  into  the 
surrounding  atmosphere. 

6CO2  +  5H2O  =  CeHioOg  +  6O2. 

In  this  process  a  large  amount  of  energy  is  absorbed,  an  energy  which 
can  be  set  free  later  by  the  oxidation  of  the  starch  to  carbon  dioxide.  lu 
the  oxidation  of  one  gramme  of  starch  about  4500  calories  are  evolved,  and 
this  represents  also  the  measure  of  the  solar  energy  which  must  be  absorbed 
by  the  chlorophyll  corpuscle  in  the  process  of  formation  of  starch  from  the 
carbon  dioxide  of  the  atmosphere.  By  this  means  the  world  of  Ufe  is  pro- 
vided with  a  source  of  energy.  At  the  expense  of  the  energy  of  the  starch 
further  synthetic  processes  are  carried  out.  By  the  oxidation  of  a  part 
of  the  carbohydrates,  sufficient  energy  may  be  supphed  to  deoxidise  other 
portions  of  the  carbohydrates  with  the  production  of  fats.     Thus 

SCgHiaOe  —  8O2  =  CigHggOa 

(Glucose)  (Stearic  acid) 

The  potential  energy  of  a  fat  is  still  greater  than  that  of  a  carbohydrate, 
one  gramme  of  fat  giving  on  complete  combustion  to  carbonic  acid  and 
water  as  much  as  9000  calories.  By  the  introduction  of  ammonia  groups 
(NHg)  into  the  molecules  of  fatty  acids,  amino-acids  may  be  formed,  from 
which  the  complex  proteins  are  built  up  to  form  the  chief  constituents  of  the 
living  protoplasm. 

The  synthesis  of  carbon  compounds  from  the  inert  carbon  dioxide  of 
the  atmosphere  can  be  effected  only  by  chlorophyll  corpuscles.  All  animals 
take  in  carbon,  hydrogen,  nitrogen,  oxygen,  and  sulphur  in  the  form  of  tlu^ 
carbohydrates,  fats,  and  proteins  which  have  been  built  up  in  the  living 
plants.  In  the  anima  lorganism  these  food-stuft"s  serve  as  sources  of  energy. 
They  undergo  a  gradual  oxidation,  and  finally  leave  the  l)0(lyin  the  form  of 


38  PHYSIOLOGY 

carbon  dioxide,  water,  ammoma  or  some  related  compound,  and  sulphates. 
A  sharp  distinction  has  therefore  often  been  drawn  between  the  metabolism 
of  plants  and  animals,  plants  being  regarded  as  essentially  assimilatory  in 
character  while  animals  are  dissimilatory,  utihsing  the  stores  of  energy  which 
have  been  accmnulated  by  the  plant.  There  is,  however,  no  definite  hne 
of  demarcation.  Although,  generally  speaking,  the  green  plant  breaks  up 
carbon  dioxide,  giving  off  oxygen  and  storing  up  carbon  compounds,  and 
the  animal  taking  in  carbon  compounds  oxidises  them  with  the  help  of  the 
oxygen  of  the  atmosphere  to  carbon  dioxide,  which  is  redischarged  into  the 
surrormding  medimn  and  is  available  for  further  assimilation  by  plants,  yet 
this  process  of  respiration  is  common  to  all  hving  organisms,  whether  plants 
or  animals.  In  the  green  plant  it  may  be  masked  by  the  assimilatory  process 
occurring  under  the  influence  of  the  sun's  rays,  but  in  the  dark  all  parts  of 
the  plant,  and  in  the  hght  all  parts  which  are  free  from  chlorophyll,  display 
a  process  of  respiration,  i.e.  they  are  constantly  taking  up  oxygen  from  the 
atmosphere  and  using  it  for  the  oxidation  of  carbon  compounds  in  their 
tissues,  with  the  production  of  carbon  dioxide. 

The  sum  total  of  the  processes  of  hfe  tend,  therefore,  to  maintain  a 
constant  proportion  of  carbon  dioxide  and  oxygen  in  the  atmosphere,  the 
decomposition  of  carbon  dioxide  by  the  green  plants  being  balanced  by  the 
oxidation  of  the  carbon  compounds  and  the  continual  discharge  of  carbon 
dioxide  by  animals.  It  is  not  certain,  however,  that  this  balance  wiU  be 
maintained  throughout  all  time.  As  Bunge  has  pointed  out,  there  are 
cosmic  factors  at  work  which  are  apparently  tending  to  cause  a  constant 
diminution  in  the  quantity  of  carbon  dioxide  in  the  atmosphere,  which  alone 
is  of  value  to  the  plant.  One  of  these  factors  is  the  variable  affinity  of  the 
sihca  and  carbon  dioxide  respectively  for  the  chief  bases  of  the  earth's  crust. 
At  a  high  temperature  sihca  can  displace  carbon  dioxide  from  its  compounds. 
Thus  chalk  heated  with  sihca  will  give  rise  to  calcium  sihcate  with  the  evolu- 
tion of  carbon  dioxide.  At  an  early  geological  epoch,  therefore,  it  is  probable 
that  the  greater  part  of  the  sihca  was  present  in  combination  with  bases  and 
that  the  proportion  of  carbon  dioxide  in  the  atmosphere  was  very  much 
higher  than  it  is  now.  At  temperatures  at  present  ruling  on  the  earth's 
surface  carbon  dioxide  is  a  stronger  acid  than  silica.  The  action  of  water 
charged  with  carbon  dioxide  on  a  sihcate  is  to  cause  its  gradual  decomposition 
with  the  formation  of  carbonate  and  sihca.  Both  these  products,  being  in- 
soluble, are  deposited  as  part  of  the  earth's  crust,  the  sihca  in  the  form  of 
sandstone,  the  carbonate  as  chalk  or  limestone.  The  carbon  dioxide  is 
being  constantly  removed  by  water  from  the  atmosphere  and  being  locked 
up  in  this  way  in  the  earth's  crust,  the  process  of  separation  of  calcium  car- 
bonate being  aided  to  a  marked  extent  by  the  agency  of  living  organisms 
themselves.  The  whole  of  the  extensive  deposits  of  limestone  and  chalk 
have  been  separated  from  the  sea-water  by  the  action  of  hving  organisms. 
With  the  cooling  of  the  earth's  crust  which  is  supposed  to  be  going  on,  the 
discharge  of  carbon  dioxide  by  volcanoes  must  get  less  and  less,  so  that  one 
can  conceive  a  time  when  the  whole  of  the  carbon'dioxide  will  be  bound  up 


THE  ELEMENTARY  CONSTITUENTS  OF  PROTOPLASM       39 

with  bases  in  the  earth's  crust,  and  Hfe,  without  any  source  of  carbon,  must 
become  extinct. 

Hydrogen  exists  ahnost  exclusively  in  the  form  of  water.  \\\  this  form 
it  is  taken  up  by  plants  and  animals,  with  the  exception  of  a  small  proportion 
absorbed  in  the  form  of  ammonia.  In  this  form  too  it  is  discharged  by  Hving 
organisms.  Oxijgen  is  the  only  element  which,  in  all  the  higher  organisms  at 
any  rate,  is  taken  up  in  the  free  state.  It  forms  one-fifth  of  the  atmosphere 
and,  as  the  oxides  of  the  various  metals,  a  considerable  fraction  of  the  earth's 
crust.  It  takes  a  position  apart  from  the  other  food- stuffs  in  that  its 
presence  is  the  essential  condition  for  the  utihsation  of  their  potential  energy. 
In  the  living  cells  it  combines  with  the  oxidisable  compounds  formed  by  the 
agency  of  the  hving  protoplasm,  with  the  production  of  carbon  dioxide  and 
water,  and  the  evolution  of  energy.  This  process  is  spoken  of  as  respira- 
tion. 

Like  the  three  elements  we  have  already  considered,  nitrogen  is  also 
derived  directly  or  indirectly  from  the  surrounding  atmosphere.  In  conse- 
quence of  its  feeble  combining  power  for  other  elements  and  the  instability  of 
its  compounds,  very  Httle  nitrogen  is  to  be  found  in  the  combined  state  in  the 
earth's  crust,  whereas  it  constitutes  four-fifths  of  the  atmospheric  gases. 
It  can  be  taken  up  by  most  plants  only  in  the  form  of  ammonia,  nitrites, 
or  nitrates.  To  animals  these  compounds  are  useless,  and  the  only  source 
of  nitrogen  to  this  class  is  the  protein  which  has  been  built  up  by  the  agency 
of  the  plant  cell.  Since  nitrogen  in  the  free  state  is  useless  to  nearly  all 
living  organisms,  the  existence  of  life  must  depend  on  the  amount  of  com- 
bined nitrogen  which  is  available.  In  view  of  the  small  tendency  presented 
by  this  element  to  enter  into  combination,  it  becomes  interesting  to  inquire 
into  the  source  of  the  combined  nitrogen  which  is  the  common  capital  of  the 
living  kingdom.  There  are  certain  cosmic  factors  which  result  in  the  pro- 
duction of  combined  nitrogen.  The  passage  of  electric  sparks  or  of  the 
silent  discharge  through  moist  air  leads  to  the  production  of  ammonium 
nitrite. 

N.2  +  2H.,0  -  NHjNOa. 

Every  thunderstorm,  therefore,  will  result  in  the  production  of  small  quan- 
tities of  ammonium  nitrite,  which  will  be  washed  do\vn  with  the  rain  and 
serve  as  a  source  of  combined  nitrogen  to  the  soil.  Every  decaying  vegetable 
or  animal  tissue  serves  as  a  source  of  ammonia,  so  that  from  various  causes 
the  soil  may  contain  nitrogen  in  the  form  of  ammonia  or  of  ammonium  nitrite. 
These  forms  of  combined  nitrogen  are  not,  however,  suitable  for  all  classes  of 
plants.  Most  moulds  can  assimilate  ammonia  as  ammonium  carbonate  or 
as  amino-acids  or  amines,  provided  that  they  are  supplied  at  the  same 
time  with  sugar,  the  oxidation  of  which  will  serve  them  as  a  source  of 
energy.  Some  moulds,  many  of  the  higher  plants,  and  especially  the  Grani- 
ineso,  which  include  the  food-producing  cereals,  require  their  nitrogen  in  the 
condition  of  nitrates.  It  is  necessary,  therefore,  that  the  ammonia  or 
nitrites  in  the  soil  shall  be  converted  into  this  highly  oxidised  form.     This 


40 


PHYSIOLOGY 


conversion  is  effected  by  a  group  of  micro-organisms.  There  are  a  number 
of  bacteria  (bacterium  nitrosomonas)  which  have  the  power  of  converting 
ammonia  into  nitrites.  Others  (bacterium  nitro- 
monas)  convert  nitrites  into  nitrates.  If  sewage 
matter  rich  in  ammonia  is  allowed  to  percolate 
through  a  cylinder  packed  with  coke  and  the  process 
be  continued  for  several  weeks,  it  is  found  after  a 
time  that  in  its  passage  through  the  filter  the  fluid 
has  lost  its  ammonia  and  contains  the  whole  of  its 
nitrogen  in  the  form  of  nitrate.  If  the  cyhnder  be 
tapped  (Fig.  13)  half-way  down,  say  at  K,  the  fluid 
will  be  found  to  contain,  not  nitrates,  but  nitrites. 
In  this  conversion  the  two  kinds  of  microbes  men- 
tioned above  are  concerned.  At  the  top  of  the 
cyhnder  the  nitrous  bacterium  is  present,  in  the 
bottom  of  the  cyhnder  the  nitrate  bacterium  is 
present.  The  conversion  of  ammonia  into  nitrates 
by  the  agency  of  bacteria  has  been  made  the  basis 
of  a  method  of  treatment  of  sewage  which  is  now 
very  largely  employed.  These  different  bacteria 
play  an  important  part  in  all  soils  in  preparing  them 
for  the  cultivation  of  crops. 

Is  the  total  capital  of  combined  nitrogen  which 
is  worked  over  by  these  bacteria  and  utilised  by 
the  whole  living  world  confined  to  the  small  quanti- 
ties produced  by  atmospheric  discharges  ?  Of  late 
years  definite  evidence  has  been  brought  forward 
that  such  is  not  the  case  and  that  organisms  exist 
which  can  utilise  and  bring  into  combination  the 
free  atmospheric  nitrogen  itself.  Thus  certain  soils 
have  been  found  to  undergo  a  gradual  enriching 
in  nitrogen  althougli  no  nitrogenous  manure  has 
been  applied  to  them.  Winogradsky  has  shown 
that  this  fixation  of  nitrogen  by  soils  is  effected  by 
a  distinct  micro-organism,  which  may  be  isolated  by 
growing  it  on  gelatinous  silica  free  from  any  trace 
of  combined  nitrogen,  so  that  the  organism  ha  3 
to  procure  its  entire  nitrogen  from  the  atmo- 
sphere. Under  such  conditions  the  numerous  other 
micro-organisms  of  the  soil  die  of  nitrogen  starva- 
tion, and  only  the  microbe  survives  which  is  able  to  utihse  free  nitrogen. 
This  organism,  which  he  called  Clostridium  pasteurianum,  grows  well  on  sugar 
solution  if  free  from  ammonia  and  enriches  the  solution  with  combined 
nitrogen.  It  is  anaerobic,  i.e.  only  grows  in  the  absence  of  oxygen.  In  the 
soil,  where  oxygen  is  constantly  present,  it  occurs  associated  in  a  sort  of 
symbiosis  with  two  species  of  bacteria  which  are  aerobic  and  protect  it  from 


Fig.  13.  Arrangement  for 
studying  the  nitrifica- 
tion of  sewage.  (Miss 
H.  Chick.) 


THE  ELEMENTARY  CONSTITUENTS  OF  PROTOPLASM       41 

the  surrounding  oxygen.  The  mechanism  by  which  this  organism  is  able 
to  fix  free  nitrogen,  and  the  nature  of  the  first  product  of  the  assimilation  are 
not  yet  ascertained.  Such  an  assimilation  will  serve  to  the  organism  as  a 
source  of  energy,  since  the  application  of  heat  is  necessary  for  the  dissociation 
either  of  ammonium  nitrite  or  of  nitrous  acid  into  nitrogen  and  water,  as  is 
seen  from  the  following  equation  : 

HNOgAq.  +  308  Cal.  =  H  +  N  +  Og  +  Aq. 
NH^NOaAq.  +  602  Cal.  =  2N  +  4H  +  20  +  Aq. 

In  addition  to  this  spontaneous  fixation  of  nitrogen  by  humus,  a  method 
has  long  been  known  to  farmers  by  which  the  fertility  of  a  soil  can  be  in- 
creased without  the  apphcation  of  nitrogenous  manures. 
If  a  plot  of  land  is  to  be  left  fallow  it  is  a  very  usual 
custom  to  sow  it  with  some  leguminous  crop  such  as  sain- 
foin. Careful  experiments  by  Boussingault,  Lawes  and 
Gilbert,  and  others  have  shown  that  the  growth  of  almost 
any  leguminous  crop  in  a  soil  poor  in  nitrogen  may  result 
not  only  in  the  production  of  a  crop  containing  much  com- 
bined nitrogen,  but  also  in  an  actual  increase  of  nitrogen  in 
the  soil  from  which  the  crop  is  taken.  It  was  then  sho^vn 
by  the  last  two  observers,  as  well  as  by  Schloesing  and 
Laurent,  that  the  power  of  a  leguminous  crop  to  enrich  the 
soil  with  nitrogen  was  dependent  on  the  presence  on  the 
roots  of  certain  small  nodules  which  had  been  described 
long  before  by  Malpighi  (Fig.  14).  They  showed  also  that 
the  production  of  these  nodules  took  place  only  as  a  result 
of  infection.  Beans  grown  in  steriUsed  sand  produced  a 
plant  free  from  nodules,  which,  however,  grew  very  scantily 
unless  nitrogenous  manure  were  added  to  the  sand.  Such  a 
crop  derived  the  nitrogen  for  its  growth  from  the  added 
nitrogen,  the  total  amount  of  which  in  the  soil  was  therefore 
diminished  by  the  crop.  If,  however,  the  sterihsed  sand 
were  treated  with  an  infusion  of  root  nodules  from 
another  plant  wthout  the  addition  of  any  combined 
nitrogen  at  all,  the  beans  developed  nodules  on  their  roots 
and  grew  luxuriantly,  and  at  the  termination  of  their 
growth  the  soil  was  richer  in  nitrogen  than  at  the  commencement.  On 
microscopic  examination  the  protoplasm  which  makes  up  these  nodules 
is  found  to  be  swarming  with  small  rods  (Fig.  15),  and  it  was  shown  by 
Beyerinck  that  these  rods  are  bacteria  and  can  be  cultivated  in  media 
apart  altogether  from  the  plant.  We  have  thus  an  example  of  a  class  of  bac- 
teria which,  like  those  of  humus,  are  able  to  assimilate  the  free  nitrogen  of  the 
atmosphere,  but,  unlike  them,  can  only  effect  this  assimilation  in  a  condition 
of  symbiosis,  i.e.  Hving  in  the  gro-^ing  tissues  of  a  leguminous  plant.  Similar 
nodules  have  been  described  on  the  roots  of  other  plants  which  can  grow  in  a 


Fig.  14.  Root  of 
vetch  with  nod- 
ules. 


42 


PHYSIOLOGY 


soil  free  from  combined  nitrogen,  e.g.  conifers,  but  it  is  in  the  leguminosse 
that  their  presence  is  most  widespread. 

The  source  of  the  combined  nitrogen,  which  can  be  built  up  by  plants 
into  proteins  and  utihsed  in  this  form  by  animals,  is  thus  not  only  the  am- 
monium nitrite  produced  by  the  agency  of  electric  discharges  in  the  atmo- 


__s 


WV^"  ^  ,^       o       \ 


Fig. 


15.     Section  of  a  root  nodule  of  Dorychnium.     (VtriLLBMm.) 
a,  cortical  tissue  ;  h,  cells  containing  bacteria. 


sphere,  but  also  the  free  nitrogen  of  the  atmosphere  assimilated  by  various 
types  of  bacteria. 

Sulphur  is  found  in  all  soils  in  the  form  of  sulphates,  generally  of  lime. 
As  sulphates  it  is  taken  up  by  plants.  In  the  plant  cell  a  process  of  deoxida- 
tion  takes  place  at  the  expense  of  the  energy  derived  either  from  the  starch 
or,  in  the  case  of  bacteria,  from  other  ingredients  of  their  food-supply.  It  is 
built  up,  together  with  nitrogen,  carbon,  and  hydrogen,  to  form  sulphur 
derivatives  and  amino-acids  such  as  cystine,  and  these,  together  with  other 
amino-acids,  are  synthetised  to  form  proteins.  Practically  the  whole  of  the 
sulphur  taken  in  by  animals  is  in  the  form  of  proteins.  It  shares  the  oxida- 
tion of  the  protein  molecule  in  the  animal  body  which  it  leaves  in  the  form  of 
sulphates.  The  output  of  sulphates  by  an  animal  can  therefore  be  regarded, 
like  the  nitrogen  output,  as  an  index  of  the  protein  metabolism.  It  is 
returned  to  the  soil  in  the  form  in  which  it  was  taken  by  the  plant,  and  the 
cycle  can  be  continuously  repeated. 

Iron,  although  forming  but  a  minute  proportion  of  the  material  basis 
of  hving  organisms  (the  whole  body  of  man  contains  only  six  grammes),  is 
nevertheless  indispensable  for  the  maintenance  of  life.  It  is  necessary,  for 
instance,  in  two  important  functions,  viz.  the  formation  of  chlorophyll  in  the 
green  plant  and  the  respiratory  process  in  the  higher  animals.  Although  iron 
forms  no  part  of  the  chlorophyll  molecule,  plants  grown  in  the  absence  of  this 


THE  ELEMENTARY  CONSTITUENTS  OF  PROTOPLASM       43 

substance  remain  etiolated,  but  form  chlorophyll  if  the  smallest  trace  of  iron 
is  added  to  the  soil  ijj -which  they  are  growing  or  even  if  the  leaves  are  washed 
with  a  very  dilute  solution  of  an  iron  salt.  In  animals  iron  forms  an  essential 
constituent  of  haemoglobin,  the  red  colouring-matter  of  the  blood,  whose 
office  it  is  to  carry  oxygen  from  the  lungs  to  the  tissues.  It  is  probable  too 
that  the  minute  traces  of  iron  in  protoplasm  exercise  an  important  function 
in  the  processes  of  oxidation  which  are  continually  going  on.  Even  in 
the  inorganic  world  iron  plays  the  part  of  an  oxygen  carrier.  In  the  earth's 
crust  it  occurs  as  ferrous  salts  and  as  ferric  oxide.  The  ferrous  siUcate,  for 
instance,  may  be  decomposed  by  water  containing  carbon  dioxide  into  sihca 
and  ferrous  carbonate  ;  the  latter  then  absorbs  oxygen  from  the  atmosphere, 
liberating  carbon  dioxide  and  forming  ferric  oxide.  In  the  presence  of 
decomposing  organic  matter,  the  ferric  oxide  parts  with  its  oxygen  to  oxidise 
the  organic  substances  and  is  converted  once  more  into  ferrous  carbonate, 
and  this  may  be  decomposed  by  the  oxygen  of  the  air  as  before.  In  the 
presence  of  sulphates  and  decomposing  organic  matter  ferrous  sulphate, 
which  is  first  formed,  undergoes  deoxidation  to  ferrous  sulphide,  and  this  may 
again  be  oxidised  to  sulphates  and  ferric  salts  on  exposure  to  the  atmosphere, 
so  that  both  the  sulphur  and  the  iron  act  as  oxygen  carriers  between  the 
atmosphere  and  the  organic  matter.  Iron  is  obtained  by  plants  from  the 
soil  as  ferrous  or  ferric  salts.  In  the  protoplasm  it  is  built  up  into  highly 
complex  organic  compounds,  and  in  this  form  is  taken  up  by  animals.  It  is 
probable  that  the  main  requirements  of  the  animal  for  iron,  which  are  very 
small,  may  be  satisfied  entirely  at  the  expense  of  these  organic  compounds, 
but  there  can  be  little  doubt  that  the  animal  can,  if  need  be,  also  utihse  the 
iron  salts  present  in  its  food.  The  animal  proceeds  extremely  economically 
with  its  supply  of  iron.  Any  excess  of  iron  above  that  needed  to  supply 
the  iron  lost  to  the  body,  as  well  as  the  latter,  is  excreted  almost  entirely  with 
the  fseces  in  the  form  of  sulphide.  In  the  soil  this  undergoes  oxidation  and 
returns  once  more  to  the  form  in  which  it  was  originally  taken  up  by  the  plant. 

PJiospJiorus  is  absorbed  by  the  plant  as  phosphates.  In  the  cell  proto- 
plasm it  is  built  up  with  fatty  acids  and  other  organic  radicals  to  form  com- 
plex compounds  such  as  lecithin,  a  phosphorised  fat,  and  nuclein,  a  com- 
bination of  phosphorus  with  nitrogenous  bases  of  great  variety.  Both  leci- 
thin and  nuclein  are  essential  constituents  of  living  protoplasm.  Practically 
the  whole  of  the  phosphorus  income  of  animals  is  represented  by  these 
lecithin  and  nuclein  compounds.  After  absorption  into  the  animal  body  they 
are  broken  down  by  processes  of  dissociation  and  oxidation,  with  the  pro- 
duction, as  a  final  result,  of  phosphates,  which  are  excreted  with  the  urine  or 
faeces  and  return  to  the  soil. 

Chlorine,  'potassium,  sodium,  calcium,  and  magnesium  are  taken  up  by 
the  plants  in  the  form  of  salts.  Although  plapng  an  essential  part  in  all 
vital  processes,  they  do  not  seem  to  be  built  up  into  organic  combination 
with  the  protein  and  other  constituents  of  the  cell  protoplasm.  They  are 
therefore  taken  up  also  by  animals  in  the  form  of  salts,  and  as  such  are  again 
excreted  with  the  urine. 


44  PHYSIOLOGY 

Little  is  known  about  the  significance,  if  any,  of  the  other  elements  which 
I  have  mentioned  as  occasional  constituents  of  living  beings.  Silicon,  which 
is  of  universal  distribution,  is  assimilated  as  sihca,  probably  in  colloidal 
solution,  and  is  distributed  in  minute  quantities  through  all  plant  and 
animal  tissues.  It  forms  a  very  large  percentage  of  the  mineral  basis  of 
grasses,  but  even  here  it  does  not. seem  to  be  indispensable,  since  these  will 
grow  in  a  medium  devoid  of  sihca  as  luxuriantly  as  under  normal  con- 
ditions. 

Fluoritie  is  found  in  the  enamel  of  the  teeth  and  in  minute  traces  in  other 
tissues  of  the  body. 

Bromine,  though  present  in  quantity  in  some  seaweeds,  appears  to  play 
no  part  in  the  economy  of  higher  animals. 

Iodine  is  found  in  large  quantities  in  many  seaweeds  and  is  present  as  an 
organic  iodine  compound  in  the  skeleton  of  certain  horny  sponges.  An 
organic  iodine  compound  is  also  found  in  the  thyroid  gland  of  the  higher 
animals,  and  may  possibly  be  the  active  principle  by  means  of  which  these 
glands  are  able  to  affect  the  nutrition  of  the  whole  body.  Iodine,  therefore, 
would  seem  to  be  an  essential  constituent  of  the  higher  animals. 

Aluminium  is  found  in  large  quantities  in  certain  lycopods.  Whether 
it  is  essential  to  their  growth  is  not  known. 

Copper  is  certainly  not  a  necessary  constituent  of  a  large  number  of 
plants  and  animals.  In  one  class,  the  cephalopods,  it  appears  to  take  the 
part  of  iron  in  the  formation  of  a  blood  pigment.  The  haemocyanine,  which 
was  described  by  Fredericq,  plays  the  same  part  in  the  blood  of  cephalopods 
that  is  played  by  haemoglobin  in  the  blood  of  vertebrates.  When  oxidised 
it  is  of  a  blue  colour,  but  gives  off  its  oxygen  and  is  reduced  to  a  colourless 
compound  on  exposure  to  a  vacuum. 

Among  these  elementary  constituents  of  the  body,  a  definite  line  of 
demarcation  can  be  drawn  between  the  carbon  and  hydrogen  on  the  one 
hand  and  all  the  other  constituents  on  the  other.  The  first  two  elements  are 
built  up  in  a  deoxidised  form  into  the  living  structure  of  the  protoplasmic 
molecule.  The  products  of  their  complete  oxidation  are  volatile,  namely, 
carbon  dioxide  and  water,  and  leave  the  body  in  these  forms.  The  nitrogen 
set  free  by  the  breaking  down  of  the  proteins  will  pass  off  as  free  nitrogen  or 
as  ammonia.  The  sulphuric  acid  formed  by  the  oxidation  of  the  sulphur 
combines  with  the  bases  to  form  non- volatile  salts.  We  may  therefore  divide 
the  ultimate  constituents  of  the  body  into  those  which  are  combustible  and 
are  driven  off  on  heating,  and  those  which  are  left  behind  as  the  ash. 


SECTION  II 

THE   PROXIMATE   CONSTITUENTS   OF   THE 
ANIMAL  BODY 

In  spite  of  the  enormous  variety  of  the  proximate  constituents  of  hving 
organisms,  they  are  all  members  or  derivatives  of  three  classes  of  compounds. 
Since  living  organisms  form  the  entire  food  of  the  animal  kingdom,  a  study 
of  these  proximate  constituents  includes  the  study  of  all  the  food-stuffs. 
These  classes  are  : 

{a)  Proteins,  containing  the  elements  carbon,  hydrogen,  nitrogen,  oxygen, 
and  sulphur  ;   in  some  cases  also  phosphorus. 

(6)  Fats,  containing  carbon,  hydrogen,  and  oxygen. 

(c)  Carbohydrates,  containing  carbon,  hydrogen,  and  oxygen,  the  two 
latter  elements  being  present  in  the  proportions  in  which  they  form  water. 

THE  CHIEF  TYPES  OF  ORGANIC  COMPOUNDS  OCCURRING 
IN  THE  ANIMAL  BODY 

The  full  consideration  of  the  various  modifications  undergone  by  these  three  classes 
of  food-stuffs  in  the  body,  especially  if  we  include  the  by-products  occurring  both 
in  plants  and  in  animal  metabolism,  involves  a  ■nade  knowledge  of  organic  chemistry 
which  indeed  at  its  origin  was  simply  the  chemistry  of  the  products  of  li^^ng  {i.e. 
organised)  beiags.  The  most  important  substances  'svdth  which  we  shall  have  to  deal 
belong  to  a  comparatively  restricted  number  of  groups.  For  the  convenience  of  the 
reader  a  short  summary  of  the  relationships  of  these  gi'oups  to  one  another  and  to  the 
hydrocarbons  is  given  here. 

THE  HYDROCARBONS  (Fatty  Series).  These  form  a  continuous  homologous 
series,  and  may  be  saturated  or  unsaturated.     Examples  of  the  saturated  series  are  : 

CH4     methane 

C2H6    ethane 

C3H3    propane 

C4Hip  butane,  and  so  on, 

the  general  formula  for  the  group  being 

C„H2„+2- 

These  paraffins,  the  lower  members  of  which  are  gaseous,  whih'  the  h.igher  membens 
form  the  petroleum  ether,  the  heavy  petroleums,  vaseline,  and  the  paraffin  wax  with 
which  we  are  all  familiar,  are  entirely  inert  in  the  aniiiial  body.  If  taken  with  the 
food  they  pass  through  the  alimentary  canal  unchanged.  In  order  to  render  them 
accessible  to  the  action  of  the  living  cell  they  must  fii-st  undergo  oxidation. 

The  unsaturated  hvdrocarbons  have  the  general  formuhe  C„Ho„.  C„Ho„  o, 
C.>H,,...,.  &c. 

45 


46  PHYSIOLOGY 

Examples  of  the  first  two  groups  are  ethylene   CH2 

II  ■      ■ 

CH2 

and  acetylene  CH 

!il 
CH 

Derivatives  of  all  these  groups  occur  in  the  body. 

THE  ALCOHOLS,  The  first  product  of  the  oxidation  of  hydrocarbons  is  the 
series  of  bodies  known  as  the  alcohols.     Examples  of  these  are  : 

CH3OH      methyl  alcohol 

C2H5OH    ethyl 

C3H7OH    propyl 

C4H9OH    butyl 

C5H11OH  amyl 

CgHigOH  capryl        „        and  so  on, 

the  general  formula  for  the  group  being 

CuH2n  +  lOH. 
Tn  all  these  alcohols  the  OH  group  is,  so  to  speak,  more  mobile  than  the  other  atoms 
connected  with  the  carbons,  and  can  therefore  be  replaced  by  other  substances  or 
groups  with  comparative  ease.  In  this  respect  therefore  an  alcohol  can  be  compared 
to  water  HOH  or  to  an  alkaline  hydroxide  NaOH  or  KOH.  The  best-known  example 
of  the  group  is  ethyl  alcohol,  the  ordinary  product  of  fermentation  of  sugar.  In  these 
alcohols  the  H  of  the  OH  group  can  be  replaced  by  Na.  Thus,  water  with  metallic 
sodium  gives  sodium  hydroxide  and  hydrogen  as  follows  : 

2H0H  +  2Na  =  2NaOH  +  Hg. 

In  the  same  way  alcohol  treated  with  metallic  sodium  gives  off  hydrogen,  and  the 
remaining  fluid  contains  sodium  ethylate,  thus  : 

2C2H5OH  +  2Na  =  2C2H50Na  +  H2 
(sodium  ethylate) 

On  the  other  hand,  the  OH  group  may  be  replaced  by  acid  radicals.  Thus,  if  ethyl 
alcohol  be  treated  with  phosphorus  pentachloride,  ethyl  chloride  is  formed  together 
with  phosphorus  oxychloride  and  hydrochloric  acid.     Thus  : 

Et.OH  +  PCI5  =  POCI3  +  HCl  +  Et.Cl 

(ethyl  chloride) 

With  concentrated  sulphuric  acid  the  reaction  is  similar  to  that  which  obtains  between 
sodium  hydrate  and  this  acid,  and  we  have  formed  ethyl  hydrogen  sulphate  and  water. 
Thus: 

Et.OH  +  H2SO4  =  Et.HSOi  +  HOH 

If  alcohol  be  warmed  with  acetic  acid  and  strong  sulphuric  acid,  among  the  products 
of  the  reaction  is  ethyl  acetate,  which  is  volatile,  and  therefore  passes  off.     Thus  : 

Et.OH  +  HC2H3O2  =  Et.C2H302  +  HOH. 

These  compoimds  of  the  hydrocarbon  group  of  the  alcohol,  such  as  methyl,  ethyl, 
propyl,  &c.,  with  an  acid,  in  which  the  ethyl  takes  the  part  of  a  base,  are  known  as 
esters. 

An  ester  treated  with  an  alkali  is  decomposed  with  the  formation  of  an  alkaline 
salt  of  the  acid,  and  the  corresponding  alcohol  which,  being  volatile,  is  given  off  on 
warming  the  mixture.     Thus  : 

Et.C2H302  +  NaHO  =  NaC2H302  +  Et.OH. 

(ethyl  acetate)  (potassium  acetate)   (alcohol) 

This  process  of  (k^'omposition  of  an  ester  with  the  formation  of  the  alkaline  salt  of  an 
acid  is  often  spoken  of  as  saponification,  i.e.  soap  formation,  though  the  term  '  soap  ' 


PROXIMATE  CONSTITUENTS  OF  THE  ANIMAL  BODY        47 

is  applied  only  to  the  compounds  of  alkalies  with  the  higher  fatty  acids.  The  series  of 
alcohols  we  have  just  dealt  with  containing  one  OH  group  replaceable  by  metals  or 
acid  radicals  are  known  as  monatomic  alcohols.  If  in  the  molecule  of  the  paraffin  two 
or  more  atoms  of  hydrogen  have  been  replaced  by  the  group  OH,  we  speak  of  diatomic 
or  polyatomic  alcohols.  Thus,  derived  from  the  paraffin  propane  C'sHs  we  may  have 
the  monatomic  alcohol  C3H7OH,  propyl  alcohol,  or  the  triatomic  alcohol  C3H5(OH)3, 
which  is  known  as  glycerin,  or  glycerol. 

Other  alcohols  of  physiological  imjiortance  arc  cholesterol  and  cetyl  alcohol. 
Cholesterol  is  a  monatomic  alcohol  with  the  formula  C27H45OH.  It  is  very  complex  in 
structure,  and  belongs  to  the  aromatic  series.  Recent  work  points  to  an  affinity  of 
cholesterol  with  the  terpenes,  wliich  have  hitherto  been  found  only  as  the  product  of 
the  metabolism  of  plant  cells.  Cholesterol  is  a  constant  constituent  of  protoplasm. 
It  occurs  in  large  quantities  in  the  medullary  sheath  of  nerves  ;  it  is  a  normal  constitu- 
ent of  bile  and  may  form  concretions  (biliary  calculi)  in  the  gall  bladder.  In  combina- 
tion with  fatty  acids  it  is  an  important  constituent  of  sebum  and  of  wool  fat. 

CH3 

Another  alcohol — cetyl  alcohol — Ci8H34^0  =  (CH2)i4  occurs  in  the  feather  glands  of 

I 
CHoOH 

the  duck  and  forms  an  important  constituent  of  the  was,  spermaceti,  obtained  from 
a  cavity  in  the  skull  of  the  sperm  whale. 

ALDEHYDES.  By  oxidation  of  any  of  the  alcohols  we  obtain  another  group  of 
compomids — the  aldehydes.  From  ethyl  alcohol,  for  instance,  by  warming  with  potas- 
sium bichromate  and  dilute  sulphuric  acid,  ethyl  aldehyde  is  produced  and  given  oii.     In 

H 
/H  I 

these  aldehydes  the  group  C,^— H  is  converted  into  the  group  C  =  O,   and  it   is   the 

possession  of  this  group  which  determines  the  aldehyde  character  of  any  compound, 
as  well  as  the  reactions  wliich  are  typical  of  this  class  of  compounds. 

Some  of  the  typical  reactions  of  aldehydes  may  be  here  shortly  summarised  : 

(1)  They  act  as  reducing  agents,  the  CHO  group  being  converted  into  the  group 
COOH,  which  is  distinctive  of  an  acid.  We  may  therefore  say  that  on  oxidation 
aldehydes  are  converted  into  the  corresponding  fatty  acids  as  follows  : 

CH3  CH3 

CHO  COOH 

(ethyl  aldehyde)       (acetic  acid) 

On  account  of  the  ease  with  which  this  oxidation  takes  place,  aldehydes  act  as  strong 
reducing  agents.  Warmed  with  an  alkaline  solution  of  cupric  hydrate,  they  take  up 
oxygen,  reducing  the  cupric  to  a  red  precipitate  of  cuprous  hydrate.  If  warmed  with 
an  ammoniacal  solution  of  silver  {i.e.  silver  nitrate  solution  to  M^hich  ammonia  has 
been  added  mitil  the  precipitate  first  formed  is  just  redissolvcd),  they  reduce  the  silver 
nitrate  with  the  formation  of  a  mirror  of  metallic  silver  on  the  surface  of  the  glass 
vessel  in  which  they  are  heated. 

(2)  On  warming  with  phenyl  hydrazine,  they  give  the  typical  compounds,  hydra- 
zones  and  osazones,  which  are  also  given  by  the  sugars  and  will  be  mentioned  in  con- 
nection with  these  bodies. 

(3)  They  also  form  addition  products.  With  ammonia,  they  yield  the  group  of 
compoimds  knoAMi  as  aldehyde  ammonia.     Thus  : 


CH3 

CH3 

1        -r  NH3  = 

i    /NH, 

CHO 

^OH 

48  PHYSIOLOGY 

With  sodium  hydrogen  sulphite  the  following  reaction  takes  place  : 

CH3  CH3 

I       +  NaHSOs  =  I       /OH 
CHO  CH<; 

\s03Na 

These  compounds  of  aldehydes  with  sodium  sulphite  can  be  readily  obtained  in  a 
crystalline  form  and  furnish  a  convenient  means  of  separating  the  aldehydes  from  their 
solutions. 

(4)  All  the  aldehydes  possess  a  strong  tendency  towards  polymerisation.  Ethyl 
or  acetic  aldehyde  treated  with  strong  sulphuric  acid  gives  the  compound  paraldehyde. 
Thus  : 

3C2H4O       -         C6H12O3. 
(acetic  aldehyde)         (paraldehyde) 

If  warmed  with  strong  potash  the  polymerisation  occurs  to  a  still  further  extent  with 
the  formation  of  resinous  substances  of  unknown  composition,  but  at  any  rate  of  a 
very  high  molecular  weight,  the  so-called  '  aldehyde  resin.'  Formic  or  methyl  aldehj'^de, 
CH2O,  may  in  the  same  way  undergo  polymerisation  with  the  formation  of  a  mixture 
of  substances  belonging  to  the  group  of  sugars,  namely,  the  hexoses,  as  follows  : 

6CH2O  =  CeHiaOg. 
This  formation  of  sugar  from  formic  aldehyde  probably  plays  an  important  part  in  the 
assimilation  of  the  carbon  from  the  carbonic  acid  of  the  atmosphere  by  the  green  parts 
of  plants. 

ACIDS.  By  the  oxidation  of  the  group  CHO  of  the  aldehydes  we  obtain  the  group 
COOH  which  is  characteristic  of  an  organic  acid,  Thus,  formic  aldehyde  on  oxidation 
gives  the  compound  HCOOH,  formic  acid.  Ethyl  or  acetic  aldehyde,  CH3CHO,  with 
an  atom  of  oxygen,  gives  the  compound  CH3COOH,  acetic  acid. 

CH3  CH3 

1+0=1 

CHO  COOH. 

Since  these  acids  are  derived  from  the  paraffins  a  whole  series  of  them  exists  corre- 
sponding to  the  series  of  paraffins,  and  known  as  the  fatty  acids.  Examples  of  this 
group  are  : 

Formic  acid  Acetic,  acid  Propionic  acid         Butyric  acid 

HCOOH  CH3  CH3  CH. 

COOH        CH2         CHo 

I  I 

COOH.       CHo 

COOH. 

In  addition  to  these  fatty  acids,  there  are  also  unsaturated  acids,  derived  from 
the  imsaturated  hydrocarbons. 

DERIVATIVES  OF  THE  FATTY  ACIDS 
AMINO-ACIDS  are  derived  from  the  fatty  acids  by  the  replacement  of  one  atom 
of  hydrogen  by  the  group  NHg. 

Thus  from  propionic  acid  we  may  have  : 

CH2NH2  CH3 

CH2  or  CH.NHo 

COOH  COOH. 

The  second  form,  the  ((-amino  acid,  is  the  only  one  which  occurs  in  the  body. 


I 


PROXIMATE  CONSTITUENTS  OF  THE  ANIMAL  BODY       49 

OXYACIDS  ;irc  foiuiocl  by  the  replacement  of  one  H  atom  by  the  group  OH. 
Thus  : 

CH3 

CHOH  is  oxypropionic  acid  or  lactic  acid. 

COOH 

KETO- ACIDS.  Oxyacids  are  formed  by  the  oxidation  of  the  group  CHg  or  CH3. 
If  at  the  same  time  the  Hg  group  be  removed  by  oxidation  a  keto-acid  may  be  formed. 
This  is  probably  the  maimer  in  which  such  acids  arise  in  the  body,  though  it  is  more 
usual  to  regard  a  keto-acid  as  the  result  of  oxidation  of  a  ketone.     Thus  : 


CH3 

CH3 

1 

CH3 

1 

CO 

1 

1 

CH3 

CH2 

OH 

COOH 

(acetone) 

(pyruvic  acid — 
a  keto-acid) 

ACID  AMIDES  are  formed  from  a  fatty  acid  by  replacing  the  -  OH  of  the  -  COOH 
group  by  -  NH2,  e.g.  : 

CH3  CH3 

I  from  I 

CO.NH2  COOH. 

(acetamide)  (acetic  acid) 

AMINES.  These  may  be  regarded  as  formed  from  ammonia  NH3  by  replacing 
one  or  more  of  the  H  atoms  by  an  organic  radical.     Thus  we  may  have  : 

/CH3  /CH3  /CH3 

N^H  NeeH3  N,^CH3 

\H  ^H  ^CH3 

(methylamine)  (dimethylamine)  (triinethylamine) 

Under  the  action  of  living  organisms  primary  amines  may  be  formed  from  a -amino 
acids  by  a  process  of  decarboxylation.     Thus  : 

CH3  CH3 

II 
CH.NH2  -  COo  =  CH2.NH2 

I 

COOH 

(a-amino-propiouic  acid)         (ethylaminc) 

AROMATIC  COMPOUNDS 

These  all  contain  a  nucleus,  made  up  of  six  carbon  atoms,  which  is  extremely  stable, 
so  that  processes  of  oxidation,  reduction,  &e.,  can  be  carried  out  in  the  compound 
without  destruction  of  the  nucleus.  The  simplest  aromatic  compoimd  is  benzene 
CeHg.  It  behaves  as  a  saturated  compomid.  It  is  represented  as  a  hexagon  with  a 
hydrogen  atom  at  each  angle. 

H 


H 


50 


PHYSIOLOGY 


All  the  hydrogen  atoms  are  of  equal  value.  They  may  be  replaced  by  other  grouj)s, 
such  as  OH,  CI,  NH2,  or  by  more  complex  groups  belonging  to  the  fatty  series,  e.g. 
CH3,  C2H5,  &c.     Monosubstitution  derivatives  exist  only  in  one  form  : 

CgH^.X 

Disubstitution  compounds  exist  in  three  forms,  according  to  the  relative  position  of  the 
substituted  H  atoms.  These  are  known  as  the  ortho,  meta,  and  para  compounds,  and 
have  the  formulae  : 

XXX 


H 


H 


H 


H 


H 


H 


H 

ortho- 


H  .^y  X 

H 

meta- 


H 


H  '\/.  H 

X 

para- 


The  following  are  some  of  the  most  important  monosubstitution  derivatives  of 
benzene  : 

Nitrobenzene  CgHg .  NO2. 

Aniline  CgHs.NHa. 

Benzene  sulphonic  acid  CgHg.SOsH. 

Phenol  CeHj.OH. 

Toluene  CgHs.CHg. 

Benzyl  alcohol  CgHg .  CHgOH. 

Benzylaldehydc  CsHj .  CHO. 

Benzoic  acid  CgHs .  COOH. 

Of  the  disubstitution  compounds,  we  need  only  mention  the  following  : 
The  dihydroxyhenzenes : 


Pyrocatechin 

or  catechol 

Resorcinol            Hydroquinone 

OH 

OH 

OH 

OH 

' 

ortho 

meta 

OH 

\/ 
OH 

para- 

Salicylic  acid  (o-hydroxybenzoic 

/OH 
acid)  CgH^/ 

^COOH. 

Tyrosin  (para 

hydr 

oxyphenyl  alanine 

): 

OH 


CH2.CH(NH2)C00H. 
Examples  of  trisuhstitution  derivatives  of  benzene  are  : 


OH 


Pyrogallol 


OH 
OH 


PROXIMATE  CONSTITUENTS  OF  THE  ANIMAL  BODY 

OH 


51 


Homogentisic 

acid 

OH 

CH2.COOH 

Adrenaline 

OH 

OH 

CH.OH 

1 

CH2.NH(CH3) 

Picric  acid 

NO2 

OH 

NO2 

NO, 


OPTICAL  ACTIVITY 

Most  of  the  compounds  produced  by  the  agency  of  living  organisms  exhibit  optical 
activity,  i.e.  have  the  property  of  rotating  the  plane  of  polarised  light  either  to  the 
right  or  to  the  left. 

In  an  ordinary  wave  of  light  the  vibrations  of  the  waves  take  place  in  all  planes 
perpendicular  to  the  direction  of  its  propagation.  When  such  a  ray  is  passed  through 
a  Nicol's  prism  (made  of  Iceland  spar)  it  emerges  as  a  plane  polarised  beam,  i.e.  waves 
in  one  plane  only  are  transmitted.  Another  Nicol's  prism  will  allow  such  a  ray  to  pass 
only  if  it  is  parallel  to  the  first  prism.  If  it  is  rotated  through  a  right  angle,  no  light 
will  pass,  A  Nicol's  prism  may  thus  be  used  to  determine  the  plane  of  polarisation 
of  any  beam  of  light. 

In  the  polarimeter  two  Nicol's  prisms  moimted  parallel  to  one  another  are  employed. 
One  of  them  (the  polariser)  is  fixed  ;    the  other  (the  analyser)  can   be  rotated  round 


hi    D 


^DjDt 


==4];ic  c^B 


^.'.''. 


Fig.  16.     Diagram  of  polarimeter, 
B,  polariser  ;  n,  analyser  ;   o,  tube  containing  solution  under  examination. 

the  axis  of  the  beam  of  light  passing  through  the  first.  When  both  prisms  are  parallel 
light  passes  through  the  analyser.  On  interposing  a  solution  of  an  optically  active 
substance  between  the  two  prisms,  the  plane  of  polarisation  of  the  beam  is  rotated, 
so  that  the  light  passing  through  the  analyser  is  diminished.  The  light  may  be  brought 
to  its  original  intensity  by  rotating  the  analyser  either  to  the  right  (clockwise)  or  to  the 
left.  In  this  way  the  direction  and  degree  of  the  optical  activity  may  be  determined. 
Optical  activity  is  connected  with  the  molecular  arrangement  of  the  substance  exhibiting 
this  property,  and  depends  on  the  presence  of  one  or  more  '  asymmetric  carbon  atoms  ' 
in  the  molecule. 

CH3  CH3 

I  1 

Thus  in  hictic  acid  H.COH,  or  in  alanine  HC.NHo,    the    middle    carljon    atom    is 


COOH  COOH 

asymmetric,  i.e.  it  is  unequally  loaded  on  the  four  sides. 


52  PHYSIOLOGY 

We  can  imagine  such  a  carbon  atom  as  occupying  the  interior  of  a  tetrahedron. 

A  B 


R3  R3 


Fig.  17. 

In  this  tetrahedron,  if  we  represent  the  four  groups  combining  with  the  carbon  by 
Rx,  R2,  Rsj  R4,  they  can  be  arranged  either  as  in  A  or  B.  It  is  evident  that  no  amount 
of  turning  about  will  convert  the  tetrahedron  A  into  tetrahedron  B,  but  that,  if  we 
hold  A  before  a  mirror,  its  image  in  the  mirror  will  be  represented  by  B.  One  arrange- 
ment is  therefore  the  mirror  image  of  the  other,  and  a  compound  containing  one  such 
carbon  atom  will  be  capable  of  existing  in  two  forms,  namely,  one  form  corresponding 
to  A,  the  other  form  corresponding  to  B.  It  is  found  that  the  unequal  loading  of  the 
carbon  atom,  which  is  present  in  such  an  asymmetric  arrangement,  causes  the  com- 
pound containing  the  asymmetric  carbon  to  have  an  action  on  polarised  light.  One 
of  the  varieties  will  rotate  polarised  light  to  the  right,  while  its  mirror  image  will  rotate 
polarised  light  to  the  left.  A  mixture  of  equal  parts  of  the  two  compotmds  will  rotate 
equally  to  left  and  right,  i.e.  will  have  no  action  on  polarised  light. 

The  variety  rotating  to  the  right  is  dextrorotatory,  and  the  other  Isevorotatory,* 
while  the  mixture  of  the  two  is  known  as  the  racemic  or  inactive  variety.  The  three 
forms  are  said  to  be  stereoisomeric,  and  are  distinguished  as  the  d,  I,  and  i  forms  re- 
spectively. If  two  asymmetric  carbon  atoms  are  present  in  a  compound,  we  may 
have  four  stereoisomers  ;  and  generally  if  there  are  n  asymmetric  atoms  in  a  molecule, 
there  will  be  2"  possible  stereoisomers.  These  will  not  all  be  necessarily  optically  active, 
since  the  dextrorotation  due  to  one  asymmetric  carbon  atom  may  be  exactly  neutralised 
by  the  laevorotation  due  to  another,  so  that  '  internal  compensation  '  takes  place  and 
the  substance  io  optically  inactive.  Thus  in  tartaric  acid  four  forms  are  known,  namely, 
d,  I,  racemic  or  i,  and  mesotartaric,  also  inactive,  in  which  internal  compensation  occurs. 
These  four  varieties  may  be  represented  as  follows  : 

COOH  COOH 

HCOH  HOCH 

HOCH  HCOH 
COOH  COOH 

cZ-tartaric  acid  Z-tartaric  acid 


COOH 
HCOH 
HCOH 

COOH 

mesotartaric  acid 


inactive  tartaric  acid 


Several  methods  may  be  employed  to  separate  the  racemic  form  into  its  two  optically 
active  components.  One  of  these  methods,  first  employed  by  Pasteur,  is  to  grow 
moulds  in  the  solution.  One  of  the  optical  isomers  is  destroyed,  leaving  the  other 
unchanged.  Another  method  is  the  fractional  crystallisation  of  the  salts  with  alkaloids, 
e.g.  strychnine  in  the  case  of  lactic  acid. 

*  The  specific  rotatory  power  of  a  substance  is  equal  to  the  number  of  degrees 
through  which  the  plane  of  polarisation  is  rotated  when  it  passes  through  a  100  per  cent, 
solution  of  the  substance  in  a  tube  1  decimetre  long.  Thus  polarised  light  passing 
through  such  a  tube  of  10  per  cent,  glucose  solution  would  show  a  rotation  of  5-25 
degrees,  i.e.  its  specific  rotatory  power  is  +  52-5. 


SECTION   III 

THE  FATS 

These  substances  are  widely  distributed  throughout  the  animal  and  vege- 
table kingdoms.  In  the  higher  animals  they  form  the  main  constituents  of 
the  fatty  or  adipose  tissue  lying  under  the  skin  and  between  the  muscles 
and  often  forming  large  accumulations  around  the  viscera.  In  the  marrow 
of  bones  they  may  amount  to  96  per  cent.  They  also  occur  in  fine  particles 
distributed  through  the  protoplasm  of  cells  and  probably  also  in  combination 
with  the  other  constituents  which  make  up  protoplasm.  Large  amounts  are 
also  found  in  certain  members  of  the  vegetable  kingdom,  as,  for  instance, 
in  the  fatty  seeds  and  nuts,  e.(j.  linseed,  olives,  Brazil  nuts. 

CHEMISTRY  OF  THE  FATS 
The  fats  are  esters  of  glycerol  and  the  fatty  acids.     Glycerol  is  a  trihydric 
or  triatomic  alcohol  and  can  therefore  form  esters  with  one,  two,  or  three 
of  its  hydroxyl  groups  ;   thus  with  acetic  acid  the  following  compounds  are 
known  : 

(1)  (2) 

CH2OH  CH2OH 

I  I 

CHOH  CH— 0— OC.CH3 

I  I 

CH2O— OC.CH3  CH2OH 

a-rnonacetin  /3-raonacetin 

monoglycerides 

(3)  (4)  (5) 

CH2— 0— OC.CH3       CH2OH  CH2— 0— OC.CH3 

I  I  I 

CHOH  CH— 0— OC.CH3  CH— 0— OC.CH3 

CH.,— 0— OC.CH3       CH2— 0— OC.CH3  CH2— 0— OC.CH3 

a,  a  diacetin  a,  /3  diacctin  triacctin 

'  Tr"i    "    Hi  trifflvccride 

diglycendes 

In  these  compounds  the  phenomenon  of  isomerism  occurs  owing  to  the 
presence  of  primary  and  secondary  alcohol  groups  in  glycerol.     In  the  case 

53 


54  PHYSIOLOGY 

of  the  diglycerides  and  the  triglycerides  mixed  esters,  in  which  the  fatty  acid 
radical  varies,  are  possible  : 

(6)  (7) 

CH,— 0— OC.CH,  CH,OH 


Lg        \J        vyv^.vy-LXg  V^XigV 


CHOH  CH— 0— OC.CH 


CH2— 0— OC.CH2.CH3  CH2— 0— OC.CHaCHg 

(8) 
CH,—0— OC.CH, 


L2       \J       vy^.v^J-13 


CH— 0— OC.CH2.CH3 
CH2— 0— OC.CH2.CH2.CH3 

The  glyceryl  esters  which  compose  the  fatty  material  of  hving  matter — 
whether  animal  or  plant — are  mainly  triglycerides,  the  monoglycerides  and 
diglycerides  being  seldom  found  in  nature.  The  natural  fat  is  usually 
found  to  consist  of  a  mixture  of  triglycerides  ;  these  triglycerides,  instead 
of  being  mixed  esters  as  in  formula  (8),  are  generally  simple  esters  as  in 
formula  (5).  The  differences  in  the  composition  of  the  natural  fats  depend 
therefore  on  the  variety  of  the  fatty  acid  radical  combined  with  the  glycerol. 

The  fatty  acids  which  enter  into  the  composition  of  the  triglycerides 
belong  to  two  main  homologous  series  : 

A.  The  saturated  fatty  acids,  namely  : 

Formic  acid,  H.COOH 
Acetic  acid,  CH3.COOH 
Propionic  acid,  CHg.CHg.COOH 
Butyric  acid,  CH3.CH2.CH2.COOH 
Valerianic  acid,  CH3.(CH2)3.C00H 
Caproic  acid,  CH3.(CH2)4.C00H 
Capryhc  acid,  CH3.(CH2)6.COOH 
Capric  acid,  CH3(CH2)8.C00H 
Laurie  acid,  CH3(CH2)io.COOH 
Myristic  acid,  CH3(CH2)i2-COOH 
Palmitic  acid,  CH3(CH2)i4.C00H 
Stearic  acid,  CH3(CH2)i6.COOH 
Arachidic  acid,  CH3(CH2)18.COOH 
Behenic  acid,  CH3(CH2)2o.COOH 
Lignoceric  acid,  CH3(CH2)22-COOH 

B.  The  unsaturated  fatty  acids,  namely  : 

(1)  Acryhc  series,  e.g.  oleic  acid  (CjjH2„_202) 

(2)  Linoleic  series,  e.g.  hnoleic  acid  (C^H2n_402) 

(3)  Linolenic  series,  e.g.  linolenic  acid  {Q'^^n^^^^i 


THE  FATS  55 

Of  the  long  list  of  fatty  acids  given  above  only  a  few  occur  to  any  extent 
in  the  animal  body.  In  milk,  although  the  greater  part  of  the  fat  consists 
of  the  triglycerides  of  oleic,  palmitic,  and  stearic  acids,  other  members  of  the 
series  given  above  are  present  in  small  amounts.  On  the  other  hand,  the 
adipose  tissue,  strictly  so  called,  consists  almost  exclusively  of  the  fats  de- 
rived from  the  fatty  acids  palmitic,  stearic,  and  oleic,  i.e.  tripalmitin,  tri- 
stearin,  and  triolein.  The  great  differences  in  the  appearance  of  the  fat  of 
different  animals  are  due  to  the  varying  amounts  in  the  relative  quantities  of 
these  three  fats  which  may  be  present.  While  triolein  is  liquid  at  0°  C,  tri- 
stearin  and  tripalmitin  are  solid  at  the  temperature  of  the  body.  According 
to  the  relative  amounts  of  these  three  substances,  therefore,  we  may  have  a 
fat  which,  like  mutton  suet,  is  solid  at  the  body  temperature,  or  a  fat  con- 
taining much  olein  which  is  still  fluid  and  runs  away  when  the  body  is  opened 
after  death,  even  when  it  has  already  cooled. 

PROPERTIES  OF  THE  FATS.  The  fats  are  colourless  substances 
devoid  of  smell.  They  are  insoluble  in  water,  in  which  they  float.  They  are 
soluble  in  warm  absolute  alcohol,  but  separate  out  into  crystalline  form  on 
cooling.  They  are  easily  soluble  in  ether.  If  they  are  strongly  heated  with 
potassium  bisulphate  they  give  off  pungent  vapours  of  acrolein  derived  from 
the  decomposition  of  the  glycerin  of  their  molecule. 

C3H.5(OH)3  -  2H2O    =  C3H4O 

If  they  are  heated  with  water  or  steam  or  submitted  to  the  action  of  certain 
ferments,  they  imdergo  hydrolysis,  taking  up  three  molecules  of  water,  and 
are  spht  into  three  molecules  of  fatty  acid  and  one  molecule  of  glycerin,  e.g., 

C3H5(CieH3i02)3  +  3H2O  =  3HCieH3,0,  +  C3H5(0H)3 

(neutral  fat — tripalmitin)  (palmitic  acid)  (glycerin) 

This  process  may  occur  spontaneously  when  fat  is  left  exposed  to  the  air. 
Fat  which  has  been  ai-tificially  spht  in  this  way  is  said  to  be  rancid.  Most 
natural  fats  generally  contain  a  small  amount  of  fatty  acid  which  gives  them 
an  acid  reaction. 

On  boiling  a  neutral  fat  for  a  long  time  with  an  aqueous  solution  of 
potassium  or  sodium  hydrate,  or  better  still  with  an  alcohohc  solution  of 
potassium  or  sodium  ethylate,  the  fat  undergoes  saponification,  giving  the 
alkaline  salt  of  a  fatty  acid  and  glycerin.  The  former  compomid  is  spoken  of 
as  a  soap.  In  water  the  soaps  form  a  sort  of  pseudo-solution  on  heating  which 
sets  to  a  solid  jelly  on  cooling.  From  a  dilute  watery  solution  the  soap  can 
be  thrown  down  in  the  solid  form  by  the  addition  of  neutral  salts.  Fats  are 
insoluble  in  and  non-miscible  with  water.  If  shaken  up  with  water  the 
droplets  rapidly  run  together  and  rise  to  the  surface,  forming  a  continuous 
layer  of  the  oil  or  fat.  The  same  thing  happens  if  an  absolutely  neutral  fat 
be  shaken  up  with  a  dilute  solution  of  sodium  carbonate.  If,  however,  the 
fat  be  slightly  rancid,  i.e.  if  fatty  acid  be  present,  the  latter  combines  with 
the  alkaU  with  the  expulsion  of  CO.^  to  form  a  soap.  The  presence  of  soap 
in  colloidal  solution  in  the  water  at  once  diminishes  or  aboUshes  the  surface 


56  PHYSIOLOGY 

tension  between  the  neutral  fat  and  the  water.  Like  many  other  colloidal 
solutions,  a  soap  solution  presents  the  phenomenon  of  surface  aggregation, 
i.e.  the  concentration  of  the  soap  at  the  surface  is  increased  to  such  an  extent 
as  to  form  practically  a  solid  pellicle  of  molecular  dimensions  on  the  surface  of 
the  fluid.  The  same  pellicle  formation  occurs  at  the  surface  of  every  oil 
globule,  so  that  on  shaking  up  rancid  oil  with  dilute  sodium  carbonate,  the 
whole  of  the  oil  is  broken  up  into  fine  droplets  which  show  no  tendency  to 
run  together  again,  and  remain  in  suspension  in  the  water.  The  suspension 
of  fine  oil  droplets,  which  has  the  appearance  of  milk,  is  spoken  of  as  an 
emulsion.  It  can  be  at  once  destroyed  by  adding  acid.  This  decomposes 
the  soap,  setting  free  the  fatty  acids,  which  are  insoluble  in  the  water.  The 
pelhcle  around  each  globule  is  destroyed,  and  the  globules  run  together  as 
neutral  oil  would  in  pure  water. 

In  order  to  characterise  any  given  animal  fat  or  mixture  of  fats  the  following  reactions 
are  made  use  of  : 

(1)  The  'acid  number  '  of  the  fat,  i.e.  its  content  in  free  fatty  acids,  is  determined 

N 
by  titrating  it  in  ethyl  alcohol  solution  with  ^r.  alcoholic  solution  of  potash,  using  phenol - 

phthalein  as  an  indicator. 

(2)  The  '  saponification  number.'  This  represents  the  number  of  milligrammes 
of  potassium  hydrate  necessary  to  saponify  completely  one  gramme  ot  fat. 

(3)  The  percentage  of  volatile  fatty  acids  is  determined  by  saponifying  the  fat, 
then  treating  it  with  a  mineral  acid  to  set  free  the  fatty  acids  and  distilling  over  the 
volatile  acids  in  a  current  of  steam. 

(4)  The  iodine  number  is  the  amount  of  iodine  which  is  taken  up  by  a  given  weight 
of  fat.  It  is  a  measure  of  the  amount  of  tmsaturated  fatty  acid  present,  i.e.  in  ordinary 
fat,  oleic  acid. 

Besides  the  glycerides,  a  certain  number  of  substances  occur  in  the  body 
derived,  not  from  a  combination  of  fatty  acids  with  glycerol,  but  from  a 
formation  of  esters  of  the  fatty  acids  and  other  alcohols,  e.g.  cholesterol  or 
cetyl  alcohol.  Thus,  spermaceti  is  a  mixture  of  cetyl  palmitate  with  small 
quantities  of  other  fats.  The  fatty  secretion  of  the  sebaceous  glands  in 
man  and  the  higher  animals,  which  furnishes  the  natural  oil  of  hair,  wool, 
and  feathers,  consists,  with  small  traces  of  glycerides  of  cholesterol  esters. 
Lanohne,  which  is  purified  wool  fat,  consists  almost  entirely  of  cholestpryl 
stearate  and  palmitate.  These  cholesterol  fats  are  attacked  with  extreme 
difiiculty  by  ferments  or  micro-organisms.  It  is  probably  on  this  account 
that  they  are  manufactured  in  the  body  for  protective  purposes.  So  far  as 
we  know,  when  once  formed,  they  are  incapable  of  further  transformation  in 
the  body.  They  are  not  appreciably  altered  by  the  digestive  ferments  of  the 
ahmentary  canal,  and  the  cholesterol  is  said  to  pass  through  the  latter 
unaltered.*  Cholesterol  is  also  found  in  combination  with  fatty  acids  in 
every  living  cell.  Whenever  protoplasmic  structures  are  extracted  with 
boihng  ether,  a  certain  amount  of  cholesterol  is  present  with  the  fats  which 
are  so  extracted.  In  view  of  the  great  stabihty  of  this  substance  when 
exposed  to  the  ordinary  mechanisms  of  chemical  change  in  the  body,  it  seems 
*  According  to  Gardner,  chplesterpl  jnp,y  be  absorbed  from  the  intestine. 


THE  FATS  57 

probable  that  the  part  played  by  cholesterol  is  that  of  a  framework  or 
skeleton,  in  the  interstices  of  which  the  more  labile  constituents  of  the  proto- 
plasm can  undergo  the  constant  cycle  of  changes  which  make  up  the  phe- 
nomena of  life. 

PHOSPHOLIPINES  OR  PHOSPHATIDES 

The  fats  form  the  chief  constituent  of  the  deposited  and  reserve  fat 
throughout  the  animal  kingdom  and  are  also  contained  in  the  protoplasm  of 
the  living  cell.  The  chief  fatty  constituents  of  protoplasm  differ  from  the 
above  fats  in  the  following  particulars  :  they  contain  phosphoric  acid  and  an 
amine.  On  this  account  they  have  been  called  phosphorised  fats.  Thudi- 
chum,  who  isolated  various  compounds  of  this  nature  from  brain,  suggested 
the  term  phosphatides  as  a  general  name  for  them.  The  term  lipoid  has  also 
been  used,  but  it  includes  all  the  substances  composing  a  cell  which  are  soluble 
in  ether,  e.g.  cholesterol,  cetyl  alcohol,  and  the  fats.  Leathes  has  suggested 
the  term  phospholipine  for  those  compounds,  for  it  denotes  that  the  com- 
pound is  partly  fat  (hp),  that  it  contains  phosphorus,  as  well  as  a  nitrogenous 
basic  radical  (ine).  The  phosphohpines  comprise  the  substances  lecithin, 
cephalin,  cuorine,  sphingomyeline.  In  brain  and  other  tissues  similar  com- 
pounds, which  contain  no  phosphorus,  occur,  and  in  the  place  of  glycerol  we 
may  find  galactose.  Leathes  has  proposed  calling  these  compounds  Hpines 
and  galactohpines. 

Lecithin,  the  chief  phosphohpine,  is  an  ester  compounded  of  two  fatty 
acid  radicals,  phosphoric  acid,  glycerol,  and  the  amine,  chohne.  The 
various  lecithins  may  be  distinguished,  according  as  they  contain  different 
fatty  acid  radicals,  as  oleyl-lecithin,  stearyl-lecithin.  The  following  formula 
represents  distearyl-lecithin  : 

CH2-0-OC.(CH2)ieCH3 
CH— 0— OC.(CH2),6CH3 

HO^'    "^O.CH.^.CH^.NiCH^), 

OH 

On  warming  with  baryta  water  lecithin  is  broken  down  into  fatty  acid, 
glycerophosphoric  acid,  and  chohne.     The  latter  base,  which  is  trimothvl- 

[C2H4OH 
oxethyl-annnonium    hydrate,    N  \  (OH-j).,    must     be     distinguished     from 

[oh 

neurine,  N  -  (CH.,).;   wliicli    is   tiiinetlivl-vitivl-aininoiiiiim    hydrate,   ami    is 

[oh 

much  more  poisonous  t  ha  lU'lioli  lie.  C'iioliue  forms  a  salt  with  liydroi'lijorieacid, 
which,  with  platinum  chloride,  yields  a  double  salt  of  characteristic  crystalline 


58  PHYSIOLOGY 

form,  insoluble  in  absolute  alcohol.  The  universal  distribution  of  lecithin 
seems  to  indicate  that  it  plays  an  important  part  in  the  metabolic  processes 
of  the  cell.  There  is  no  doubt  that  it  may  serve,  inter  alia,  as  a  source  of 
the  phosphorus  required  for  building  up  the  complex  nucleo- proteins  of  cell 
nuclei.  It  seems  to  represent  an  intermediate  stage  in  the  utilisation  of  neu- 
tral fats  by  protoplasm,  and  its  occurrence  in  the  brain  as  a  constituent  of 
more  complex  molecules,  which  contain  also  a  carbohydrate  nucleus  (galacto- 
sides,  such  as  cerebrin),  might  be  interpreted  as  indicating  some  share  also  in 
the  metabohsm  of  carbohydrates. 

Lecithin  may  be  extracted  from  tissues  by  boihng  with  absolute  alcohol. 
On  coohng  the  alcohohc  extract  in  a  freezing  mixture,  the  lecithin  separates 
out  as  granules  or  semi-crystalline  masses.  When  dried  in  vacuo,  it  forms 
a  waxy  mass,  which  melts  at  40°  to  50°  C.  In  water  it  swells  up  to  form  a 
paste,  which,  under  the  microscope,  is  seen  to  consist  of  oily  drops  or  threads, 
the  so-called  myehn  droplets.  In  a  large  excess  of  water  it  forms  an  emulsion 
or  a  colloidal  solution.  Its  power  of  taking  up  water  on  the  one  hand,  and 
its  solubihty  in  alcohol  and  similar  media  on  the  other,  give  it  an  intermediate 
position  between  the  water-soluble  crystalloids  and  the  insoluble  fats,  and 
enable  it  to  play  an  important  part  both  as  a  vehicle  of  nutritive  substances 
and  as  a  constituent  of  the  hpoid  membrane,  which  bounds  and  determines 
the  osmotic  relationships  of  all  Hving  cells. 

The  phospholipines  are  provisionally  classified  according  to  the  proportions  of 
N  and  P  in  their  molecule,  as  follows  : 

(a)  Mono-aminc-monophosphatides,  N :  P  =  1 : 1  (including  lecithin  and  cephalia). 

(6)  Diamino-mono-phosphatides,  N  :  P  =  2  :  1  {e.g.  sphingomyelin). 

(c)  Mono-amino  diphosphatides,  N  :  P  =  1  :  2  {e.g.  cuorin,  a  lipine  extracted  from 

heart  muscle  by  Erlandsen). 
{d)  Diamino-diphosphatides,  N  :  P  =  2  :  2. 

(e)  Triamino-monophosphatide,  N  :  P  =  3  :  1  (an  example  has  been  reported  as 
occurring  in  egg  yolk). 
All  these  bodies  (except  cuorin)  are  obtained  by  the  extraction  of  the  brain  or  of  nerve 
fibres.  Many  also  occur  in  egg  yolk.  The  galacto-lipines  include  two  substances 
extracted  from  the  brain,  viz.  phrenosin  and  kerasin.  Both  these  on  decomposition 
yield  galactose,  a  nitrogenous  base  called  sphingosine  and  a  fatty  acid.  We  know 
little  or  nothing  of  their  significance. 


SECTION  IV 
THE  CARBOHYDRATES 

The  carbohydrates  are  a  group  ot  bodies  oi  wide  distribution  and  great 
importance  in  both  the  vegetable  and  animal  kingdoms.  In  plants  the  first 
product  of  assimilation  of  carbon  is  a  carbohydrate,  and  in  animals  these 
substances  form  one  of  the  most  important  sources  of  energy.  They  consist 
of  the  elements  carbon,  hydrogen,  and  oxygen,  the  two  last-named  being 
almost  invariably  in  the  proportions  necessary  to  form  water.  It  is  on  this 
account  that  the  term  carbohydrate  has  been  given  to  the  group.  Their 
general  formula  might  be  expressed  C^HgnOn-  Certain  derivatives  of  the 
group,  obtained  by  the  substitution  of  methyl  and  other  radicals  for  a 
hydrogen  atom,  though  necessarily  classified  with  carbohydrates  on  account 
of  their  reactions,  do  not  conform  to  this  general  formula,  e.g.  rhamnose, 
CgHiaOg.'  All  the  carbohydrates  which  are  of  importance  in  the  animal 
economy  contain  six  carbon  atoms  or  a  multiple  of  this  number.  Analogous 
substances,  however,  can  be  prepared  containing  less  or  more  than  this 
number  of  carbon  atoms.  A  series  of  compounds  exist  which  contain  in  their 
molecule  2,  3,  4,  5,  6,  7,  8,  9  carbon  atoms,  and  are  termed  dioses,  trioses, 
tetroses,  pentoses,  hexoses,  heptoses,  and  so  on  ;  the  termination  '  ose  '  with 
the  Greek  numeral  prefixed,  indicating  the  number  of  carbon  atoms,  gives 
them  a  distinct  designation.  These  are  all  oxidation  products  of  pol3'atomic 
alcohols,  being  either  ketones  or  aldehydes  of  these  alcohols.     Thus  from 

COH 

glycerol    we    may    obtain    glyceryl    aldehyde    CHOH    and    dioxyacetone 

CH2OH  CH2OH 

CO.     Both  these  substances  behave  as  sugars  and  beloiig  to  the  group  of 

CH2OH 

trioses.     They  are  generally  obtained  together  and  are  called  glycerose. 

"  CH2OH 

From  the  hexatomic  alcohol  (CHOH),  we  may  obtain  either  the  aldehyde 


CH2OH 


59 


60  PHYSIOLOGY 

CH2OH 

COH  CO 

(CH0H)4  or  the  ketone  (CH0H)3.     These  two  oxidation  products  of  the 


CH2OH  CH2OH 

polyatomic  alcohols  are  known  as  aldoses  and  ketoses  respectively.  All  these 
compounds  are  distinguished  by  the  termination  '  ose.'  It  is  convenient 
to  call  those  compounds  containing  six  carbon  atoms  the  sugars,  because 
it  is  to  this  group  that  the  natural  sugars  belong. 

Stereoisomerism  in  the  Sugars.     It  will  be  noticed  that  of  the  six  carbon 

CH2OH 

atoms   contained  in  the  sugar  molecule,   e.g.   the   aldose   (CII0H)4,  four 

COH 

are  asymmelric,  i.e.  their  four  combining  affinities  are  saturated  with  groups 
of  different  kinds,  viz.  several  carbon  atoms,  one  H  atom,  and  one  OH 
group :  ^ 

H— C— OH 

C 

They  must  therefore  present  many  stereoisomeric  forms.  If  n  represent  the 
number  of  asymmetric  carbon  atoms  in  a  compound,  the  possible  number  of 
stereoisomers  is  2".  Thus  an  aldehexose  with  four  asymmetric  carbon  atoms 
(CH0H)4  must  present  2*  isomers,  i.e.  sixteen  isomeric  compounds,  so  that 
there  must  be  sixteen  sugars  all  possessing  the  formula  CH20H(CHOH)4COH, 
in  addition  to  the  inactive  sugars  obtained  by  a  mixture  of  two  oppositely 
active  members  of  this  group.  Of  the  sixteen  possible  sugars  of  this  formula, 
as  many  as  fourteen  have  been  found  or  have  been  artificially  prepared. 
Only  a  small  number  are,  however,  of  any  physiological  importance.  These 
include  the  aldoses,  glucose,  mannose,  and  galactose,  and  the  ketose,  fructose 
or  levulose.  All  the  other  sugars  are  unassimilable  by  the  animal  cell  and 
are  not  manufactured  by  plants. 

Since  these  sugars  can  be  divided  into  the  optically  active  and  the  inactive 
varieties,  an  obvious  mode  of  designation  would  be  to  represent  them  as 
d-,  1-,  and  i-  varieties  respectively,  i.e.  dextro-rotatory,  Isevo-rotatory,  and 
inactive.  On  Fischer's  suggestion,  however,  this  mode  of  nomenclature  has 
been  altered  in  favour  of  representing,  by  the  letter  prefixed,  not  the  optical 
qualities  of  the  substance  in  question,  but  its  relation  to  other  substances, 
especially  glucose.  Thus,  d-fructose  means  that  fructose  is  the  ketose  corre- 
sponding to  the  dextro-rotatory  glucose,  d-fructose  itself  being  leevo-rotatory, 
though  its  active  asymmetric  C  atoms  are  identically  arranged  with  those  in 


THE  CARBOHYDRATES  61 

glucose.  With  this  hmitation  one  may  say  that  it  is  only  the  d-hexoses  of  a 
particular  form  which  are  assimilable,  and  therefore  of  physiological  im- 
portance. The  small  differences  in  the  configuration  of  the  four  d-sugars  can 
be  readily  seen  if  their  graphic  formulae  be  compared  : 

CHO  CHO  CH2OH  CHO 

H.C.OH  HO.C.H  CO  H.C.OH 


HO.C.H 

HO.C.H 

HO.C.H 

HO.C.H 

H.C.OH 

H.C.OH 

H.C.OH 

HO.C.H 

H.C.OH 

H.C.OH 

H.C.OH 

H.C.OH 

CH2OH 

CH2OH 

CH2OH 

CH2OH 

d-ghicose 

d-mannose 

d-fructose 

d-galactose 

THE  PENTOSES.  C5H10O5 
These  bodies  occur  largely  iu  plants  in  the  form  of  complex  polysaccharides,  the 
pentosanes,  wliich  give  pentoses  on  hydrolysis  with  acids.  Two  forms  of  pentose 
have  been  found  in  the  animal  body,  namely,  i-arabinose,  which  has  been  isolated 
from  the  urine  in  cases  of  pentosuria,  and  1-xylose  (or  d-ribose,  Levene),  which  occurs 
built  up  into  the  nucleic  acid  molecule  of  the  pancreas  and  perhaps  other  organs.  The 
pentoses  can  apparently  be  utilised  by  herbivora  as  food-stuffs.  We  know  nothing  as 
to  the  part  they  play  in  the  animal  body  or  as  to  the  causation  of  the  rare  condition  of 
jientosuria.  Since,  however,  they  are  reducing  substances  and  the  presence  of  pentose 
in  urine  might  therefore  lead  to  a  suspicion  of  diabetes,  it  is  necessary  to  mention  the 
tests  by  which  the  presence  of  pentoses  may  be  detected.  The  two  following  are  the 
chief  tests  for  pentoses  : 

(1)  The  solution  supposed  to  contain  a  pentose  is  mixed  with  an  equal  volume  of 
concentrated  hydrochloric  acid.  To  the  mixture  is  added  a  small  quantity  of  solid 
orcin  and  the  whole  is  heated.  If  pentose  is  present  the  solution  becomes  at 
first  reddish-blue  and  later  bluish-green.  The  colour  can  be  extracted  on  shaking 
the  fluid  with  amyl  alcohol,  the  solution,  on  spectroscopic  examination,  showing  an 
absorption  band  between  C  and  D. 

(2)  Instead  of  adding  orcin,  we  may  add  phloroglucin  to  the  mixture  of  hydrochloric 
acid  and  pen'ose.  The  solution  on  heating  becomes  first  cherry  red  and  then  cloudy. 
On  shaking  with  amyl  alcohol  a  red  solution  is  obtained  which  shows  a  band  between 
D  and  E. 

THE  HEXOSES   AND  THEIR   DERIVATIVES 
The  most  important  of  the  carbohydrates  belong  to  this  class  and  are 
either  hexoses  or  formed  by  a  combination  of  two  or  more  hexose  molecules. 
They  are  divided  into  three  main  groups  : 

(1)  MonosaccJiarides,  with  the  fornnda  CgHjaOe,  examples  of  which  are 
glucose,  fructose,  &c. 

(2)  Disaccharides,  which  are  derived  from  two  molecules  of  a  monosac- 
charide with  the  elimination  of  a  molecule  of  water,  as  follows  : 

^CgHiaOg  —  Hp  =  CiaHgaOii- 
(Examples,  maltose  and  cane  sugar.) 


62  PHYSIOLOGY 

(3)  Polysaccharides,  composed  of  three  or  more  molecules  of  a  mono- 
saccharide. The  number  of  molecules  which  are  associated  in  the  com- 
pounds of  this  group  may  be  very  large.  We  can  regard  their  general  forma- 
tion as  represented  by  the  following  equation  : 

nCeHi^Oe  -  nH^O  =  {C,B.r,0,),. 

(Examples,  starch,  dextrin,  &c.) 

THE  MONOSACCHARIDES 

Only  four  hexoses  out  of  the  large  number  which  have  been  synthetised 
are  assimilable  by  the  animal  body.  These  are  mannose,  glucose,  galactose, 
and  fructose,  the  three  former  being  aldoses,  while  the  last  is  a  ketose.  All 
of  them  are  derivatives  of  d-glucose.  They  may  be  synthetised  in  several 
ways.  The  most  interesting,  because  it  probably  represents  the  mechanism 
of  synthesis  of  hexoses  in  plants,  is  the  formation  from  formaldehyde.  In 
alkahne  solutions  formaldehyde  polymerises  with  the  formation  of  a  mixture 
of  hexoses  known  as  acrose.  From  this  mixture  a-acrose  can  be  isolated  by 
the  formation  of  its  osazone  and  the  reconversion  of  this  osazone  into  sugar. 
It  is  found  to  be  identical  with  i- fructose.  If  a  solution  of  this  i-fructose  be 
treated  with  yeast,  d-fructose  is  fermented,  leaving  1-fructose  behind.  For 
the  preparation  of  d-fructose  it  is  necessary  to  convert  the  inactive  sugar  into 
the  corresponding  acid,  mannonic  acid.  This  with  strychnine  or  morphia 
forms  salts  which  can  be  separated  into  the  d-  and  1-  groups  by  fractional 
crystallisation.  From  the  d-  modification  d-mannose  can  be  obtained,  and 
this  by  conversion  into  the  osazone  and  reconversion  into  a  sugar  gives 
d-fructose. 

All  the  monosaccharides,  however  many  carbon  atoms  they  contain, 
present  certain  general  reactions  determined  by  their  chemical  composition. 

(o)  Like  ordinary  aldehydes  and  ketones,  the  sugars  act  as  strongly 
reducing  substances,  and,  hke  aldehydes,  reduce  ammoniacal  solution  of 
silver  to  metalhc  silver,  and  many  of  the  higher  oxides  of  metals  to  lower 
oxides.  On  this  behaviour  is  founded  the  commonest  of  all  the  tests  for  the 
presence  of  reducing  sugar- — Trommer's  test. 

(6)  On  oxidising  a  monosaccharide  the  COH  group  becomes  converted 
to  COOH.     Thus,  glucose  on  oxidation  gives  gluconic  acid  : 

COH(CHOH)4CH20H  -f  0  =  C00H(CH0H)4CH20H. 

On  further  oxidation  the  end  group  CHgOH  also  is  affected,  and  we  obtain 
a  dibasic  acid.     Thus  glucose  gives  saccharic  acid. 

(c)  By  means  of  nascent  hydrogen  the  monosaccharides  can  be  reduced 
to  the  corresponding  polyatomic  alcohol.  Thus  the  three  hexoses,  glucose, 
fructose,  and  galactose,  give  the  corresponding  three  alcohols,  sorbite,  man- 
nite,  and  dulcite  C6H14O6. 

{d)  Another  important  general  reaction  of  the  monosaccharides  depending 
on  the  COH  or  the  CO  group  is  the  reaction  with  phenyl  hydrazine.  On 
warming  a  solution  of  sugar  with  a  solution  of  phenyl  hydrazine  in  acetic 


THE  CARBOHYDRATES  63 

acid,  the  following  reactions  take  place.  The  first  reaction  results  in  the 
production  of  a  hydrazone  : 

CH20H(CHOH)3CHOHCHO  +  H^N.NH.CeH^  = 
CH20H(CHOH)3CHOH.CH  :  N.NH.CeHs  +  H.p. 

The  hydrazone  then  reacts  with  another  molecule  of  phenyl  hydrazine  with 
the  production  of  an  osazone  : 

CH2(OH)(CHOH)3CHOH.CH  :  N.NH.CeH^  +  H^N-NHCeHs  = 
CH20H(CH0H)3C.CHN.NH.CeH5 

II 

N.NH.CcH^  +  H2O  +  H2. 

The  hydrogen  formed  in  this  reaction  acts  upon  a  second  molecule  of  phenyl 
hydrazine,  splitting  it  into  aniline  and  ammonia.  On  this  account  it  is 
always  necessary  to  have  an  excess  of  phenyl  hydrazine  in  the  operation. 

The  osazones  form  well-defined  crystalUne  products  which  are  generally 
yellowish  in  colour  and  difier  in  their  melting-point  and  in  their  crystalline 
form.  They  are  therefore  of  extreme  value  in  the  separation  and  identifica- 
tion of  different  carbohydrates.  They  can  be  also  used  for  the  artificial 
preparation  of  certain  sugars.  Under  the  influence  of  acetic  acid  and  zinc 
dust  they  form  osamines,  which  on  treatment  with  nitrous  acid  are  recon- 
verted into  the  corresponding  sugar,  generally  a  ketose. 

GLUCOSE,  DEXTROSE  or  GRAPE  SUGAR,  is  the  chief  constituent  of  the 
sugar  of  fruits,  especially  of  grapes.  It  occurs  in  the  body  as  the  end- 
product  of  the  digestion  of  starch.  When  pure  it  forms  white  crystals  which 
melt  at  100°  C,  and  lose  the  one  molecule  of  water  of  crystalHsation  at  110° 
C.  It  is  easily  soluble  in  water,  and  the  solution  shows  bi-rotatiou.  Its  final 
specific  rotatory  power  at  20°  C.  is  52-74. 

TESTS  FOR  GLUCOSE.  Trommer's  test  depends  on  the  power  possessed  in 
comnion  with  the  other  sugars  of  reducing  cupric  hydrate  to  cuprous  oxide.  The 
sugar  solution  is  made  alkaline  with  caustic  potash  or  soda,  and  a  few  drops  of  coppex 
sulphate  solution  added.  On  heating  the  blue  solution  thus  obtained  to  boiling,  it 
turns  yellow,  and  a  yellowish-red  precipitate  of  cuprous  hydrate  is  prodiiccd.  This 
test  is  generally  performed  with  Fehling's  solution,  which  consists  of  an  alkaline  solution 
of  cupric  hydrate  in  Rochelle  salt.  The  proportions  in  making  the  solutions  are  so 
arranged  that  10  c.c.  of  Fehling's  solution  are  completely  reduced  by  -05  gramme  glucose. 
This  reaction  is  made  use  of  for  the  quantitative  determination  of  glucose  in  solution. 
The  determination  may  be  carried  out  either  volumetrically,  as  in  Fehling's  or  Pa\'y"s 
method,  or  gravimetrically,  as  in  Aliihn's  method. 

Moore's  Test.  A  solution  of  glucose  treated  with  a  little  sti'ong  caustic  potash 
or  soda  and  warmed,  becomes  first  yellow  and  then  gradually  dark  brown,  and  gives 
off  a  smell  of  caramel. 

With  ordinary  yeast,  glucose  solution-s  ferment  readily,  giving  off  COo,  and  form 
alcohol  with  small  traces  of  amyl  alcohol,  glycerin,  and  succinic  acid. 

With  phenyl  hydrazine  glucose  gives  well-marked  needles  of  glucosazone.  These 
are  precipitated  when  the  liquid  is  still  hot,  the  precipitate  being  increased  as  the 
liquid  cools.  The  crystals  form  bundles  of  fine  yellow  needles  which  are  almost  in- 
soluble in  water,  but  are  soluble  in  boiling  alcohol.  When  purified  by  recrystallisation 
they  melt  at  204-205°  C. 

On  treating  a  watery  solution  of  glucose  with  benzoyl  cJiloride  and  caustic  soda 


64  PHYSIOLOGY 

and  shaking  till  the  smell  of  benzoyl  chloride  has  disappeared,  an  insoluble  precipitate 
is  produced  of  the  benzoic  ester  of  glucose.  This  method  has  been  often  used  for 
isolating  glucose  from  fluids  in  which  it  occurs  in  minute  quantities. 

Molisch's  Test.  On  treating  0-5  c.c.  of  dilute  glucose  solution  with  one  drop  of  a 
10  per  cent,  alcoholic  solution  of  a-naphthol,  and  then  jDouring  1  c.c.  of  concentrated 
sulphuric  acid  gradually  down  the  side  of  the  tube,  a  purple  ring  is  produced  at  the 
junction  of  the  two  fluids,  which  on  shaking  spreads  over  the  whole  fluid.  This  reaction 
depends  on  the  formation  of  furfurol  from  the  glucose. 

In  order  to  identify  glucose  in  a  normal  fluid,  the  following  tests  may  be  applied, 
after  removing  any  protein  which  may  be  present : 

(1)  Reduction  of  cupric  hydrate  or  Fehling's  solution. 

(2)  Estimation  of  reducing  power  of  solution. 

(3)  Estimation  of  rotatory  power  of  solution  on  polarised  light. 

(4)  Formation  ©f  osazone  crystals  with  phenyl  hydrazine.  These  crystals  must 
come  down  while  the  fluid  is  still  hot.  They  must  be  purified  and  their  melting-point 
taken.  A  determination  by  combustion  of  their  nitrogen  content  will  give  direct 
information  whether  the  sugar  is  a  monosaccharide  or  disaccharide. 

(5)  The  solution  is  made  acid  and  boiled  for  some  time.  It  is  then  made  up  to  its 
former  volume  and  its  reducing  power  and  efliect  on  polarised  light  once  more  taken. 
In  the  case  of  a  disaccharide,  which  would  be  converted  into  monosaccharide  by  boiling 
in  acid  solution,  these  two  readings  would  be  altered,  whereas  neither  the  rotatory 
power  nor  the  reducing  power  of  glucose  would  undergo  any  change. 

(6)  Fermentation  with  ordinary  yeast. 

A  positive  result  would  exclude  glycuronic  acid. 

D-FRUCTOSE,  or  LEVULOSE,  occurs  mixed  with  dextrose  in  honey 
and  in  fruit  sugar.  It  is  also,  with  glucose,  formed  by  the  digestion  or  inver- 
sion of  cane  sugar.  It  is  crystallisable  with  difficulty.  Its  watery  solution 
is  Isevo-rotatory,  and  reduces  Fehling's  solution  somewhat  less  strongly  than 
glucose,  its  reducing  power  being  92,  if  we  take  that  of  glucose  as  100.  It 
ferments  readily  with  yeast ;  with  phenyl  hydrazine  it  gives  the  same  osazone 
as  is  formed  from  glucose. 

GALACTOSE  is  formed  by  the  digestion  or  hydrolysis  of  milk  sugar  or 
lactose.  It  is  also  obtained  on  hydrolysing  cerebrin,  a  constituent  of  the 
brain,  with  dilute  mineral  acids,  and  by  the  hydrolysis  of  certain  vegetable 
gums.  It  is  much  less  soluble  in  water  than  glucose.  It  is  dextro-rotatory 
and  shows  marked  bi-rotation.  With  ordinary  yeast  it  ferments  but  ex- 
tremely slowly.  One  species  of  yeast  is  known,  namely,  saccharomyces  apicu- 
latus,  which,  while  fermenting  d-fructose  and  glucose,  has  no  effect  on  galac- 
tose. This  yeast  can  therefore  be  used  to  isolate  galactose  from  a  mixture  of 
the  monosaccharides.  It  reduces  Fehling's  solution,  its  reducing  power 
being  somewhat  less  than  that  of  glucose.  Yeasts  can  be  trained  to  ferment 
galactose. 

MANNOSE.  Mannose,  though  an  assimilable  sugar,  is  of  such  rare  occurrence  in 
our  food-stuffs  that  it  plays  practically  no  part  in  animal  physiology.  It  is  dextro- 
rotatory, reduces  Fehling's  solution,  ferments  easily  with  ordinary  yeast,  and  gives 
■m  osazone  which  is  identical  with  that  derived  from  glucose. 


DERIVATIVES  OF  THE  HEXOSES 

Two  'derivatives  of  glucose  are  of  considerable  physiological  importance, 
namely,  glucosamine  and  glycuronic  acid. 


THE  CARBOHYDRATES  65 

Glucosamine,  CgHiaNOs,  has  the  structural  formula  : 

CH2OH 

(GH.0H)3 

CH.NH2 

CHO 

It  is  obtained  from  chitin,  which  forms  the  exoskeleton  of  large  numbers 
of  the  invertebrata,  by  boiling  this  with  concentrated  hydrochloric  acid.  It 
is  stated  to  have  been  obtained  as  a  decomposition  product  of  certain  proteins 
and  their  derivatives,  such  as  the  mucins.  It  is  of  special  interest  as  affording 
an  intermediate  product  between  the  carbohydrates  and  the  oxy- amino 
acids  which  can  be  obtained  by  the  disintegration  of  proteins.  In  solution 
it  is  dextro-rotatory,  reduces  FehHng's  solution,  and  gives  an  osazone 
resembling  that  derived  from  glucose. 

GLYCURONIC  ACID,  CgHioO,,  may  be  regarded  as  one  of  the  first  results 
of  oxidation  of  the  glucose  molecule.  The  group  which  has  undergone 
oxidation  is  not  the  readily  oxidisable  CHO  group,  but  the  CHgOH  group  at 
the  other  end  of  the  molecule.     The  formula  of  this  acid  is  therefore  : 

COOH 

t  I 
(CH.OH)^ 

CHO. 

In  the  free  state  it  does  not  occur  in  the  animal  body.  It  is  constantly  found 
in  the  urine  after  administration  of  certain  drugs  such  as  phenol,  camphor,  or 
chloral,  and  then  occurs  as  a  conjugated  acid  with  these  substances.  These 
conjugated  acids  are  Isevo-rotatory,  though  the  free  acid  is  dextro-rotatory. 
In  the  free  state  it  reduces  FehHng's  solution  and  gives  an  osazone  which  is  not 
sufficiently  characteristic  to  distinguish  from  glucosazone.  It  does  not 
undergo  fermentation  with  yeast.  This  test  is  therefore  the  best  means  of 
distinguishing  the  acid  in  urine  from  glucose. 


THE  FORMATION  OF   GLUCOSIDES 

Tlio  graphic  forinuhi?  given  on  p.  Gl  do  not  explain  all  the  possible  modes  of  arrange- 
ment of  the  groups  of  the  sugar  molecules.  Many  of  these  sugars,  when  dissolved  in 
water,  present  the  phenomenon  known  as  multi-rotation.  K  their  rotatory  power 
be  taken  immediately  after  solution,  it  is  found  to  be  greater  or  less  than  the  rotatory 
power  taken  some  hours  or  days  later.  Glucose,  for  instance,  immediately  after  solu- 
tion, has  a  high  specific  rotatory  power,  which  diminishes  rapidly  if  the  solution  be 
boiled,  and  more  slowly  if  it  be  allowed  to  stand.  Finally,  the  specific  rotatory  ix)wer 
becomes  constant  at  +  52-5°  D.  This  change  in  rotatory  power  seems  to  be  associated 
with  a  change  in  the  arrangement  of  the  groups,  the  aldose,  for  example,  assuming, 
by  the  shifting  of  a  mobile  oxj-gcn  atom,  what  is  known  as  a  lactone  arrangement. 

o 


66 


PHYSIOLOGY 


Thus  glucose  COH(CHOH).CHOH.CHOH.CHoOH  becjmes 
CHOH .  (CHOH)o .  CH .  CHOH .  CHoOH 


0 

This  change  in  the  arrangement  of  the  molecule  renders  a  further  stereoisomer  it  m 
possible,  owing  to  the  fact  that  now  the  end  group  which  was  formerly  COH  becomes 

H 

I 
0— (>-0H 


so  that  now  there  are  five  instead  of  four  asymmetric  ca  -bon  atoms.  The  two  isomers 
of  glucose,  which  are  thus  rendered  possible,  are  represented  by  the  following  structural 
formulse  :     H— C— OH  OH— C— H 


HCOH 


HCOH 


CH2OH  CH2OH 

In  these  molecules  the  OH  attached  to  the  end  group  can  be  replaced  by  other  radicals, 
including  other  sugar  molecules.  In  this  way  we  get  the  formation  of  glucosides.  Thus,  if 
glucose  be  dissolved  in  methyl  alcohol  and  be  treated  with  hydrochloric  acid,  we  obtain 
a  and  ft  methyl  glucosides,  the  formulae  of  which  would  b3  represented  as  follows  : 

H— C— OCH3  CH3O— Cc-H 


HCOH 


HCOH 


CH2OH  CH2OH 

Instead  of  methyl  we  might  insert  other  groups,  and  even  other  hexose  groujjs,  such 
a?  glucose  or  galactose,  obtaining  the, two  sugars  maltose  and  lactose,  which  may  thus 
b3  regarded  as  glucosides — maltose  as  the  a  glucoside  of  glucose,  lactose  as  the  ft  galac- 
toside  of  glucose.  The  mode  of  combination  of  the  two  hexose  groups  to  form  these 
disaccharides  may  be  represented  as  follows  : 

H       H    OH     H     H  ^ 

CH2OH  — C—  C  —  C— C  —  C  glucose  rest 
OH         \  HOH 


^  maltose. 


HO       H  HO    HO 
OHC  —  C^C  —  C  —  C-^  CH,  glucose  rest 
H   OH     H      H 


THE  CARBOHYDRATES 

H 
CHoOH  —  C 

/OH      h\ 
—  C  —  C  —  C  —  C    galactose  r3st 

OH 

H      H  OH 

0 

HO 

H  HO   HO 

OHC  — C 

—  C  —  C  —  C  —  CHo  glucose  rest 

H 

OH     H      H 

67 


lactose 


A  very  large  number  of  glucosides  occur  as  plant  products.     Among  these  we  may 
mention  amygdalin,  salicin,  phloridzin.  indican,  &c. 

THE   DISACCHARIDES 

The  disaccharides  are  formed  by  the  union  of  two  molecules  of  mono- 
saccharides with  the  elimination  of  one  molecule  of  water,  and  can  be  re- 
garded, according  to  the  manner  in  which  the  molecules  are  combined,  as 
glucosides,  galactosides,  &c.  On  hydrolysis,  e.g.  on  heating  with  acids,  they 
take  up  one  molecule  of  water  and  are  spUt  up  into  the  corresponding  mono- 
saccharides. Thus,  cane  sugar  gives  equal  parts  of  glucose  and  fructose, 
maltose  gives  equal  parts  of  glucose  and  glucose,  while  milk  sugar  or  lactose 
gives  equal  parts  of  glucose  and  galactose. 

CANE  SUGAR,  sometimes  known  as  saccharose,  is  widely  distributed 
throughout  the  vegetable  kingdom,  and  forms  an  important  article  of  diet. 
It  has  no  reducing  power  on  Fehhng's  solution.  It  is  strongly  dextro-rota- 
tory and  has  a  specific  rotatory  power  of  +  66-5°.  On  hydrolysis  it  is 
converted  into  equal  molecules  of  glucose  and  fructose.  Owing  to  the  fact 
that  fructose  rotates  polarised  light  more  strongly  to  the  left  than  glucose 
does  to  the  right,  the  mixture  of  the  two  monosaccharides  so  obtained  is- 
laevo-rotatory.  On  this  account  the  change  from  free  cane  sugar  to  the 
mixture  of  monosaccharides  is  known  as  inversion,  and  the  mixture  is  often 
spoken  of  as  '  invert  sugar.'  The  term  '  inversion  '  has  since  been  loosely 
applied  to  the  process  of  hydrolysis  itself,  so  that  we  often  speak  of  the 
inversion  of  maltose  or  of  lactose,  meaning  thereby  the  hydrolysis  of  these 
sugars  with  the  production  of  their  constituent  monosaccharides.  With 
yeast,  cane  sugar  first  undergoes  inversion  by  a  special  ferment  present  in  the 
yeast  {invertase),  and  the  mixture  of  fructose  and  glucose  is  then  fermented. 

MALTOSE  is  formed  during  the  hydrolysis  of  starch  by  acids  or  by 
digestive  ferments,  and  is  also  the  chief  sugar  in  germinating  barley  or  malt. 
It  is  strongly  dextro-rotatory,  ferments  easily  with  yeast,  and  reduces 
Fehling's  solution  ;  its  reducing  power  is  about  70  per  cent,  of  that  of 
glucose.  With  phenyl  hydrazine  it  gives  phenyl  maltosazone,  which  forms 
definite  yellow  crystals  with  a  melting-point  of  206°  C. 

MILK  SUGAR  or  LACTOSE  is  found  only  as  a  constituent  of  milk. 
It  forms  colourless  rod-like  crystals,  which  are  much  less  soluble  in  water 
than  are  the  two  other  disaccharides.  On  account  of  this  solubility  it  is  much 
less  sweet  than  either  cane  sugar  or  maltose.     It  is  dextro-rotatory  and 


68  PHYSIOLOGY 

shows  bi-rotation.  It  is  not  fermented  by  ordinary  yeast.  Before  fermen- 
tation can  occur  the  lactose  must  be  spht  by  the  agency  of  acids  or  by  a 
ferment,  lactase,  which  occurs  in  the  animal  body  and  in  certain  moulds,  into 
the  monosaccharides  glucose  and  galactose.  Lactose  reduces  Fehling's 
solution  and  gives  with  phenyl  hydra2dne  lactosazone,  which  is  easily  soluble 
in  hot  water  and  therefore  does  not  come  down  mitil  the  fluid  is  cold. 

THE  POLYSACCHARIDES 

These  play  an  important  part  throughout  the  whole  vegetable  kingdom, 
where  all  the  supporting  tissues  of  the  plants,  their  protective  substances, 
and  many  of  their  reserve  materials  consist  of  members  of  this  group.  In 
the  animal  body,  where  the  supporting  tissues  are  composed  chiefly  of  deriva- 
tives of  proteins,  the  sole  significance  of  polysaccharides  hes  in  their  value  as 
food-stuffs.  In  plants,  anhydrides  both  of  hexoses  and  pentoses  occur  in 
bewildering  variety.  Here,  however,  we  may  confine  our  attention  to  those 
members  of  the  group  of  polysaccharides  which  are  important  as  food-stufls. 

STARCH  (CgHioOg)  is  present  in  large  quantities  in  nearly  afl  vegetable 
foods,  and  is  an  important  constituent  of  the  cereals,  from  which  flour  and 
bread  are  derived,  as  well  as  of  tubers,  such  as  the  potato.  In  the  plant  cells 
it  occurs  as  concentrically  striated  grains  within  minute  protoplasmic 
structures — ^the  amyloplasts,  the  office  of  which  it  is  to  manufacture  starch 
from  the  glucose  present  in  the  cell  sap.  When  freed,  by  breaking  up  the 
cells  and  washing  with  water,  it  forms  a  white  powder  consisting  of  micro- 
scopic grains,  each  of  which  presents  the  characteristic  concentric  striation. 
It  is  insoluble  in  cold  water.  In  hot  water  the  grains  swell  up  and  burst, 
forming  a  thick  paste,  which  sets  to  a  jelly  on  coohng.  This  semi-solution, 
as  well  as  the  original  starch-grains,  gives  an  intense  blue  colour  on  the 
addition  of  iodine.  On  treating  starch  with  cold  alkahes  or  cold  dilute  acid, 
it  is  converted  into  a  soluble  modification,  the  so-called  soluble  starch  or 
amylodextrin,  which  also  gives  a  blue  colour  with  iodine.  This  modification 
is  also  produced  as  the  first  stage  of  the  action  of  diastatic  ferments  upon 
starch.  On  boihng  with  dilute  acids,  starch  is  converted  first  into  a  mixture 
of  dextrins,  then  into  maltose,  and  finally  into  glucose.  On  acting  upon  starch 
with  various  ferments,  such  as  the  diastase  which  may  be  extracted  from 
malt  or  germinating  barley,  or  with  the  amylase  occurring  in  sahva  or  pan- 
creatic juice,  it  undergoes  hydrolysis,  the  final  result  of  the  action  being  a 
mixture  of  four  parts  of  maltose  to  one  part  of  dextrin.  As  to  the  inter- 
mediate stages  in  this  reaction  opinions  are  still  divided.  The  first  product 
is  soluble  starch,  amylodextrin,  giving  a  blue  colour  with  iodine.  This 
breaks  up  into  a  reducing  sugar,  and  another  dextrin,  erythrodextrin,  which 
gives  a  red  colour  with  iodine,  and  this  dextrin,  on  further  hydrolysis, 
yields  reducing  sugar  and  achroodextrin,  which  is  not  coloured  by  the 
addition  of  iodine.  Thus  there  are  a  series  of  successive  hydrolytic  decom- 
positions of  the  molecule,  each  resulting  in  the  splitting  off  of  a  molecule  of 
sugar  and  the  production  of  a  lower  dextrin. 

The  DEXTRINS  are  ill-defined  bodies  which  are  difiicult  to  separate. 


THE  CARBOHYDRATES  69 

They  are  amorphous  white  powders,  easily  soluble  in  water,  forming  solutions 
which,  when  concentrated,  are  thick  and  adhesive.  They  are  insoluble  in 
alcohol  and  ether.  With  cupric  hydrate  and  caustic  alkah  they  form  blue 
solutions,  which  reduce  shghtly  on  boiUng.  They  are  not  precipitated  by 
saturation  with  ammonium  sulphate.  On  boiUng  with  dilute  acids,  they  are 
converted  entirely  into  glucose. 

The  changes  undergone  by  starch  during  its  hydrolysis  by  means  of  diastase  have 
been  used  by  Brown  and  his  co-workers  as  a  method  of  arriving  at  some  idea  of  the 
size  and  structm'e  of  the  starch  molecule.  Proceeding  from  the  discovery  that  the 
end-products  of  this  reaction  consisted  of  81  per  cent,  maltose  and  19  per  cent,  dextrin, 
they  concluded  that  starch  must  consist  of  five  dextrin-like  groups,  four  of  which  are 
arranged  symmetrically  round  the  fifth.     At  each  stage  one  of  these  groups  is  split  off  and 

hydrolysed    to  form   malto-dextrin :  - L^i  ^u  ""/->  "\   \    ^^^   molecule   of   water   being 

■^  "^  l(Cl2H2oOio)2J 

taken  up.  The  malto-dextrin  group  is  then  changed  into  maltose  by  the  further 
assimilation  of  two  molecules  of  water.  The  central  dextrin-like  group  is  attacked 
with  great  difficulty  by  the  ferment,  and  therefore  remains  at  the  end  of  the  reaction  as 
achroodextrin.  The  malto-dextrin,  the  penultimate  stage  in  the  action  of  diastase, 
can  be  regarded  as  formed  by  the  condensation  of  three  molecules  of  maltose  attached 
by  the  oxygen  of  two  CHO  groups,  so  that  one  CHO  group  remains  free  and  determines 
the  reducing  power  of  the  malto-dextrin  molecule.  Its  formula  may  therefore  be  repre- 
sented as  follows  : 

K 
/C12H20O9 

the  sign,-'    being  used  to  denote  the  open  terminal  CHO  group. 

They  further  found  that  the  stable  dextrin  remaim'ng  at  the  end  of  the  diastatic 
hydrolysis  of  starch  probably  had  the  formula  of  4OC6H10O5H0O,  and  might  be  regarded 
as  a  condensation  of  forty  glucose  molecules  with  the  elimination  of  thirty-nine  molecules 
of  water.  The  starch  molecule  caimot  be  less  than  five  times  that  of  the  stable  achroo- 
dextrin. Since  the  latter  has  a  molecular  weight  of  6498,  the  molecular  weight  of  starch 
cannot  be  less  than  32,400,  and  its  empirical  formula  can  be  represented  by  : 

IOOC12H20O10,  or  (8OC10H00O10.4OC6H10O5). 

INULIN.  Another  kind  of  starch,  known  as  inuUn,  occurs  in  dahUa 
tubers.  It  is  easily  hydrolysed  by  weak  acids,  and  is  entirely  converted  into 
d-fructose,  or  levulose. 

GLYCOGEN,  or  animal  starch,  is  found  in  the  Hver,  muscles,  and  other 
tissues  of  the  body,  and  occurs  in  large  quantities  in  all  foetal  tissues.  It  is 
a  white  powder,  soluble  in  water,  forming  an  opalescent  solution.  It  is 
precipitated  from  its  solution  on  the  addition  of  alcohol  to  60  per  cent.,  or  by 
saturation  with  solid  ammonium  sulphate.  On  boiling  with  acids,  it  is 
entirely  converted  into  glucose.  It  is  affected  by  the  ferments  diastase  and 
amylase,  in  the  same  way  as  vegetable  starch,  giving  first  dextrins  and  finally 
a  mixture  of  maltose  and  dextrin.  With  iodine  it  gives  a  mahogany-red 
colour,  which,  like  the  blue  colour  produced  in  starch,  is  destroyed  by  boiling, 
to  return  again  on  coohng.  We  shall  have  occasion  to  consider  its  properties 
more  fully  when  we  are  deaUng  with  the  functions  of  the  Hver. 


70  PHYSIOLOGY 

THE  CELLULOSES.  Cellulose  (C6Hio05)^  is  a  colourless,  insoluble 
material,  or  mixture  of  materials,  which  compose  the  cell  walls  of  the  youPxger 
parts  of  plants,  and  therefore  forms  a  constituent  of  most  of  our  vegetable 
foods.  It  is  insoluble  in  water  or  dilute  acids  or  alkalies,  its  only  solvent 
being  an  ammoniacal  cupric  oxide  solution.  On  boiUng  with  strong  acids, 
it  gradually  undergoes  hydrolysis  and  yields  sugar,  the  nature  of  which 
varies  according  to  the  source  of  the  cellulose.  In  herbivorous  animals  cellu- 
lose undergoes  digestive  changes  and  forms  an  important  constituent  of  their 
food.  The  solution  of  the  cellulose  in  this  case  is  effected  by  the  agency,  not 
of  ferments  secreted  by  the  wall  of  the  gut,  but  of  micro-organisms  which 
swarm  in  the  paunch  of  ruminants  and  in  the  caecum  of  other  herbivora.  In 
some  cases  the  effective  agent  is  a  cytase  present  in  the  vegetable  cells 
themselves.  Since  this  ferment  is  destroyed  by  boiUng,  cooked  hay  is  much 
less  digestible  than  in  the  raw  condition.  In  certain  invertebrata  it  seems 
probable  that  a  true  cellulose- digesting  ferment,  or  cytase,  is  secreted  by  the 
walls  of  the  ahmentary  canal.  In  man  cellulose  undergoes  practically  no 
change  in  digestion,  and  serves  merely  by  its  bulk  to  promote  peristalsis  and 
the  normal  evacuation  of  the  bowels.  A  further  consideration  of  its  chemical 
properties,  as  well  as  of  the  closely  allied  vegetable  materials,  gums,  pectins, 
mucilages,  derived  for  the  most  part  from  the  condensation  of  pentose 
molecules,  may  be  dispensed  with  here. 


SECTION  V 
THE    PROTEINS 

As  sources  of  energy  to  the  organism  all  three  classes  of  food-stuffs  are 
valuable  in  proportion  to  their  heat  equivalents,  and  it  is  often  a  matter  of 
indifference  whether  the  main  bulk  of  the  energy  required  is  supphed  at 
the  expense  of  fat  or  at  the  expense  of  carbohydrate.  The  proteins,  however, 
form  the  most  important  constituent  of  hving  protoplasm.  On  this  account 
protein  must  always  be  present  in  the  food  to  supply  the  material  necessary 
for  building  up  new  protoplasm  in  the  growing  animal  and  for  replacing 
the  waste  of  hving  material  which  is  taking  place  in  the  discharge  of  its 
normal  functions.  Regarding  the  complexity  of  reaction  presented  by  hving 
protoplasm  as  determined  in  the  first  instance  by  the  chemical  and  physical 
complexity  of  this  material  itseK,  we  should  expect  to  find  that  the  proteins 
forming  its  main  constituents,  would  themselves  partake  of  some  of  this 
quahty.  The  carbohydrates  and  fats,  although  in  many  cases  made  up  of 
huge  molecules,  are  nevei-theless  built  up  on  a  very  simple  type.  Starch, 
for  instance,  with  a  molecular  weight  of  over  30,000,  is  formed  simply  by  the 
polymerisation  of  glucose  molecules.  The  ordinary  fats,  stearin  and 
palmitin,  consist  of  fatty  acids  with  long  straight  chains  of  CHg  groups 
combined  with  the  glyceryl  radical.  Their  molecular  weight  is  very  large, 
but  their  molecules  are  simple  in  structure.  When,  however,  we  break  up  a 
protein  molecule  we  meet  with  a  great  number  of  subsidiary  groups,  the 
presence  of  which  is  essential  to  the  making  of  a  nutritive  protein. 

Owing  to  this  complexity  of  structure  it  is  not  easy  to  give  a  simple 
definition  in  chemical  terms  of  what  we  mean  by  the  term  '  protein.'  It  is 
necessary  rather  to  describe  certain  of  the  quahties  presented  by  this  group, 
the  possession  of  which  we  regard  as  essential  to  the  conception  of  a  protein. 

Elementary  Composition.  All  proteins  contain  oxygen,  hydrogen,  nitro- 
gen, carbon,  and  sidphur.  The  proportion  of  these  elements  in  the  various 
proteins  may  be  represented  as  follows  : 

C    50-6-54-5  per  cent. 
H     6-5-  7-3     „     „ 
N  15-0-17-6     „     „ 
S     0-3- 2-2     „     „ 
0  21  •5-23-5    „     „ 

Nearly  all  the  proteins  contain  a  small  trace  of  phosphorus  varying  from 

71 


72  PHYSIOLOGY 

0-4  to  0*8  per  cent.  It  is  doubtful,  however,  how  far  this  phosphorus  forms 
an  integral  part  of  the  protein  molecule. 

Physical  Characters.  The  proteins  are  amorphous  indiifusible  substances 
belonging  to  the  class  of  bodies  known  as  colloids.  Most  of  them  are  soluble 
either  in  water,  weak  salt  solutions,  or  in  dilute  acids  or  alkalies.  They  are 
inert  bodies  and  tasteless.  Although  they  form  compounds  with  various 
metalhc  salts,  acids,  or  alkahes,  these  compounds  are  but  ill  defined,  and  the 
relative  proportions  of  the  ingredients  vary  according  to  the  conditions  under 
which  the  compound  was  formed.  As  is  the  case  with  most  colloids  when 
in  solution  or  pseudo-solution,  they  can  be  brought  into  an  insoluble  form 
by  various  simple  agencies,  such  as  shaking,  change  of  temperature,  alteration 
of  reaction,  or  addition  of  neutral  salts.  Coagulation  by  heat  forms  a  dis- 
tinguishing feature  of  a  number  of  members  of  this  class,  which  are  therefore 
spoken  of  as  '  coagulable  proteins.'  For  instance,  white  of  egg  is  a  solution 
of  different  proteins.  On  diluting  it  with  weak  salt  solution  no  precipitation 
takes  place.  If,  however,  the  solution  be  heated  to  about  80°  C.  a  precipitate 
of  coagulated  protein  is  formed.  If  a  strong  solution  be  boiled  the  whole 
fluid  sets  to  a  sohd  white  mass  (hydrogel).  This  change  is  irreversible,  i.e.  it 
is  not  possible  by  lowering  the  temperature  to  bring  the  white  of  egg  again 
into  solution,  and  many  properties  of  the  protein  have  been  changed  in  the 
act  of  coagulation.  With  certain  proteins  and  their  allies  the  coagulation  on 
change  of  temperature  is  a  reversible  process.  Thus  an  alkaline  solution 
of  caseinogen,  the  chief  protein  of  milk,  if  treated  with  a  Httle  calcium 
chloride  and  heated,  undergoes  coagulation  and  sets  into  a  jelly,  but  on  cool- 
ing the  mixture  the  coagulum  once  more  enters  into  solution.  Ordinary 
gelatin,  which  is  closely  allied  to  the  proteins,  with  water  forms  a  solid  jelly 
below  20°  C,  and  a  fluid  solution  above  this  temperature. 

If  a  protein  be  heated  in  a  current  of  air  or  oxygen  it  undergoes 
combustion.  In  all  cases  a  certain  amount  of  incombustible  material  is  left, 
consisting  of  inorganic  salts  which  were  closely  attached  to  the  protein 
molecule.  If  a  solution  of  protein  be  subjected  to  long- continued  dialysis, 
the  proportion  of  ash  may  be  diminished  very  largely,  but  in  no  case  has 
any  experimenter  succeeded  in  obtaining  a  preparation  of  protein  absolutely 
ash-free.  On  this  account  it  has  been  thought  that  the  salts  of  the  ash  must 
be  in  chemical  combination  with  the  protein ;  but  having  regard  to  the 
physical  character  of  colloidal  solutions,  which  we  shall  study  in  the  next 
chapter,  and  the  power  of  adsorption  of  substances  possessed  by  such  solu- 
tions, there  is  no  need  to  regard  these  salts  as  essential  constituents  of  the 
protein. 

Crystallisation  of  Proteins.  Although  the  indiffusibihty  of  protein  solu- 
tions differentiates  them  from  the  crystalloid  substances  such  as  sugar  or 
sodium  chloride,  under  certain  conditions  it  is  possible  to  obtain  crystals 
consisting,  largely  at  any  rate,  of  proteins.  Thus  in  the  seeds  of  certain 
plants,  e.g.  hemp  seeds,  Brazil  nut,  pumpkin  and  castor-oil  seeds,  the  so-called 
aleurone  crystals  may  be  seen  under  the  microscope  enclosed  in  the  proto- 
plasm of  the  cells.     These  crystals  consist  of  proteins  belonging  to  the  class  of 


THE  PROTEINS  73 

globulins.  By  chemical  means  they  can  be  separated  from  the  surrounding 
tissues  and,  after  washing,  dissolved  in  a  solution  of  magnesia.  Drechsel 
showed  that  on  dialysing  such  a  solution  against  alcohol,  the  fluid  undergoes 
gradual  concentration,  and  crystalline  granules  of  the  magnesia  compound 
of  the  protein  separate  out.  These  crystals  contain  1 4  p.c.  MgO.  A  better 
method  of  obtaining  such  crystals  has  been  devised  by  Osborne.  The 
ground  seeds  are  extracted  with  10  per  cent,  sodium  chloride  solution,  and 
filtered.  The  filtrate  is  diluted  with  water  heated  to  50°  or  60°  C.  until  a 
shght  turbidity  forms.  After  warming  the  diluted  solution  until  this 
turbidity  disappears,  and  then  allowing  it  to  cool  slowly,  the  protein  separates 
in  well-developed  crystals.  It  is  possible  also  to  obtain  crystals  of  animal 
proteins.  Haemoglobin,  the  oxygen- carrying  protein  of  the  red  blood 
corpuscles,  can  be  made  to  crystalhse  with  extreme  ease.  With  some 
animals,  such  as  the  rat,  it  is  only  necessary  to  bring  the  haemoglobin  into 
solution,  by  the  addition  of  a  httle  distilled  water  and  ether  to  the  blood,  to 
cause  the  crystalUsation  of  the  hberated  haemoglobin. 

Egg  albumin  and  serum  albumin  may  also  be  crystalhsed  with  ease  by 
a  method  devised  by  Hofmeister  and  improved  by  Hopkins.  If,  for  instance, 
we  wish  to  crystalhse  egg  albumin,  white  of  eggs  is  treated  with  an  equal 
bulk  of  saturated  solution  of  ammonium  sulphate  in  order  to  precipitate 
the  globulin.  It  is  then  filtered,  and  the  filtrate  is  treated  with 
saturated  ammonium  solution  until  a  shght  permanent  precipitate 
is  produced.  This  precipitate  is  then  just  redissolved  by  the  cautious 
addition  of  water,  and  dilute  acetic  acid  (10  per  cent.)  is  added  drop  by  drop 
until  a  shght  precipitate  is  produced.  The  flask  is  now  corked  and  allowed 
to  stand  for  twenty-four  hours,  when  the  precipitate,  which  will  have  in- 
creased in  quantity,  will  be  found  to  consist  entirely  of  acicular  crystals.  A 
similar  method  may  be  used  for  serum  albumin.  In  each  case  the  crystals 
contain  a  considerable  proportion  of  ammonium  sulphate.  This  may  be 
replaced  by  sodium  chloride  by  washing  the  crystals  with  a  saturated  solution 
of  this  salt.  By  absolute  alcohol  the  crystals  may  be  coagulated  and  may  be 
then  washed  practically  free  from  salt,  but  it  is  not  possible  to  obtain  crystals 
of  coagulable  protein  free  from  the  presence  of  some  salt. 

Although  by  repeated  crystalhsation  of  egg  albumin  a  product  may  be 
obtained  which  is  absolutely  constant  in  both  its  physical  and  chemical 
characters,  we  cannot  ascribe  to  crystalhsation  the  same  importance  in 
securing  purity  and  homogeneity  of  the  substance  that  we  can  when  we  are 
dealing  with  inorganic  salts.  This  is  due  to  the  fact  that  these  crystals  take 
up  other  colloids  with  great  ease.  When  haemoglobin,  for  instance,  is  crystal- 
hsed from  blood,  the  first  crop  of  crystals,  although  thoroughly  washed  from 
their  mother  liquor,  always  contain  a  considerable  proportion  of  serum 
albumin.  Indeed,  the  presence  of  colloidal  material  seems  to  render  the  pro- 
duction of  the  so-called  mixed  crystals  much  more  easy.  Thus  Schultz  has 
shown  that  in  urine  mixed  inorganic  crystals  can  be  obtained.  Human 
urine  is  allowed  to  stand  twenty-four  to  forty-eight  hours  with  dicalcium 
phosphate  and  then  filtered.     On  allowing  the  filtrate  to  evaporate  slowly, 

3* 


74  PHYSIOLOGY 

a  crystalline  precipitate  is  produced  consisting  of  whetstone-shaped  crystals 
which  are  doubly  refracting.  On  treating  these  crystals  with  dilute  acetic 
acid  this  acid  extracts  calcium  phosphate  from  the  crystals.  The  original 
shape  of  the  crystals  is,  however,  retained.  The  only  difierence  under  the 
microscope  consists  in  the  fact  that  they  have  now  lost  their  doubly  refracting 
power  on  polarised  hght.  They  consisted  of  a  mixture  of  calcium  sulphate 
and  calcium  phosphate,  from  which,  on  treatment  with  acid,  only  the  calcium 
phosphate  was  dissolved  out. 

The  Molecular  Weight  of  Proteins.  We  may  arrive  at  an  approximate  idea 
of  the  minimum  size  of  the  protein  molecule  in  various  ways,  though  in  all 
cases  om'  calculations  are  apt  to  be  vitiated  by  the  difficulty  of  obtaining  a 
preparation  which  is  homogeneous,  i.e.  chemically  pure,  and  by  the  ease 
with  which  molecules  of  the  size  which  we  must  assume  for  proteins  form 
adsorption  combinations  in  varying  proportions  with  other  substances. 
If  we  assrnne  that  each  molecule  of  the  respective  protein  contains  only  one 
atom  of  sulphur,  we  can  calculate  its  molecular  weight.  It  is  evident  that 
the  protein  which  contains  1  per  cent,  of  sulphur  will  have  a  molecular  weight 
of  3200.  In  this  way  the  following  molecular  weights  have  been  arrived  at 
(Abderhalden)  : 


Sulphur  per  cent. 

Molecular  weight, 

Edestin 

0-87 

3680 

Oxyhsemoglobin     . 

. 

0-43 

7440 

(horse) 

Serum  albumin 

. 

1-89 

1700 

(horse) 

Egg  albumin 

. 

1-30 

2460 

Globulin 

, 

1-38 

2320 

The  greater  part  at  any  rate  of  the  sulphur  in  the  protein  molecule  occurs 
as  a  constituent  of  a  substance,  cystine,  each  molecule  of  which  contains  two 
atoms  of  sulphur.  Each  molecule  of  protein  must  also  contain  two  atoms  of 
sulphur,  and  we  must  regard  double  the  molecular  weight  given,  in  this  Table 
as  the  minimum  molecular  weights  of  these  various  proteins.  Some  idea  of 
the  molecular  complexity  represented  by  these  weights  may  be  gained  by 
writing  out  the  empirical  formulae  of  the  various  proteins,  e.g., 

Egg  albumin C204H322N52O66S2 

Protein  in  hsemoglobin  (from  horse)     ,         .         .  C680H1098N210O241S2 

Protein  in  haemoglobin  (from  dog)       .         .  .  C725H1171N194O214S2 

Crystalhsed  globuhn  (from  pumpkin  seeds)  .  039211481^2008382 

With  some  proteins  we  may  make  use  of  other  elements  to  arrive  at  an 
idea  of  the  approximate  molecular  weight.  Thus,  oxyhsemoglobin  contains 
between  04  and  0-5  per  cent.  iron.  If  we  assume  that  each  molecule 
of  oxyhsemoglobin  contains  one  atom  of  iron,  its  molecular  weight  must  be 
from  11,200  to  14,000. 

Attempts  have  been  made  to  solve  the  same  question  by  studying  the 
compounds  of  proteins  with  inorganic  salts  or  oxides.  Thus,  the  crystals  of 
.globuhn  from  pumpkin  seeds  prepared  with  magnesia  contain  1-4  per  cent. 


THE  PROTEINS  75 

MgO.     Assuming  that  one  molecule  of  protein   has  coml)ined   with   one 
molecule  MgO,  the  molecular  weight  of  the  protein  must  be  about  28(J(j. 
(If  a;  be  the  molecular  weight 
X      100  —  1-4 


40  1-4 

.-.  X  =  2817) 

Harnack  has  shown  that  many  proteins  are  precipitated  from  their 
solutions  as  copper  compounds  by  the  addition  of  copper  sulphate.  Harnack 
found  that  this  precipitate  of  copper  contained  either  1-34  —  1-37  Cu.  or 
2-48  —  2-73  per  cent.  Cu.  The  smaller  percentage  would  correspond  to  a 
molecular  weight  of  4700,  while  the  second  number  might  be  accounted  for 
on  the  hypothesis  that  each  molecule  of  protein  was  combined  wath  two 
atoms  of  copper.  Similar  attempts  have  been  made  by  determining  the 
amount  of  acid  or  alkali  necessary  to  keep  certain  types  of  protein  in  solution. 
We  shall  see  later  on,  however,  that  the  amovmts  vary  largely  with  the  physical 
condition  and  previous  history  of  the  colloidal  substance.  We  are  dealing 
here  not  with  compounds  in  the  strict  chemical  sense  of  the  term,  but  with 
adsorption  compounds,  where  the  quantities  taken  up  are  determined  not 
only  by  the  chemical  nature  of  the  protein  itself,  but  by  the  state  of  aggrega- 
tion of  its  molecules.  It  is  therefore  impossible  to  lay  any  great  stress  on  the 
determinations  of  the  molecular  weight  which  have  been  effected  in  this  way. 

Some  clue  to  the  size  of  the  protein  molecule  is  afforded  by  determinations 
of  the  osmotic  pressure  or  molecular  concentration  of  their  solutions  by 
physical  methods.  When  w^e  determine  the  freezing-point  or  boiling-point 
of  protein  solutions,  the  depression  of  freezing-point,  or  elevation  of  boiling- 
point  is  so  small  that  it  falls  within  the  hmit  of  experimental  error  or  is 
no  greater  than  can  be  accounted  for  by  the  inorganic  salts  present  in  the 
solution.  Since,  however,  colloidal  membranes,  such  as  films  of  gelatin 
or  vegetable  parchment,  are  impervious  to  proteins,  we  can  directly  deter- 
mine the  osmotic  pressure  of  their  solutions.  In  many  cases  no  osmotic 
pressure  whatever  is  found.  In  other  cases,  e.g.  egg  albumin,  or  serum,  the 
colloidal  constituents  of  these  solutions  are  found  to  give  an  osmotic  pressure 
of  such  a  height  that  1  per  cent,  protein  corresponds  to  about  4  mm.  Hg. 
pressure.  Such  an  osmotic  pressure  would  indicate  a  molecular  weight  for 
the  serum  proteins  of  about  30,000.  A  determination  of  the  osmotic  pressure 
of  haemoglobin  by  Hiifner  gave  a  molecular  weight  about  16,000.  These 
results,  however,  must  be  received  with  caution,  since  we  are  not  justified 
in  applying  to  these  gigantic  molecules  data  derived  from  a  study  of  smaller 
molecules  such  as  salt  or  sugar.  Even  if  we  accept  these  determinations  of 
osmotic  pressure  as  indicating  the  molecular  weights  I  have  just  quoted,  it  is 
evident  that  a  very  shght  degree  of  aggregation  of  the  molecules  into  larger 
complexes  will  bring  the  osmotic  pressure  below  the  point  at  which  it  is 
measurable,  and  would  transform  the  solution  into  a  suspension  of  particles 
in  which  one  could  not  expect  to  find  any  osmotic  pressure  whatsoever. 


76  PHYSIOLOGY 

THE  STRUCTURE  OF  THE  PROTEIN  MOLECULE 

We  can  arrive  at  some  idea  of  the  manner  in  which  the  protein  molecule 
is  built  up  only  by  breaking  it  down  bit  by  bit,  employing  methods  which, 
while  resolving  the  large  molecule  into  its  proximate  constituents,  will  not 
act  too  forcibly  in  changing  the  whole  arrangements  of  these  constituents. 
The  relation  of  the  starches  or  polysaccharides  to  the  sugars  was  found  by 
studying  the  hydrolysis  of  the  former,  and  it  is  by  the  hydrolysis  of  the  pro- 
teins that  we  have  arrived  at  most  of  our  present  knowledge  of  their  con- 
stitution. Contributory  evidence  may  also  be  gained  by  the  use  of  oxidising 
agents  or  by  employing  the  refined  methods  of  analysis  possessed  by  certain 
hving  organisms — ^bacteria,  by  which  means  we  can  effect  hmited  oxidations 
or  reductions  or  can  replace  an  NHg  group  by  H,  or  a  COOH  group 
byH. 

ACID  HYDROLYSIS  OF  PROTEINS.  For  this  purpose  rather  stronger 
acids  are  used  than  for  the  hydrolysis  of  starch.  The  protein  is  heated  for 
twenty-four  hours  in  a  flask  fitted  with  a  reflux  condenser  either  with  con- 
centrated hydrochloric  acid  or  with  a  25  per  cent,  sulphuric  acid.  Hydro- 
chloric acid  was  first  made  use  of  by  Hlasiwetz  and  Habermann,  who  added  a 
certain  amount  of  stannous  chloride  to  the  mixture  in  order  to  prevent  any 
oxidation  taking  place.  We  obtain  in  this  way  an  acid  fluid  containing  an 
extremely  complex  mixture  of  various  substances,  all  of  which  belong  to  the 
class  of  amino-acids,  and  must  be  regarded  as  the  proximate  constituents  of 
the  protein  molecule. 

A  similar  hydrolytic  change  may  be  effected  by  the  use  of  digestive 
ferments  obtained  either  from  the  ahmentary  canal  of  higher  vertebrates  or 
from  certain  plants.  Thus  we  may  use  pepsin,  the  active  constituent  of  the 
gastric  juice,  trypsin,  the  proteolytic  ferment  secreted  by  the  pancreas, 
papaine,  or  other  vegetable  ferments  obtained  from  papaya,  from  pineapple 
juice,  and  so  on.  These  ferments  are  all  milder  in  their  action  than  the 
strong  acids.  Pepsin,  for  instance,  only  efiects  a  partial  decomposition  of  the 
protein  molecule.  Its  action  results  in  the  formation  of  substances  which 
still  present  all  the  protein  reactions  d,nd  are  classified  as  hydrated  proteins 
or  as  proteoses  and  peptones.  Trypsin  carries  the  protein  a  stage  further 
and  gives  a  mixture  of  amino-acids.  Certain  groups,  however,  of  the  protein 
molecule  present  a  considerable  resistance  to  the  action  of  trypsin,  so  that 
when  its  action  is  complete  these  groups  are  still  found  not  yet  broken  down 
into  their  constituent  amino-acids. 

The  putrefactive  processes  determined  by  the  process  of  bacteria  in 
solutions  of  proteins  are  somewhat  too  comphcated  in  their  results  to  throw 
much  illumination  on  the  structure  of  the  protein  molecule  itself.  This 
method  is,  however,  of  extreme  value  when  it  is  appHed  to  isolated  con- 
stituents of  the  proteins.  Under  the  action  of  these  bacteria  we  may  have  a 
process  of  deamination  which  may  be  accompanied  by  simple  hydrolysis  or 
by  reduction.  In  the  former  case  an  amino-acid  may  be  converted  into 
an  oxyacid,  in  the  latter  case  into  a  fatty  acid. 


THE  PROTEINS  77 

Thus  tyrosine  under  the  action  of  bacteria  of  putrefaction  may  spUt  up 
into  ammonia  and  oxyphenyl  propionic  acid. 

OH.C6H4.CH2.CHNH2.COOH  +  H2  = 
HO.C6H4.CH2.CH2.COOH  +  NH3 

Under  the  action  of  yeasts  an  amine  may  become  an  alcohol. 

C5H11.NH2  +  H2O  =  C5H11.OH  +  NH3 

(amylamine)  (amylalcohol) 

On  the  other  hand,  the  effect  of  the  bacteria  may  be  to  spUt  off  carbon  dioxide 
from  the  amino-acids.     Thus,  the  diamino-acid,  lysine, 

CH2NH2  CH2NH2 

CH2  CHa 

I  I 

CH2  becomes  CHg  pentamethylene  diamine. 

CH2  CH2 

CH.NH2  CH2NH2 

I 
COOH 

Tyrosine  becomes  p.  oxyphenylethylamine,  a  substance  ha^^ng  marked 
physiological  effects,  and  an  important  constituent  of  ergot.  Phenylalanine 
C6H5.CH2.CH.NH2.COOH,  becomes  phenylethylamine  CeHs.CHa.CHg.NHj. 
These  reactions  are  therefore  of  value  in  determining  the  exact  grouping  of  the 
atoms  in  the  more  complex  of  the  proximate  constituents  of  the  proteins. 

Since  all  the  known  disintegration  products  of  the  proteins  belong  to  the 
class  of  amino-acids,  it  may  be  of  value  to  point  out  some  of  the  distinguishing 
features  of  this  class  of  bodies. 

PROPERTIES  OF  AMINO-ACIDS.  An  amino-acid  is  derived  from  an 
organic  acid  by  the  replacing  of  one  atom  of  hydrogen  by  the  amino  group 
NHg.     Thus  from  the  acids, 

acetic  acid  propionic  acid 

CH3  CH3 

I  I 

COOH  CH, 

I     " 
COOH 

we  may  obtain  the  mono-amino-acids, 

amino-acetic  acid  alanine  or  a-amino-propionic  acid 

CH2NH2  CH3 

COOH  CH.NH2 

COOH 


78  PHYSIOLOGY 

It  will  be  noticed  that  in  the  fatty  acids  with  more  than  two  atoms  of  carbon 
the  position  of  the  NHg  group  may  be  varied.  Thus,  instead  of  alanine 
we  may  have  another  amino-propionic  acid,  namely  : 

CH2NH2 
CH2 

COOH 

This  acid  would  be  spoken  of  as  ^-amino-propionic  acid,  alanine  being 
a-amino-propionic  acid.  This  nomenclature  is  always  used  to  distinguish 
the  position  of  the  NHg  group,  so  that  we  may  have  mono-amino-acids  «, 
l3,  y,  S,  €  •  •  •  and  so  on.  Practically  all  the  amino-acids  which  occur  as 
constituents  of  the  protoplasmic  molecule  belong  to  the  a  group. 

On  inspection  of  the  formula  of  glycine  it  is  evident  that  only  one  isomer 
of  this  body  is  possible.  In  alanine,  however,  the  carbon  atom  to  which 
NHg  is  attached,  is  asymmetric,  since  its  four  combining  affinities  are  each 
attached  to  different  groups.     Thus  : 

C  ' 

H— C— NH2 

C 

In  this  case,  therefore,  there  is  a  possibility  of  stereoisomerism,  and  alanine 
must  have  an  influence  on  polarised  hght.     If  the  compound 

CH3 

I 
HCNH2 

I 
COOH 

is  dextro-rotatory,  then  its  stereoisomer 

CH3 

I 
HgNCH 

•'  COOH 

will  be  laevo-rotatory,  and  it  will  be  possible  to  obtain  a  racemic  modification 
without  any  influence  on  polarised  light  by  mixing  equal  molecules  of  these 
two  isomeric  forms.  All  the  amino-acids  derived  from  proteins  are  optically 
active,  whereas  those  obtained  by  synthesis  are  inactive,  and  special  means 
have  to  be  devised  in  order  to  obtain  from  the  artificially  formed  racemic 
amino-acid  either  the  d-  or  Z-amino-acid. 

If  more  than  one  hydrogen  atom  in  an  organic'acid  be  replaced  by  NHg 


THE  PROTEINS  7d 

we  obtain  diamino-  and  triamino-acids.  Thus,  ornithine,  obtained  by  the 
spHtting  up  of  arginine,  one  of  the  commonest  disintegration  products  of 
protein,  is  a-o-diamino- valerianic  acid. 

CH2NH2 

CH2 

I 
CH2 

I 
CH.NH2 

COOH 

The  presence  in  the  amino-acids  of  the  basic  radical  NHg  and  of  the 
acid  group  COOH  lends  to  these  bodies  a  double  character.  In  themselves 
devoid  of  strong  chemical  quahties,  possessing  neither  acid  nor  alkaline 
reaction,  they  are  able  in  the  presence  of  strong  acids  or  bases  to  act  either  as 
base  or  acid.  When  in  solution  by  themselves  it  is  possible  that  there  is  an 
actual  closing  of  the  ring  by  a  soluble  union  between  the  NHg  group  and  the 
COOH  group,  so  that,  e.g.  the  formula  of  glycine  xnory  be  : 

CH2— NH3 

CO  — 0 

When  such  a  neutral  compound  is  treated  with  acid  this  bond  is  loosed  and  we 
have  the  salt  of  the  amino-acid.  Thus,  with  hydrochloric  acid,  glycine  forms 
glycine  hydrochlorate  : 

CH2NH2HCI 

I 
COOH 

a  salt  which  still  possesses  an  acid  group  and  which  is  therefore  capable  of  com- 
bining with  ethyl  to  form  the  hydrochlorate  of  the  ester  of  the  amino-acid. 
Thus  : 

CH2.NH2HCI 

COOC2H5 

With  bases  the  amino-acids  form  salt-Like  compounds  such  as  potassium 
amino-acetate  : 

CH2NH2 

COOK 

Amino-acids  also  combine  with  one  another.  This  power  of  combination 
much  increases  the  difficulty  of  separating  the  constituents  from  a  mixture 
of  amino-acids.  Amino-acids,  which  singly  are  extremely  insoluble,  are 
readily  soluble  when  in  the  presence  of  other  amino-acids. 

Ou  account  of  the  dual  nature  of  the  amino-acid  molecule,  these  sub- 


80  PHYSIOLOGY 

stances  act  as  feeble  conductors  of  the  electric  current,  i.e.  as  electrolytes. 
The  charge  carried  by  an  amino-acid  and  its  ionisation  depends  upon  the 
conditions  in  which  it  is  placed.  Since  it  may  act  either  as  the  cation  or  the 
anion,  it  is  spoken  of  as  an  amphoteric  electrolyte. 

One  reaction  of  the  amino-acids  is  of  special  interest  in  connection  with 
the  respiratory  functions  of  the  body,  namely,  the  formation  of  carbamino- 
acids.  If  a  stream  of  carbon  dioxide  be  passed  into  a  mixture  of  an  amino- 
acid,  e.g.  glycine,  with  lime,  the  carbon  dioxide  is  taken  up.  On  filtering 
the  mixture  a  clear  liquid  passes  through  which  gradually  in  course  of  time 
deposits  a  precipitate  of  calcium  carbonate.  The  filtrate  first  obtained 
contains  a  compound  of  calcium,  calcium  glycine  carbonate.  The  formula  is 
as  follows : 

CHa.NH 

\o.co 

coo  Ca 

METHODS  OF  SEPARATING  AMINO-ACIDS,  By  the  hydrolysis  of 
protein  by  means  of  acid  or  of  trypsin,  we  obtain  a  complex  mixture  of 
amino-acids.  From  this  mixture  certain  amino-acids  are  separated  with 
ease.  Thus,  tyrosine,  which  is  extremely  insoluble,  crystallises  out  on 
concentrating  the  fluid,  and  further  concentration  leads  to  the  separation  of 
leucine.  The  other  acids,  which  keep  each  other  mutually  in  solution,  are 
however  very  difl&cult  to  isolate.  We  owe  to  Fischer  the  first  general 
method  for  their  separation.     We  may  take  one  experiment  as  an  example. 

Five  hundred  grammes  of  casein  are  heated  for  some  hours  under  a  reflux  con- 
denser with  IJ  litres  of  strong  hydrochloric  acid.  The  liquid  is  then  saturated  with 
gaseous  hydrochloric  acid  and  allowed  to  stand  for  three  days  in  the  ice-chest.  Crystals 
of  hydrochlorate  of  glutamic  acid  separate  out.  The  filtrate  from  these  crystals  is 
evaporated  at  40°  C.  under  diminished  pressure  to  a  syrupy  consistence,  and  is  then 
dissolved  in  1|^  litres  of  absolute  alcohol.  Hydrochloric  acid  is  then  passed  into  the 
solution  to  complete  saturation,  the  mixture  being  warmed  for  a  short  time  on  the 
water  bath,  and  the  mixture  is  once  more  evaporated  to  a  syrupy  consistence.  By  this 
treatment  all  the  amino-acids  have  been  converted  into  the  hydrochlorates  of  their 
esters,  e.g. : 

CH2NH2HCI  C2H4NH2HCI 

1  I 

COOC2H5  COOCgHs  &c. 

From  the  hydrochlorates  the  esters  are  set  free  by  the  addition  of  potassium  carbonate, 
the  mixture  being  cooled  in  a  freezing  mixture.  By  this  means  the  esters  of  aspartic 
and  glutamic  acids  are  separated  and  are  extracted  by  shaking  with  ether.  The 
remaining  esters  are  then  liberated  by  the  addition  of  33  per  cent,  caustic  soda  together 
with  potassium  carbonate,  and  are  again  extracted  by  ether.  The  combined  ethereal 
solutions  are  dried  by  standing  over  fused  sulphate  of  soda  and  then  evaporated,  when 
a  residue  containing  the  free  esters  is  obtained.  These  esters  are  then  separated  by 
fractional  distillation  under  a  very  low  pressure  obtained  by  means  of  the  Fleuss 
pump,  the  second  receiver  of  the  apparatus  being  cooled  in  liquid  air.  The  various 
fractions  of  aminoesters  obtained  in  this  way  are  hydrolysed- — the  lower  fractions  by 
boiling  for  some  hours  with  water,  the  higher  fractions  by  boiling  with  baryta.     The 


THE  PROTEINS  81 

acids  obtained  by  the  hydrolysis  can  then  be  further  purified  by  means  of  fractional 
crystallisation. 

THE  DISINTEGRATION  PRODUCTS  OF  THE  PROTEINS 

By  the  methods  just  described  the  following  substances  have  been 
isolated  from  proteins  : 

A.     FATTY  SERIES 

(1)     Mono-amino-acids  {Monobasic) 

GLYCINE  or  GLYCOCOLL.  This,  the  simplest  member  of  the  group,  is 
amino-acetic  acid  : 

CH2NH2 

COOH 

It  occurs  in  considerable  quantities  among  the  disintegration  products  of 
gelatin  and  to  a  shght  extent  among  those  derived  from  certain  of  the  pro- 
teins.    Like  the  other  a-amino-acids,  it  has  a  sweetish  taste,  whence  its  name 
was  derived  {yXvKoa-  =  sweet,  /coAXrj  =  glue). 
ALANINE  is  a-amino-propionic  acid  : 

CH3 

CH.NHo 

COOH 

It  is  optically  active,  the  alanine  derived  from  proteins  being  dextro- 
rotatory. 

Closely  allied  to  alanine  is  the  amino-acid  SERINE,  which  was  first  ob- 
tained by  the  hydrolysis  of  silk  and  has  since  been  found  as  a  constituent 
of  a  large  number  of  proteins.     Its  formula  is  : 

CH2OH 

CH.NH2 

COOH 

i.e.  it  is  amino-oxypropionic  acid.  Its  special  interest  Ues  in  the  fact  that 
it  was  one  of  the  first  of  the  amino- oxyacids  to  be  isolated,  and  it  is  possible 
in  these  acids  that  we  must  seek  the  intermediate  stages  between  carbo' 
hydrates  and  proteins. 

AMINO-VALERIANIC  ACID  has  the  formula 

CH3  CH3 


CH 
CH.NH2 

COOH 
It  occurs  only  in  small  quantities  in  the  protein  molecule. 


82  PHYSIOLOGY 

LEUCINE,  one  of  the  oldest  known  members  of  the  group  of  amino-acids, 

is  obtained  in  large  quantities  from  the  disintegration  of  nearly  all  the  animal 

proteins,  of  which  in  some  cases  it  may  form  as  much  as  20  per  cent.     It 

has  the  formula 

CH3  CH3 

\/ 
CH 

I 

CH.NH2 

COOH 

i.e.  it  is  amino-isobutyl  acetic  acid.  On  evaporating  a  tryptic  digest  of 
protein,  impure  leucine  crystalHses  out  in  the  form  of  imperfect  crystals, 
the  so-called  '  leucine  cones.' 

Lately  another  isomer  of  leucine  has  been  discovered,  namely,  a -amino -methyl 
ethyl  propionic  acid.     This  is  called  isoleucine. 


(2)    Mono-amino  Derivatives  of  Dibasic  Acids 
Of  these  two  are  known,  namely,  aspartic  and  glutamic  acids. 
ASPARTIC  ACID  is  a-amino-succinic  acid  : 

COOH 

I 
CH.NH2 

CH, 

I 
COOH 

and  glutamic  acid  is  the  next  homologue,  namely,  a-amino-glutaric  acid  : 

COOH 

CH.NH2 

CH., 

CH^ 

I 
COOH 

Owing  to  the  possession  of  two  carboxyl  groups  these  amino-acids  have  a 
much  more  pronounced  acid  character  than  is  the  case  with  the  other 
members  of  the  group  which  we  have  been  studying. 


THE  PROTEINS  83 

Aspartic  acid  was  first  found  in  the  shoots  of  asparagus  in  the  form  of  I  lie  amide, 
asparagine : 

COOH 

I 
CHNHg 

I 

CONH2 

This  substance  is  very  widely  distributed  throughout  the  vegetable  kingdom  and 
is  present  in  seedlmgs  in  very  large  quantities,  as  much  as  25  per  cent,  of  the  dried 
weight.  In  plants  it  apparently  serves  either  as  a  reserve  material  or  as  the  form 
in  which  the  greater  part  of  the  nitrogen  is  conveyed  from  the  reserve  organs  to  be 
built  up  into  the  protoplasm  of  the  growing  parts  of  the  plant. 

(3)     Diamino-acids 

Of  these  two  are  known,  namely,  lysine  and  ornithine.  Owing  to  the 
presence  of  two  NHg  groups  in  their  molecule,  they  possess  marked  basic 
characters,  and  are  precipitated  from  the  acid  solution  obtained  by  the 
hydrolysis  of  proteins  on  adding  phosphotungstic  acid.  Since  lysine,  argi- 
nine,  and  histidine  (another  amino-acid  which  will  be  described  later)  all 
contain  six  carbon  atoms  in  their  molecule,  these  three  bodies  were  classed 
together  by  Kossel  as  the  '  hexone '  bases.  Apart,  however,  from  their  high 
content  in  nitrogen,  the  chemical  resemblance  between  these  bodies  is  no 
closer  than  between  them  and  the  other  members  of  the  amino-acid  series. 

Another  body  isolated  by  Fischer  in  small  quantities  is  supposed  to 
belong  to  this  class  and  to  have  the  composition  diamino-trioxydodecoic  acid. 

LYSINE  CgHi^NgOa  is  a-e-diamino-caproic  acid  having  the  formula 

CH,NH, 

(CH,)3 

CH.NH2 

COOH 
ARGININE,   which  was  first  discovered  in  plants  (the  cotyledons  of 
lupins),  is  not  a  simple  amino-acid,  but  a  compound  of  an  amino-acid  with 
guanidin.     If  boiled  with  baryta  water  it  spUts  up  into  urea  and  a  substance 
reacting  as  a  base  which  was  called  ornithine.* 

ORNITHINE,  diamino- valerianic  acid,  has  the  formula 

CH2NH2 

I 

(CH^)^ 

CH.NH2 
COOH 

*  Ornithine  had  b?en  previousl}^  discovered  in  the  urine  of  fowls,  after  tlie  admini- 
stration of  benzoic  acid,  in  the  form  of  an  acid  known  as  ornithuric  acid. 


84  PHYSIOLOGY 

The  constitution  of  arginine  is  analogous  to  that  of  creatine,  one  of  the 
most  abundant  nitrogenous  extractives  of  muscle,  which  has  the  formula 


HN  =  C 


H^N 


-N(CH3)CH2C00H 


It  is  methyl  guanidine  acetic  acid.  On  boihng  creatine  with  baryta  water 
it  takes  up  a  molecule  of  water  and  sphts  in  the  situation  of  the  dotted  line 
in  the  formula,  giving 


H^N 


\C0  (urea)  and  NH(CH3)CH2COOH  (methyl  glycine). 

_  hX 

This  later  substance  is  known  as  sarcosine  and  is  derived  from  glycine  by 
the  replacement  of  one  atom  of  hydrogen  by  a  methyl  group  CHg. 

Arginine  has  a  similar  formula.  On  the  left-hand  side  of  the  dotted  line 
the  formula  would  be  identical  with  that  of  creatine.  On  the  right-hand 
side  the  sarcosine  group  is  replaced  by  a  diamino-acid  of  the  fatty  series, 
diamino-valerianic  acid  or  ornithine. 

DIAMINO-TRIOXYDODECOIC  acid  is,  as  its  name  imphes,  a  derivative 
of  a  twelve  carbon  acid.  Its  constitutional  formula  has  not  yet  been  made  out. 

B.     AMINO-ACIDS  CONTAINING  AN  AROMATIC  NUCLEUS 
The  best  known  of  these  is  TYROSINE,  which  has  the  formula 

OH 


CeHi 


CH2CH.NH2COOH 

It  is  paraoxyphenyl  a-alanine.     It  is  one  of  the  first  of  the  amino-acids  to  be 

spht  off  from  the  protein  molecule  under  the  influence  of  hydrolytic  agents. 

Owing    to    its    insolubihty    it 

rapidly      separates      out      as 

bundles  of  fine  needle-shaped 

crystals  at  the  sides  and  bottom 

of  the  vessel. 

When  tyrosine  is  treated 
with  an  acid  solution  of 
mercuric  nitrate  containing  a 
httle  nitrous  acid,  a  precipi- 
tate is  produced,  and  on 
boihng,  the  precipitate  and 
the  supernatant  fluid  assume 
a  deep  red  colour.  This  re- 
action is  given  by  all  benzene 
derivatives  in  which  one  atom 
of  hydrogen  in  the  ring  is  re- 
placed by  one  OH  group.     This  Fig.  is.     Tyrosine  crystals.     (Plimmeb.) 


THE  PROTEINS  85 

is  known  as  Hoffmann's  test,  but  is  identical  with  Millon's  reaction,  which  is 
given  by  all  proteins  containing  tyi'osine  in  their  molecules. 

Closely  alhed  to  the  foregoing  compound  is  another  aromatic  aniino-acid, 
namely,  PHENYL  a-ALANINE  : 


C«H. 


CH2CH.NH2COOH 

It  is  an  almost  constant  constituent  of  proteins. 

TRYPTOPHANE  was  known  long  before  it  had  been  isolated,  owing  to 
the  fact  that  with  bromine  water  it  gives  a  rose-red  colour.  It  had  long 
been  observed  that  this  substance  was  to  be  obtained  at  a  certain  stage  in  the 
digestion  of  proteins  by  pancreatic  juice,  but  nothing  was  known  about  its 
constitution  until  Hopkins  succeeded  in  isolating  it  by  precipitation  with 
mercuric  sulphate  dissolved  in  5  per  cent,  sulphuric  acid.  Cystine  is  also 
precipitated  by  this  reagent,  but  comes  down  with  a  less  concentration  of  the 
salt  than  trytophane,  so  that  it  is  possible  to  separate  the  two  substances 
by  a  species  of  fractional  precipitation.  Tryptophane  can  be  isolated  by 
decomposing  the  mercury  salt  with  sulphuretted  hydrogen,  and  is  obtained 
in  a  crystalhsed  form.  On  distillation  it  gives  an  abundant  yield  of  indol  and 
skatol,  bodies  also  obtained  during  the  putrefaction  of  proteins.  Tr}^to- 
phane  itself  is  indol  amino-propionic  acid  : 


C.CH2CHNH2.COOH 
CH 


CsH,    . 


NH 

C.      AMINO-ACIDS  OF  HETEROCYCLIC  COMPOUNDS 

Three  of  the  disintegration  products  of  proteins  can  be  grouped  in  this 
class.     Two  of  them  contain  the  pyrrol  ring,  namely,  prohne  and  ox}-proline. 

PROLINE,  which  was  first  isolated  by  Fischer,  is  a-pyrrohdin  carboxyhc 
acid  and  has  the  formula 

CH2-CH2 

CH2    CH.COOH 


NH 

OXYPROLINE  is  the  oxy-derivative  of  this  body  and  has  the  formula 
C5H9NO3,  the  exact  position  of  the  oxy- group  having  not  yet  been  deter- 
mined. Doubts  have  been  expressed  whether  the  pyrrol  group  is  present 
as   such   in   the    protein    molecule,    or   whether   prohne,    for   example,   is 


86  PHYSIOLOGY 

not  formed  by  the  closing  of  an  open  chain  of  a  compound  belonging 
to  the  amiuo-acids  in  the  fatty  series.  Thus  from  an  oxy-amino-valeri- 
anic  acid  CH2OH.CH2.CH2.CH.NH2.COOH  we  can  by  dehydration  make 
the  compoimd  CH2CH2.CH2.CH.COOH,  the  formula  of  which  will  be  seen 

NH 

to  be  identical  with  that  given  for  proUne. 

The  third  member  of  this  group  contains  the  iminazol  ring  : 

CH— NH. 

Il  >CH 

CH ^N^ 

and  is  known  as  HISTIDINE.     Its  structural  formula  is  as  follows  : 

CH— NH 

I!         >CH 
c w 

CH2.CH.NH2.COOH 

i.e.  it  is  iminazol  a-amino-propionic  acid  or  iminazol  alanine.  Since  it  occurs 
in  the  phosphotungstic  precipitate  from  the  products  of  acid  disintegration 
of  proteins  and  contains  six  carbon  atoms,  it  was  formerly  classified  with 
lysine  and  arginine  as  a  hexone  base. 

D.  SULPHUR-CONTAINING  AMINO- ACIDS 
Sulphur  forms  an  integral  part  of  the  molecule  of  aU  classes  of  proteins 
except  protamines.  In  some  substances  alhed  to  proteins,  such  as  keratin, 
it  may  occur  to  the  extent  of  3  per  cent.  On  boihng  proteins  with  caustic 
potash  or  soda,  a  portion  of  the  sulphur  is  spht  off  to  form  a  sulphide,  which 
gives  a  black  precipitate  on  addition  of  copper  salts.  On  this  account  it  was 
formerly  thought  that  the  sulphur  must  be  present  in  two  forms,  the  oxidised 
and  the  unoxidised,  in  the  protein  molecule.  Recent  investigation  has 
shown,  however,  that  practically  the  whole  of  the  sulphur  is  present  in  the 
form  of  CYSTINE,  and  that  this  body  on  boihng  with  alkahne  solutions  gives 
up  only  a  little  more  than  haM  its  content  in  sulphur. 

This  substance,  which  has  been  known  for  many  years  as  the  chief  con- 
stituent of  a  rare  form  of  urinary  calculus  and  as  occurring  in  the  urine  in 
certain  cases  of  disordered  metabohsm,  is  again  a  derivative  of  the  three- 
carbon  propionic  acid.  On  reduction  it  gives  a  body  known  as  cysteine, 
which  is  a-amino-thiopropionic  acid. 

CH2SH 

CH.NH2 

COOH 


THE  PROTEINS  87 

Cystine  itself  is  compounded  of  two  cysteine  molecules  joined  together  by 
their  sulphur  atoms  and  has  the  formula 

C  H  2 — S^ — S^ — ^CH  2 


CH.NH2         CH.NH2 

I  I 

COOH  COOH 

E.  OTHER  CONSTITUENTS  OF  THE  PROTEIN  MOLECULE 
When  we  add  together  the  total  amino-acids  obtainable  by  the  acid 
disintegration  of  any  given  protein,  a  considerable  proportion  of  the  original 
protein  remains  imaccounted  for.  This  remainder  must  have  a  greater 
content  in  hydrogen  and  oxygen  than  the  amino-acids  enumerated  above, 
and  it  has  been  suggested  that  among  the  missing  unascertained  con- 
stituents of  proteins  may  be  oxyamino-acids,  of  which  serine  would  form 
one  of  the  lowest  members.  The  isolation  of  such  substances  would  present 
considerable  interest,  in  that  it  would  supply  the  intermediate  stages  between 
the  constituent  groups  of  the  protein  molecule  and  the  carbohydrates,  the 
first  product  of  assimilation  by  living  organisms.  Only  one  such  intermediate 
body  has  so  far  been  isolated,  namely,  glucosamine,  an  amino-derivative  of 
glucose.  It  was  first  shown  by  Pavy  that  from  the  products  of  disintegration 
of  a  protein  such  as  egg-white  it  was  possible  to  obtain  a  reducing  substance 
and  to  isolate  an  osazone  resembhng  in  its  characters  those  derived  from  the 
sugars.  Since  then  various  observers  have  shown  that  this  reducing  sub- 
stance is  most  probably  glucosamine  : 

CH2OH 
(CH0H)3 
CH.NH2 

CHO 

Although  this  substance  may  be  obtained  from  crystaUised  egg  albumin  or 
crystalhsed  serum  albumin,  authorities  are  not  yet  con\nnced  that  it  forms 
an  integral  part  of  these  proteins.  Both  egg-white  and  serum  contain 
proteins  belonging  to  the  class  of  mucins,  ovomucoid  and  serimi  mucoid,  each 
of  which  yields  on  acid  hydrolysis  from  16  to  30  per  cent,  glucosamine.  Since 
various  observers  have  obtained  results  varying  from  1  to  16  per  cent,  gluco- 
samine for  crystalhsed  egg  albumin,  it  seems  possible  that  in  every  case 
the  crystals  carried  down  with,  them  some  of  the  carbohydrate-rich  mucoid, 
and  that  the  varying  results  were  due  to  the  difierent  amomits  of  nuicoid 
present  in  the  crystals.  By  our  ordinary  methods  it  is  impossible  to  prepare 
a  specimen  of  either  egg  albumin  or  serum  albumin  which  is  entirely  free  from 
this  amino-derivative  of  carbohydrate. 

Connected  with  this  group  of  proteins  may  be  reckoned  the  diamino- 


88  PHYSIOLOGY 

trioxydodecoic  acid  already  mentioned  as  occurring  among  th.e  disintegration 
products  of  proteins. 

THE  BUILDING  UP  OF  THE  PROTEIN  MOLECULE 

By  simple  hydrolysis  the  protein  molecule  may  be  broken  down  into  a 
large  number  of  amino-acids.  Analyses  of  various  proteins  show  that  these 
amino-acids  are  present  in  difierent  proportions  in  the  individual  proteins, 
so  that  in  many  cases  a  large  number  of  identical  amino-acid  groups  must 
be  present  in  the  protein  molecule  with  smaller  numbers  of  other  groups. 
In  endeavouring  to  form  an  idea  of  the  manner  in  which  the  amino-acids  can 
be  hnked  together  into  one  gigantic  molecule,  Hofmeister  first  put  forward 
the  idea  that  the  hnkage  follows  the  general  formula  : 

— CHa— NH— CO— 
or        — NH— CHa— CO— NH— 

This  theory  o£  the  constitution  of  proteins  was  based  on  the  fact  that  a 
similar  grouping  was  known  to  occur  in  leucinimide,  obtained  by  the  con- 
densation of  two  molecules  of  leucine, 

C4H9 

/CH\ 
NH         CO 

CO  NH 

\ch/ 

C4H9 

and  also  by  the  fact  that  only  a  small  proportion  of  the  NHg  groups  present 
in  the  separated  amino-acids  exist  free  in  the  protein  molecule.  By  the 
action  of  nitrous  acid  the  terminal  NHg  groups  are  split  off  and  replaced  by 
OH.  When  proteins  are  treated  with  nitrous  acid  only  a  small  proportion  of 
the  total  nitrogen  is  spHt  off  in  this  way.  The  linking  of  the  amino  groups 
must  therefore  take  place  by  means  of  the  nitrogen,  i.e.  by  NH  groups. 
Synthetic  experiments  have  fully  confirmed  this  hypothesis.  In  1883 
Curtius  obtained  a  substance  giving  the  biuret  reaction,  the  so-called 
'  biuret  base,'  by  the  spontaneous  polymerisation  of  glycocoll  ester.  This 
base  has  been  shown  by  recent  researches  to  consist  of  four  glycine  molecules 
arranged  together  in  an  open  chain.  The  clue  to  the  structure  of  this  base 
was  given  by  Fischer,  who  has  devised  a  number  of  ingenious  methods  for 
combining  together  amino-acids  of  any  character  and  in  any  number.  Thus 
from  two  molecules  of  glycine  we  may  obtain  the  compound  glycyl  glycine, 
as  follows  : 

NH2.CH2.COOH  -f  HNH.CH2.COOH  -  H2O  = 
NH2.CH2.CO.NH.CH2.COOH 


THE  PROTEINS  89 

This  may  be  prepared  in  various  ways.  In  one  method  glycine  is  converted  into 
its  ester  CH2.NH2.CO.OCH3.  In  a  watery  solution  this  undergoes  spontaneous 
conversion  into  glycine  anhydride  which  belongs  to  the  class  of  bodies  known  as  diketo- 
piperazins,  as  follows  : 

yCHa— C0\ 

2NH2.CH2CO.OCH3  -  2CH3OH  +  NH< 

methyl  alcohol 


>NH 
CO— CH/ 


On  treating  this  with  dilute  alkali  it  takes  up  water,  splitting  in  the  situation  of  the 
dotted  line  and  forming  glycyl  glycine,  NH2CH2CO .  NH .  CHgCOOH. 

More  general  methods  have  been  devised  by  Fischer  for  the  same  purpose,  depending 
on  the  use  of  the  halogen  acyl  clilorides. 

Thus  chloracetylcliloride  and  alanine  yield  chloracetalanine  : 

Cl.CHo.COCl  +  NHo.CH(CH3).C00H  = 
CI.CH2.CO  -  NH.CH(CH3)C00H  +  HCl. 

By  the  subsequent  action  of  ammonia,  the  halogen  group  is  replaced  by  the  amino 
group,  and  a  dipeptide  results  : 

CI.CH2.CO  -NH.CH(CH3)C00H  +  2NH3  = 
NH2.CH2.CO  -  NH.CH(CH3)C00H  +  NH4CI. 

Different  halogen  acyl  chlorides  are  used  for  introducing  the  various  amino-acid 
radicals,  e.g.  chloracetylchloride  for  glycyl,  o-bromopropionylchloride  for  alanyl,  &c. 

By  various  such  methods  Fischer  has  succeeded  in  combining  compounds 
contaiuing  as  many  as  eighteen  amino-acids,  e.g.  alanyl  leucine,  glycyl 
tyrosine,  dialanyl  cystine,  dileucyl  cystine,  leucyl  pentaglycyl  glycine,  and 
so  on.  The  last  named  would  be  built  up  out  of  one  molecule  of  leucine  and 
six  molecules  of  glycine.  These  compounds  have  been  designated  by 
Fischer  as  polypeptides,  to  signify  their  close  connection  with  the  peptones 
produced  by  the  agency  of  digestive  ferments  on  the  proteins.  He  dis- 
tinguishes di-,  tri-,  tetra-,  &c.,  peptides  according  to  the  number  of  indi^ddual 
amino-acids  taking  part  in  the  formation  of  the  compound.  The  poly- 
peptides resemble  in  all  respects  the  peptones.  Most  of  them,  even  if 
derived  from  relatively  insoluble  amino-acids,  are  soluble  in  water,  insoluble 
in  absolute  alcohol.  They  dissolve  in  mineral  acids  and  in  alkaUes  with  the 
formation  of  salts,  thus  resembling  in  their  behaviour  the  amino-acids. 
They  have  a  bitter  taste,  although  the  amino-agids  from  which  they  are 
formed  have  a  shghtly  sweet  taste,  in  this  way  again  resembhng  the  natural 
peptones.  The  higher  members  of  the  series  give  certain  reactions,  such  as 
the  biuret  reaction,  which  are  regarded  as  characteristic  of  peptones,  and  like 
the  latter  are  precipitated  by  phosphotungstic  acid.  Their  behaviour  with 
trypsin  depends  on  the  optical  behaviour  of  the  amino-acids  from  which  they 
are  formed.  If  synthetised  from  the  amino-acids  identical  with  those 
occurring  in  the  disintegration  of  natural  proteins,  they  resemble  the  pep- 
tones in  undergoing  hydrolysis  and  disintegration  into  their  constituent 
amino-acids.  Trypsin,  however,  has  no  influence  on  polypeptides  com- 
pounded of  the  inactive  amino-acids,  or  of  the  amino-acids  which  are  the 
optical  opposites  of  those  which  form  the  constituents  of  normal  proteins. 
Though  most  of  the  amino-acids  which  occur  natm-ally  are  Isevo-rotatory, 
the  polypeptides  formed  from  them  are  generally  strongly  dextro-rotatory. 


1.90  PHYSIOLOGY 

Thus  in  the  building  up  of  the  protein  molecule  there  is  an  almost  indefi- 
nite coupHng  up  of  numerous  amino- acid  groups,  the  connecting  element  in 
each  case  being  the  nitrogen.  Of  the  two  or  more  optical  isomers  possible  of 
each  amino-acid  containing  more  than  two  carbon  atoms,  only  one  is  made 
use  of  for  this  purpose.  A  still  further  fiexibihty  in  its  reactions  to  its 
environment  is  conferred  on  the  protein  molecule  by  changes  occurring  with 
great  readiness  in  the  intra-molecular  grouping  of  its  constituent  atoms. 
Thus,  if  we  take  the  simplest  member  of  the  class  of  polypeptides,  glycjl 
glycine,  four  structural  formulae  are  possible,  namely  : 

(1)  NH2CH2CO  -  NH.CH2.COOH 

(2)  NH.CH2.CO  \ 

C0.CH2.NH3^ 

(3)  NH2.CH2.C(0H)  =  N.CH2.COOH 

(4)  N.CH2.CO 

II  >o 

C(0H)CH2.NH3/ 

(2)  and  (4)  being  the  intramolecular  form  of  the  formulae  (1)  and  (3).  (3)  and 
(4)  are  sometimes  spoken  of  as  the  enohc  form.  If  we  consider  that  perhaps 
some  hundred  of  the  amino-acid  groups  may  go  to  making  up  a  single  protein 
molecule,  it  is  possible  to  form  some  conception  of  the  enormous  variabiUty 
in  reaction  possible  to  such  a  compound. 

THE  CONSTITUTION  OF  DIFFERENT  PROTEINS 

All  the  proximate  constituents  of  proteins,  so  far  as  we  know,  are  amino- 
acids.  Of  these  the  following  have  been  isolated,  namely,  glycine,  alanine, 
amino-valerianic  acid,  leucine,  isoleucine,  prohne,  oxyprohne,  serine,  phenyl 
alanine,  glutamic  acid,  aspartic  acid,  tyrosine,  tryptophane,  cystine,  lysine, 
histidine,  arginine,  and  '  di-amino-trioxydodecoic  '  acid. 

The  question  now  arises  whether  aU  the  diSerent  varieties  of  protein  owe 
their  pecuMarities  to  the  presence  of  different  amino-acids  or  whether  the 
greater  number  of  the  amino-acids  above  mentioned  are  present  in  all  pro- 
teins, the  differences  between  the  latter  being  determined  by  differences  in  the 
arrangement  and  relative  amounts  of  their  proximate  constituents.  A  large 
number  of  analyses  of  different  proteins  have  been  made  by  Abderhalden, 
Osborne,  and  others,  utiUsing  the  methods  for  the  isolation  of  amino-acids 
devised  by  Fischer.  The  constitution  of  some  representative  proteins  as 
determined  in  this  way  are  given  in  the  Table  opposite. 

These  results  show  that  all  the  proteins  contain  a  very  considerable 
proportion  of  the  total  number  of  amino-acids  which  have  as  yet  been 
isolated  from  acid  digests  of  proteins.  The  differences  in  various  proteins 
cannot  therefore  be  determined  by  quahtative  differences  in  their  constituent 
molecules,  but  must  depend  on  the  relative  amounts  of  the  amino-acids 
which  are  present  and  on  their  arrangement  in  the  whole  molecule.  As  regards 
relative  amounts  of  amino-acids  we  find  very  striking  differences.     Thus, 


THE  PROTEINS 


91 


s'i 

Hi    « 

Edestin 

(hemp 

seeds) 

■3 

3 

a 

to 

o 

1 

3 
o 

3 

"a 
O 

Keratin 
(from  horse 
ihair) 

Glycine 

0 

(J 

3-8 

0-9 

0 

0 

0 

lG-5 

4-7 

Alanine 

2-7 

8-1 

3-6 

2-7 

1-5 

4-2 

— 

— 

0-8 

1-5 

Serine 

0-6 

— 

0-33 

012 

0-5 

OG 

7-8 

— 

0-4 

0-6 

Amino  -  valeri  - 

anic  acid 

— 

— 

present 

0-3 

7-2 

— 

4-3 

— . 

1-0 

0-9 

Leucine 

20-0 

71 

20-9 

6-0 

9-35 

29-0 

0 

— 

21 

7-1 

Proline 

1-0 

2-25 

1-7 

2-4 

6-70 

2-3 

110 

— 

5-2 

3-4 

Oxyproline 

— 

— 

2-0 

— 

0-23 

1-0 

— 

— 

3-0 

— 

Gtlutamic  acid      . 

7-7 

8-0 

6-3 

36-5 

15-55 

1-7 

— 

— 

0-88 

3-7 

Aspartic  acid 

31 

1-5 

4-5 

1-3 

1-39 

4-4 

— 

— 

0-56 

0-3 

Phenylalanine     . 

31 

4-4 

2-4 

2-6 

3-2 

4-2 

— 

— 

0-4 

0 

Tyi'osine    . 

2-1 

11 

2-1 

2-4 

4-5 

1-5 

— 

— 

0 

3-2 

Tryptophane 

present 

present 

present 

1-0 

1-50 

present 

— 

— 

0 

— 

Cystine 

2-3 

0-2 

0-25 

0-45 

? 

0-3 

— 

— 

— 

ov.  10 

Lysine 

— 

2-15 

1-0 

0 

5-95 

4-3 

0 

120 

2-75 

M 

Arginino     . 

— 

2-14 

11-7 

3-4 

3-81 

5-4 

87-4 

58-2 

7-62 

4-5 

Histidine   . 

" 

" 

11 

1-7 

2-5 

11-0 

0 

12-9 

0-4 

0. 

glutamic  acid,  which  forms  8  per  cent  of  egg  albumin  and  only  1-7  per  cent 
of  globin  (derived  from  haemoglobin),  amounts  to  36-5  per  cent,  in  ghadin, 
the  protein  extracted  from  wheat  flour.  Striking  differences  are  also  notice- 
able in  the  relative  proportions  of  the  diamino- acids  and  bases,  the  so-called 
hexone  bases.  Whereas  in  casein  they  form  about  12  per  cent,  of  the  total 
molecule,  in  globin  they  form  about  20  per  cent.,  and  in  the  protamines, 
salmine  and  sturiue,  about  85  per  cent,  of  the  total  molecule  consists  of  these 
bodies.  On  this  account  the  two  last-named  bodies  have  a  strongly  basic 
character.  From  these  figures  it  is  evident  also  that  certain  of  the  amino- 
acids  must  occur  many  times  over  in  the  protein  molecule.  Thus  in  globin, 
if  we  assume  the  presence  of  one  tyrosine  molecule,  there  must  be  at  least 
thirty-two  leucine  and  ten  histidine  molecules.  On  these  data  the  molecular 
weight  of  ha)moglobin  would  come  out  at  about  14,000,  a  figure  which  agrees 
with  that  derived  from  a  study  of  the  amounts  of  sulphur  and  iron  respec- 
tively in  its  molecule. 

THE  DISTRIBUTION  OF  NITROGEN  IN  THE  PROTEIN 

MOLECULE 

Attempts  have  been  made  to  differentiate  among  the  proteins  by  a 
metho.d  which,  while  less  laborious  than  the  isolation  and  recognition  of  the 
individual  amino-acids,  may  yet  throw  some  light  on  the  manner  in  which 
the  nitrogen  is  combined  within  the  molecule,  and  on  the  relative  amoimts  of 
the  different  classes  of  nitrogen  groups  which  may  be  present.  One  method, 
which  was  devised  by  Hausmann,  is  carried  out  as  follows.  One  gramme  of 
the  protein  is  dissociated  by  boihng  with  strong  hydrochloric  acid.  The 
nitrogen,  which  has  been  split  ofi  as  ammonia  and  is  present  in  the  solution 


92 


PHYSIOLOGY 
Table  I. 


Group 

Protein 

Source 

N  per 
cent. 

Amide 

N 

Amino 

Basic 

N 

Humin* 

Protamines 

1  Salmine 
i^Sttirine 

Salmon-roe 
Sturgeon-roe 

— 

0 

0 

87-8 
83-7 

Histones 

Histone 

Thymus 

— 

3-3 

38-7 

Albumins 

\ 

and 

Ovalbumin 

Egg-white 

15-51 

8-64 

68-13 

21-27 

1-87 

phospho- 

Caseinogen 

Milk 

15-62 

10-36 

66-00 

22-34 

1-34 

proteins 

, 

Globulins 

/Globulin 
i^Edestin 

Wheat 
Hemp  seed 

18-39 

18-64 

7-72 
10-08 

53-40 

57-83 

37-10 
31-70 

1-52 
0-64 

Alcohol- 
soluble 
proteins 

Izein 
1  Gliadin 

[Prot- 

Maize 

Wheat  and  rye 

Witte's 

16-13 
17-66 

18-40 
23-78 

77-56 

70-27 

3-03 
5-54 

0-99 
0-79 

Albumoses 

albumose 
Hetero- 

peptone 
Witte's 

— 

7-14 

68-17 

25-42 

— 

albumose 

peptone 

— 

6-45 

57-4 

38-93 

— 

Table  II. — Distbibution  oe  the  Niteogen  est  Vabious  Pboteins 

(Van  Slyke) 


Gliadin 

Edestin 

Hair 
(dog) 

Gelatin 

Fibrin 

Hsemo- 
cyanin 

Ox  hsemo- 
globin 

Ammonia  N    . 

25-52 

9-99 

10-05 

2-25 

8-32 

5-95 

5-24 

Melanine  N     . 

0-86 

1-98 

7-42 

0-07 

3-17 

1-65 

3-60 

Cystine  N 

1-25 

1-49 

6-60 

0 

0-99 

0-80 

0? 

Arginine  N 

5-71 

27-05 

15-33 

14-70 

13-86 

15-73 

7-70 

Histidine  N     . 

5-20 

5-75 

3-48 

4-48 

4-83 

13-23 

12-70 

Lysine  N 

0-75 

3-86 

5-37 

6-32 

11-51 

8-49 

10-90 

Amino    N    of    the 

filtrate 

51-98 

47-55 

47-50 

56-30 

54-30 

51-30 

57-00 

Non-amino  N  of  the 

filtrate      (proline, 

oxyproline,           \ 

tryptophane) 

8-50 

1-70 

3-10 

14-90 

2-70 

3-80 

2-90 

Sum 

99-77 

99-37 

99-85 

99-02 

99-58 

100-95 

100-00 

as  ammonium  chloride,  is  then  distilled  ofi  with  magnesia  and  received 
into  decinormal  acid,  where  its  amount  can  be  determined  by  titration.  This 
nitrogen  is  variously  designated  as  amide  nitrogen,  ammonia  nitrogen,  or 

*  When  a  protein  is  boiled  for  a  long  time  with  strong  acid,  a  black  precipitate  may 
occur  which  contains  Nitrogen.     This  is  known  as  humin  nitrogen. 


THE  PROTEINS  93 

easily  displaceable  nitrogen.  The  remaining  fluid,  freed  from  ammonia,  is 
precipitated  with  phosphotungstic  acid.  By  this  means  all  the  diamino-acids 
and  bases  are  thrown  down.  The  nitrogen  in  the  preciptate  is  determined 
by  Kjeldahl's  method  and  is  called  diamino-  or  basic  nitrogen.  In  the 
remaining  fluid,  which  contains  mono-amino-acids,  the  total  nitrogen,  the 
mono-amino-nitrogen,  is  determined  by  Kjeldahl's  method.  Table  I.,  p.  92, 
gives  some  of  the  results  obtained  in  this  manner,  and  shows  that  there  are 
considerable  differences  in  the  distribution  of  the  different  kinds  of  nitrogen 
among  the  various  classes  of  proteins.  The  method  is,  however,  only  a 
rough  one  as  compared  with  the  separation  of  the  individual  amino-acids. 

An  improved  means  of  determining  the  distribution  of  nitrogen  in  the 
protein  molecule  has  been  devised  by  Van  Slyke.  Some  of  his  results  are 
given  in  Table  II.,  p.  92. 

TESTS  FOR  PROTEIN 
A.     COLOUR   REACTIONS  OF  THE  PROTEINS 

These  are  of  importance  since  in  many  cases  they  are  an  indication  of 
the  nature  of  the  groups  present  in  the  protein  molecule. 

(1)  THE  BIURET  REACTION.  When  a  solution  of  a  protein  is  made 
strongly  alkaline  with  caustic  potash  or  soda,  and  dilute  copper  sulphate 
added  drop  by  drop,  a  colour  varying  from  pink  to  violet  is  produced.  In 
the  case  of  the  proteoses  and  peptones  (the  hydrated  proteins)  the  coloiu-  is 
pink  ;  in  the  case  of  the  coagulable  proteins,  violet.  According  to  Schifi  this 
colour  is  given  by  all  compounds  containing  the  following  groups  : 

.CO.NH2 

NH<^ 

\C0.NH2 
.CO.NH2 
CHgv 

^CO.NHa 
CO— NH2 

I 
CO— NH2 

and  the  group 

I  I 

(NH2)C— CO— NH— C 

We  have  already  seen  that  this  grouping  is  typical  of  the  protein  molecule. 

(2)  THE  XANTHO-PROTEIC  REACTION.  On  adding  strong  nitric  acid 
to  a  solution  of  protein  and  boiling,  a  yellow  colour  is  produced  which  turns 
to  a  deep  orange  when  excess  of  caustic  alkali  or  ammonia  is  added.  The 
production  of  this  reaction  points  to  the  existence  of  benzene  derivatives  in 
the  protein  molecule,  and  it  is  therefore  a  general  test  for  the  presence  of 
aromatic  groups. 


94  PHYSIOLOGY 

(3)  MILLON'S  REACTION.  Millon's  reagent  is  a  solution  of  mercuric 
nitrate  in  water  containing  free  nitrous  acid.  On  adding  a  few  drops  of  this 
to  a  protein  solution  a  white  precipitate  is  produced  which  turns  a  brick-red 
colour  on  boihng.  It  depends  on  the  presence  in  the  protein  of  a  hydroxy- 
derivative  of  benzene,  and  is  determined  in  the  protein  by  the  tyrosine,  which 
is  oxyphenylalanine. 

(4)  SULPHUR  REACTION.  On  warming  a  solution  of  protein  with 
caustic  soda  in  the  presence  of  lead  acetate  a  black  colour  is  produced  owing 
to  the  precipitation  of  lead  sulphide.  The  depth  of  coloration  gives  a  rough 
indication  of  the  amount  of  sulphur  in  the  protein  under  investigation. 

(5)  THE  HOPKINS-ADAMKIEWICZ  REACTION.  It  was  stated  by 
Adamkiewicz  that  on  the  addition  of  acetic  acid  and  concentrated  sulphuric 
acid  to  protein,  a  violet  colour  was  produced.  Hopkins  and  Cole  showed 
that  the  success  of  this  reaction  depended  on  the  presence  of  glyoxyhc  acid 
CHO.COOH  as  an  impurity  in  the  acetic  acid  used.  The  test  is  therefore 
performed  now  as  follows  : 

Glyoxyhc  acid  is  prepared  by  the  action  of  sodium  amalgam  on  a  solution 
of  oxahc  acid.  A  few  drops  of  this  solution  are  added  to  the  solution  of 
protein,  and  strong  sulphuric  acid  poured  down  the  side  of  the  tube.  A 
bluish  violet  colour  is  produced  at  the  junction  of  the  two  fluids.  This  re- 
action is  due  to  the  presence  in  the  protein  of  tryptophane. 

The  so-called  Liebermann's  reaction  has  been  shown  by  Cole  to  be  essentially  a 
modification  of  the  above,  and  is  due  also  to  the  presence  of  tryptophane.  In  this 
test  the  protein  is  precipitated  by  alcohol,  washed  with  ether,  and  heated  with  con- 
csntrated  hydrochloric  acid,  when  a  blue  colour  is  produced,  glyoxylic  acid  being 
derived  from  the  alcohol  and  ether. 

(6)  REACTIONS  INDICATING  THE  PRESENCE  OF  CARBOHYDRATES. 

Mohsch's  test  is  apphed  as  follows.  A  few  drops  of  alcohohc  solution  of 
a-naphthol  and  then  strong  sulphuric  acid  are  added  to  a  protein  solution. 
A  violet  colour  is  produced,  which  on  addition  of  alcohol,  ether,  or 
potash  turns  yellow.  The  reaction  is  determined  by  the  presence,  either 
as  an  impurity  or  a  constituent  part  of  the  molecule,  of  a  carbohydrate 
radical  which,  under  the  influence  of  strong  sulphuric  acid,  is  converted  into 
furfurol.     The  furfurol  gives  the  colour  reaction  with  the  a-naphthol. 

Another  test  for  the  carbohydrate  radical  is  the  orcin  reaction.  A  small 
quantity  of  the  dried  albumin  is  added  to  5  c.c.  of  fuming  hydrochloric  acid, 
and  the  mixture  is  then  warmed.  When  the  albumin  is  nearly  all  dissolved 
a  httle  sohd  orcin  is  added  on  the  point  of  a  knife,  and  then  a  drop  of  ferric 
chloride  solution.  After  warming  this  mixture  for  some  minutes  a  green 
colour  is  produced  which  is  soluble  in  amyl  alcohol  and  gives  a  definite 
absorption  spectrum. 

B.     METALLIC  SALTS 

The. following  metallic  salts  form  double  insoluble  compounds  with  pro- 
teins, ^nd  therefore  cause  a  double  precipitation  when  added  to  solutions  of 
these  bodies  :  ferric  chloride,  copper  sulphate,  mercuric  chloride,  lead  acetate, 
zinc  acetate. 


THE  PROTEINS  95 

C.      ALKALOIDAL   REACTIONS 

Proteins,  like  the  polypeptides  and  the  amino-acids  of  which  they  are 
composed,  may  function  either  as  weak  acids  or  as  weak  bases,  according  as 
they  are  treated  with  bases  or  acid  radicals  respectively.  In  the  presence  of 
strong  acids,  therefore,  proteins  act  like  organic  bases,  and  are  thrown  down 
in  an  insoluble  form  by  the  various  alkaloidal  precipitants.  With  certain 
proteins,  such  as  the  protamines,  where  there  is  a  preponderance  of  basic 
groups,  it  is  not  necessary  to  add  mineral  acid  in  order  to  ensure  the  precipita- 
tion. The  following  are  the  principal  alkaloidal  precipitants  which  may  be 
employed  : 

(a)  Phosphotungstic  acid. 

(b)  Phosphomolybdic  acid. 

(c)  Tannic  acid. 

(d)  Potassium  mercuric  iodide. 

(e)  Acetic  acid  and  potassium  ferrocyanide. 

(f)  Trichloracetic   acid.     (In   order   to   precipitate   all   the   coagulable 

proteins  from  a  solution  it  is  treated  with  an  equal  volume  of  10 
per  cent,  trichloracetic  acid,  well  shaken  and  filtered.) 

{g)  Metaphosphoric  acid. 

(7i)  Salicyl-sulphonic  acid. 

These  two  latter  are  generally  employed  in  a  5  per  cent,  solution. 

{{)  Picric  acid. 

A  mixture  of  picric  and  citric  acids  is  largely  employed,  under  the 
name  of  Esbach's  reagent,  as  a  precipitant  for  coagulable  proteins 
in  the  urine. 

D.     TESTS   DEPENDING  ON  THE  COLLOIDAL  CHARACTER 
OF  THE  PROTEIN 

(1)  HEAT  COAGULATION.  On  boiling  proteins  in  a  very  shghtly  acid 
solution  some  are  coagulated  and  form  an  insoluble  white  precipitate. 
This  test  is  applicable  to  albumins,  globulins,  and  under  certain  conditions 
to  the  derived  albumins.  In  order  that  the  separation  of  protein  in  this  way 
may  be  complete  it  is  necessary  to  provide  for  the  presence  of  neutral  salts 
and  also  for  the  maintenance  of  a  slight  acidity.  The  best  method  of  carry- 
ing out  this  test,  therefore,  is  to  boil  the  protein  in  slightly  alkaline  or  neutral 
solution  after  the  addition  of  2-5  per  cent,  of  sodium  chloride  or  sodium 
sulphate.  While  the  solution  is  in  active  ebullition  1  per  cent,  acetic  acid  is 
added  drop  by  drop  until  the  reaction  is  just  acid  to  litmus.  By  this  means 
a  nearly  perfect  separation  of  all  the  coagulable  proteins  mav  be  effected. 

(2)  HELLER'S  TEST.  On  pouring  a  solution  of  protein  carefully  down 
the  side  of  a  test-tube  containing  strong  nitric  acid  so  as  to  form  a  layer 
on  the  top,  a  white  layer  of  coagulated  protein  is  produced  at  the  junction 
of  the  two  fluids.  A  similar  coagulative  effect  is  produced  by  other  strong 
mineral  acids. 


96  PHYSIOLOGY 

(3)  PRECIPITATION  BY  NEUTRAL  SALTS.  On  addition  of  a  neutral 
salt  in  excess  to  a  colloidal  solution  the  relation  between  the  solvent  and  the 
particles  which  are  in  suspension  or  pseudo-solution  are  altered.  It  is 
therefore  possible  in  many  cases  by  the  addition  of  neutral  salts  to  separate 
out  the  dissolved  colloid  without  otherwise  altering  its  characters  in  any  way, 
so  that,  on  collecting  the  precipitate  and  separating  the  salt  carried  down 
with  it,  it  can  be  dissolved  again  by  adding  water.  Some  classes  of  proteins 
can  be  salted  out  very  readily,  while  others  require  a  much  higher  concentra- 
tion of  salt  before  they  are  precipitated. 

The  salts  which  are  generally  employed  for  salting  out  proteins  have  been 
divided  by  Schryver  into  three  classes  : 

Class  I.  Class  II.  Class  III. 

Sodium  chloride.  Potassium  acetate.  Ammonium  sulphate. 

Sodium  sulphate.  Calcium  chloride.  Zinc  sulphate. 

Sodium  acetate.  Calcium  nitrate. 
Sodium  nitrate. 
Magnesium  sulphate. 

The  two  calcium  salts  are,  however,  rarely  employed,  as  they  tend  to 
render  the  precipitated  protein  insoluble. 

The  salts  of  the  first  class  require  much  higher  concentration  for  the  pre- 
cipitation of  the  proteins  than  those  of  the  second,  and  these  than  those  of 
the  third.  Since  the  degree  of  concentration  of  any  salt  necessary  for  the 
precipitation  of  any  particular  protein  is  characteristic  for  this  body,  it  is 
possible  to  employ  a  fractional  process  of  salt  precipitation  in  order  to 
separate  mixtures  of  proteins  into  their  components.  Owing,  however,  to 
the  tenacity  with  which  different  colloids  adhere  to  one  another  it  is  diffi- 
cult, even  after  many  repetitions  of  the  process  of  fractional  salting  out,  to 
obtain  products  which  can  be  regarded  as  free  from  admixture.  For  the 
purpose  of  fractional  precipitation  the  salts  most  frequently  employed 
are  those  of  the  third  class,  namely,  ammonium  sulphate  and  zinc  sulphate. 
We  shall  have  to  deal  with  results  obtained  by  this  method  when  treating 
of  the  separation  of  albumoses  and  peptones.  The  precipitabihty  of 
different  proteins  with  neutral  salts  serves  also  as  the  basis  of  the  ordinary 
classification  of  these  bodies. 

THE  CLASSIFICATION  OF  PROTEINS 

It  is  possible  that  in  the  future,  when  we  know  all  the  disintegration 
products  of  the  various  proteins  and  the  manner  in  which  they  are  arranged 
in  the  molecule,  the  classification  of  these  bodies  will  be  based  on  their  con- 
stitution. At  the  present  time  it  is  obviously  impossible  to  make  any  classi- 
fication on  such  a  basis,  since  the  necessary  knowledge  is  wanting,  and 
we  have  therefore  to  use  a  purely  artificial  classification,  such  as  that 
adopted  by  the  Chemical  and  Physiological  Societies  in  1907,  based  chiefly 
on  the  solubilities  of  the  various  proteins  in  water  and  salt  solutions.  We 
shall  here  only  indicate  the  characters  of  the  main  groups  into  which  proteins 


THE  PROTEINS  97 

are  conventionally  divided,  and  leave  the  closer  study  of  the  individual 
proteins  to  be  dealt  with  in  connection  with  the  organs  or  tissues  in  which 
they  occur. 

(1)  THE  PROTAMINES.  These  occur  in  the  body  only  in  combination 
with  other  groups.  They  are  obtained  from  the  ripe  spermatozoa  of  certain 
fishes,  where  they  occur  in  combination  with  nucleic  acid.  They  are  charac- 
terised by  the  very  large  amomit  of  bases  contained  in  their  molecule, 
amounting  to  85  per  cent,  of  the  total  substance.  It  was  formerly  thought 
by  Kossel  that  the  protamines  contained  only  diamino-acids  and  bases,  but 
it  has  been  shown  later  that  a  small  proportion  of  mono-amino-acids  may 
also  be  obtained  from  their  disintegration  {v.  Table,  p.  91).  On  account  of 
their  constitution  they  possess  strongly  basic  characters  and  form  well- 
marked  salts,  e.g.  sulphates  and  chlorides,  as  well  as  double  salts  vnth. 
platinum  chloride.  They  contain  no  sulphur  and  do  not  coagulate  on 
heating. 

(2)  HISTONES.  This  class  of  proteins,  like  the  protamines,  only  occurs 
in  combination  with  other  groups,  such,  for  instance,  as  nuclein  and  hsematin. 
They  may  be  obtained  from  red  blood-corpuscles,  where  they  form  the 
globin  part  of  the  hseraoglobin  molecule,  or  from  the  leucocytes  of  the  thymus 
gland,  or  from  the  spermatozoa  of  fishes.  The  histones  are  precipitated 
from  their  watery  solutions  by  addition  of  ammonia,  but  are  soluble  in 
excess  of  this  reagent.  In  the  presence  of  salts  they  are  coagulated  on  boiling. 
With  cold  nitric  acid  they  give  a  precipitate  which  dissolves  on  warming,  but 
is  thrown  down  again  on  cooling.  The  most  characteristic  feature  of  this 
class  of  bodies  is,  however,  the  high  proportion  of  diamino-acids  and  bases 
contained  in  their  molecule. 

(3)  ALBUMINS.  These  are  soluble  in  pure  water  and  are  precipitated 
by  complete  saturation  with  ammonium  sulphate,  zinc  sulphate,  or  sodio- 
magnesium  sulphate. 

Egg  Albumen  forms  the  greater  part  of  the  white  of  egg.  It  gives 
the  ordinary  protein  tests,  coagulates  on  heating  at  about  75°  C,  and 
is  precipitated  from  its  solutions  if  shaken  with  a  drop  of  dilute  acetic 
acid  in  excess  of  ether.  It  is  laevo-rotatory,  its  specific  rotatory  power 
being  -35-5°. 

Serum  Albumen  occurs  in  large  quantities  in  the  blood  plasma,  serum, 
lymph,  and  tissue  fluids  of  the  body.  It  coagulates  at  75°  C,  and  is  dis- 
tinguished from  egg  albumen  by  its  greater  specific  rotatory  power,  —56°, 
and  by  the  fact  that  it  is  not  precipitated  by  ether  and  sulphuric  acid.  Some 
vegetable  proteins  belong  to  this  class,  e.g.  the  leucosin  of  wheat. 

(4)  GLOBULINS.  These  bodies  are  insoluble  in  pure  water  and  require 
the  presence  of  a  certain  amount  of  neutral  salt  to  dissolve  them.  They  are 
precipitated  from  their  solutions  by  complete  saturation  with  magnesium 
sulphate  or  by  half-saturation  with  ammonium  sulphate.  The  chief  members 
of  this  class  are  : 

Crystallin,  obtained  from  the  crystalline  lens  by  passing  a  stream  of 
caibon  dioxide  through  an  aqueous  extract  of  this  body. 

4 


98  PHYSIOLOGY 

Serum  Globulin  or  Paraglobulin,  a  constituent  of  blood  plasma  and 
blood  serum. 

Fibrinogen,  wMcli  occurs  in  blood  plasma  and  is  converted  into  fibrin 
when  the  blood  clots. 

Paramyosinogen,  a  normal  constituent  of  muscle. 

Midway  between  these  two  groups  may  be  placed  the  muscle  protein, 
myosin  (or  myosinogen),  which,  though  soluble  in  pure  water,  resembles 
the  class  of  globuhns  in  the  ease  with  which  it  is  precipitated  by  the  addition 
of  neutral  salts. 

In  addition  to  the  members  of  the  globuhns  named  above  and  derived 
from  the  animal  body,  proteins  alUed  to  this  class  form  an  important  con- 
stituent of  plants,  and  are  found  in  large  quantities  in  many  seeds  used  as 
articles  of  food.  These  are  vegetable  globulins.  Prominent  members  of  the 
group  are  the  edestins,  which  may  be  obtained  from  hemp  seeds,  cotton  seeds, 
and  sunflower  seeds,  zein  from  maize,  legumin  from  beans. 

(5)  GLI ADINS,  contained  in  cereals,  and  soluble  in  alcohol. 

(6)  GLUTELINS,  proteins  also  obtained  from  cereals  and  soluble  in  weak 
alkahes. 

(7)  DERIVATIVES  OF  PROTEINS.  A.  METAPROTEINS.  These  may 
be  regarded  as  compounds  of  the  protein  molecule  or  of  part  of  the  molecule 
with  acid  or  basic  radicals. 

Acid  Albumin,  or  acid  metaprotein,  is  formed  by  the  action  of  warm  dilute 
acids  or  of  strong  acids  in  the  cold  on  any  of  the  preceding  bodies.  If  a  weak 
alkah  be  added  so  as  to  nearly  neutrahse  the  solution  of  acid  metaprotein, 
this  latter  is  precipitated.  If  the  precipitate  be  suspended  in  water  and 
heated,  it  is  coagulated  and  becomes  insoluble  in  dilute  acids  or  alkahes. 

Alkali  Albumin,  or  alkahne  metaprotein,  is  formed  by  the  action  of 
strong  caustic  potash  on  white  of  egg  or  on  any  other  protein,  or  by  adding 
alkah  in  excess  to  a  soluion  of  acid  metaprotein.  It  is  precipitated  on 
neutrahsation  of  its  solution. 

In  close  association  with  this  group  may  be  included  the  proteins  as  they  occur 
in  combination  with  the  metallic  salts,  such  as  copper  sulphate.  On  splitting  off  the 
copper  moiety  from  these  compounds,  the  protein  left  is  practically  free  from  ash,  and 
behaves  in  many  respects  like  an  albuminate,  being  insoluble  in  absolutely  pure  water, 
but  easily  dissolved  by  the  addition  of  a  trace  of  free  acid  or  alkali. 

A  group  of  protein  derivatives  described  by  Hopkins  is  produced  by  the  action 
of  the  free  halogens  on  protein  solutions.  We  get  in  this  way  two  definite  classes 
of  compounds.  One  class,  which  contains  the  largest  percentage  of  halogen,  is  obtained 
by  treating  a  protein  solution  with  chlorine,  bromine,  or  iodine,  dissolving  up  the 
resultant  precipitate  in  alcohol  and  pouring  the  alcoholic  solution  into  ether,  when  the 
halogen  compound  is  thrown  down  as  a  fine  white  precipitate.  By  dissolving  this 
precipitate  in  weak  soda  and  precipitating  with  acid,  we  obtain  a  series  of  compounds 
containing  only  about  one-third  as  much  of  the  halogen  as  is  contained  in  the  first 
precipitate,  suggesting  that  the  halogen  forms  both  substitution  and  additive  compounds 
with  the  protein  molecule. 

Albumins,  globulins,  and  metaproteins  are  often  associated  together  as 
the  coagulable  proteins,  since  they  may  be  thrown  down  entirely  from  their 
solution  on  boihng  in  shghtly  acid  medium  in  the  presence  of  neutral  salts. 


THE  PROTEINS  99 

B.  HYDRATED  PROTEINS.  When  proteins  are  subjected  to  the 
action  of  superheated  water  or  steam,  or  heated  ^^^th  acids,  or  acted  on  at 
the  body  temperature  by  certain  ferments,  e.g.  pepsin,  trypsin,  or  papain, 
they  undergo  a  change  which  is  attended  by  the  addition  of  a  number  of 
molecules  of  water  to  the  protein  molecule  (hydrolysis).  This  action,  when 
carried  to  its  end,  results  in  the  production  of  the  amino-acids  which  we  have 
already  dealt  with. 

These  hydrolytic  changes  proceed  by  a  series  of  stages,  so  that  the 
intermediate  products  still  present  many  of  the  protein  reactions.     The 
hydrated  proteins  are  divided  into  two  groups,  proteoses  and  peptones. 
The  formation  of  these  intermediate  products  is  especially  marked  with  the 
proteolytic  ferments.     Pepsin  with  hydrochloric  acid,  the  ferment  of  the 
gastric  juice,  for  example,  only  breaks  down  the  protein  molecule  as  far  as  the 
proteoses  and  peptones.     Trypsin  also  gives  rise  to  both  proteoses  and  pep- 
tones as  intermediate  products.     The  action  of  these  ferments  on  proteins  is 
in  fact  closely  analogous  to  the  action  of  diastase  on  the  great  polysaccharide 
molecule  of  starch.     In  this  case,  as  intermediate  products  we  have  first 
dextrins  of  various  complexity,  secondly  maltose,  and  finally,  if  the  ferment 
maltase  be  also  present,  dextrose.     The  monotony  of  the  starch  molecule 
determines  a  great  similarity  of  composition  between  its  various  disintegra- 
tion products.     It  may  be  regarded  as  an  anhydride  of  many  (100  or  more) 
molecules  of  a  hexose,  and  the  intermediate  stages  in  this  hydrolysis  are  also 
hexoses  and  their  anhydrides.     The  protein  molecule  is  distinguished  bv  the 
variety  of  the  groups  which  enter  into  its  formation,  and  this  heterogeneous 
character  of  the  molecule  renders  possible  a  nmch  greater  variety  of  inter- 
mediate products  than  we  find  in  the  starches.     Thus  a  protein  molecule  may 
consist  of  the  groups  A,  B,  C,  D,  E,  F,  G,  H,   &c.     When  hydrolysis  occurs 
it  may  result  in  the  immediate  sphtting  off,  say,  of  part  of  group  A,  while 
the  residue  breaks  up  into  a  series  of  proteoses  whose  composition  may  be 
represented  as  ABF,  ABC,  DFG,  BDEF,  &c.     With  further  hydrolysis  these 
groups  are  broken  into  still  smaller  ones,  and  the  penultimate  stages  of  the 
hydrolysis  will  be  polypeptides  similar  to  those  which  have  been  synthetisod 
by  Fischer  from  the  ultimate  products  of  protein  hydrolysis.     No  sharp 
dividing  line  can  be  drawn  between  the  proteoses,  peptones,  and  poly- 
])eptides.     Of  the  last  group  we  have  already  seen  that  the  higher  members 
give  the  biuret  reaction  as  well  as  the  other  protein  reactions,  if  the  necessary 
groups,  e.g.  tyrosine,  tryptophane,  are  present  in  the  molecule.     The  prote- 
oses and  peptones  are,  however,  ill-defined  bodies.     We  have  at  present  no 
satisfactory  means  of  isolating  the  dift'erent  members  of  these  groups  and 
obtaining  them  in  a  state  of  chemical  purity.     Their  classification  is  there- 
fore, like  that  of  the  proteins  generally,  a  conventional  one,  depending  on 
their  solubilities  and  their  precipitability  by  neutral  salta,  especially  ammo- 
nium sulphate.     Both  proteoses  and  peptones  give  the  xanthoproteic  and 
Millon's  reactions  common  to  all  proteins,  and,  like  these,  are  precipitated 
by  such  reagents  as  mercuric  chloride,  potassio-mercuric  iodide,  or  phospho- 
tungstic  acid.     On  adding  excess  of  caustic  potash  and  a  drop  of  dilute 


100  PHYSIOLOGY 

copper  sulphate  to  solutions  of  either  of  these  classes  of  bodies,  a  pink  colour 
is  produced  which  deepens  to  a  violet  on  addition  of  more  copper  (the  biuret 
reaction).  Their  solutions  can  be  boiled  without  undergoing  coagulation. 
Many  of  them  may  be  thrown  down  from  their  solutions  by  absolute  alcohol, 
but  are  not  rendered  insoluble  even  by  prolonged  standing  under  the  alcohol. 
The  characters  of  the  different  members  of  these  groups  will  be  considered 
at  greater  length  when  deahng  with  the  changes  undergone  by  the  proteins 
during  the  process  of  digestion.  At  present  we  may  merely  summarise  the 
distinguishing  features  of  these  two  classes. 

(a)  Pkoteoses,  e.g.  albumose  from  albumin,  caseose  from  casein,  elastose 
from  elastin.  All  of  these  are  precipitated  from  their  solutions  on  saturation 
with  ammonium  sulphate.  In  the  presence  of  a  neutral  salt  they  give  a 
precipitate  on  the  addition  of  nitric  acid.  This  precipitate  is  dissolved 
on  heating  the  solution,  but  reappears  on  cooling.  All,  with  the  exception  of 
heteroalbumose,  are  soluble  in  pure  water,  and  all  are  soluble  in  weak 
salt  solutions  or  dilute  acids  or  alkahes.  They  are  shghtly  diffusible  through 
animal  membranes. 

(&)  Peptones,  e.g.  fibrin  peptone,  gluten  peptone.  These  are  all  soluble 
in  pure  water,  diffuse  fairly  readily  through  animal  membranes,  but  other- 
wise give  the  same  reactions  as  albumoses.  From  the  latter  class  peptones 
are  distinguished  by  the  fact  that  they  are  not  precipitated  on  saturation  of 
their  solutions  either  in  acid  or  alkahne  reaction  with  ammonium  sulphate 
or  any  other  neutral  salt.     Many  of  them  are  soluble  in  alcohol. 

(8)  THE  PHOSPHOPROTEINS.  In  this  class  may  be  grouped  a  number 
of  substances  of  very  diverse  properties  which,  however,  resemble  one 
another  in  containing  phosphorus  as  an  integral  part  of  their  molecule. 
When  subjected  to  digestion  with  pepsin  and  hydrochloric  acid  they  are 
dissolved,  but  a  small  quantity  of  a  phosphorus- containing  complex  may 
remain  behind  undissolved.  This  residue  has  been  called  paranuclein  or 
pseudonuclein.  It  is  in  reahty  derived  from  nucleoprotein,  which  is  present 
in  the  phosphoprotein  as  impurity  and  should  be  called  simply  nuclein.  The 
phosphoproteins  have  markedly  acid  characters.  They  are  insoluble  in  pure 
water,  easily  soluble  in  alkahes  and  ammonia  from  which  the  original  body 
is  thrown  down  again  on  addition  of  acid.  Their  solutions  in  alkali  are  not 
coagulated  by  heating.  To  this  class  belong  caseinogen,  the  chief  protein  of 
milk,  vitelhn,  the  main  protein  in  the  yolk  of  egg,  and  the  vitelhns  in  the  eggs 
of  fishes  and  frogs.  The  vitellins  are  generally  associated  with  a  large  amount 
of  lecithin.  The  phosphoproteins  differ  from  the  nucleoproteins,  which  also 
contain  phosphorus,  in  the  facts  that  they  are  readily  decomposed  by  caustic 
alkali  with  the  liberation  of  phosphoric  acid,  and  do  not  contain  purine 
bases.  The  phosphorus  of  the  nucleoproteins  is  not  split  of!  by  alkali 
(1  per  cent.),  and  on  hydrolysis  the  nucleic  acid  constituent  gives  rise  to 
purine  bases. 

(9)  CONJUGATED  PROTEINS.  Various  complex  bodies  which  play  an 
important  part  in  building  up  cells  and  in  the  various  processes  of  the  body 
make  up  this  group  of  compounds.     They  resemble  one  another  only  in  the 


THE  PROTEINS  101 

fact  that  in  each  of  them  a  protein  radical  is  combined  with  some  other  body, 
often  spoken  of  as  the  prosthetic  group.* 

{a)  Chromoproteins.  Of  this  class,  consisting  of  a  colouring- matter 
combined  with  a  protein,  the  most  important  is  hcemoglobin.  This  substance, 
which  is  the  red  colouring-matter  of  the  red  corpuscles  of  the  blood  and  plays 
an  important  part  in  the  processes  of  respiration,  acting  as  an  oxygen  carrier 
from  the  lungs  to  the  tissues,  is  composed  of  the  protein,  globin,  united  with 
an  iron-containing  body,  haematin.  Oxyhsemoglobin  contains  from  4-5  per 
cent,  hsematin  (C32H32N404Fe).  It  is  easily  crystallisable,  and  its  physical 
and  chemical  characters  have  therefore  been  more  precisely  determined  than 
is  the  case  with  most  other  members  of  the  group  of  conjugated  proteins.  We 
shall  have  to  deal  more  fully  with  its  properties  in  the  chapters  on  Blood  and 
Respiration. 

[b)  The  Nucleoproteins.  These  are  formed  by  the  combination  of  a 
phosphorised  organic  acid,  nucleic  acid,  with  a  protein  which  may  belong  to 
any  of  the  classes  we  have  enumerated  above.  Some  of  the  best-marked 
members  of  this  group  consist  of  compounds  of  nucleic  acid  with  basic  histones 
or  protamines.  The  combination  between  protein  and  the  prosthetic  group 
seems  to  take  place  in  two  stages.  If  a  nucleoprotein  be  subjected  to  gastric 
digestion  a  large  amount  of  the  protein  goes  into  solution  as  proteose  or 
peptone,  leaving  an  insoluble  remainder.  This  precipitate  is  not,  however, 
nucleic  acid,  but  still  contains  a  protein  group,  the  compound  being  spoken 
of  as  nuclein.  From  the  latter  nucleic  acid  can  be  spUt  off  by  heating  with 
strong  acids  or  other  means.  The  nucleoproteins  are  soluble  in  water  and 
salt  solutions,  and  are  easily  soluble  in  dilute  alkalies.  They  have  acid 
characters  and  are  precipitated  by  the  addition  of  acids.  The  nuclei ns,  on 
the  other  hand,  are  insoluble  in  water  and  salt  solutions,  but  are  easily 
dissolved  by  dilute  alkahes.  The  nucleins  and  nucleoproteins  form  the  chief 
and  invariable  constituent  of  cell  nuclei.  They  may  be  therefore  prepared 
from  the  most  diverse  organs.  The  heads  of  the  spermatozoa  of  the  salmon 
consist  entirely  of  nuclein.  Miescher  and  Schmiedeberg  found  that  the 
nuclein  obtained  from  this  source  contained  60-5  per  cent,  nucleic  acid  and 
3r)-56  protamine,  and  was  in  fact  a  nucleate  of  protamine.  The  nuclein 
derived  from  the  spermatozoa  of  echinoderms  has  been  found  to  be  a  com- 
pound of  nucleic  acid  and  histone.  From  organs  rich  in  cells,  such  as  the 
thymus  and  the  pancreas,  and  from  nucleated  red  blood-corpuscles,  nucleo- 
proteins may  be  obtained  which  can  be  broken  down  into  nuclein  and  protein, 
the  nuclein  again  being  composed  of  a  protein  residue  with  nucleic  acid. 

As  tirst  extracted  from  the  animal  cell  the  nucleoproteins  are  associated  with  a 
considerable  proportion  of  lecithin,  and  in  this  labile  compound  form  the  '  tissue 
iibrinogen  '  of  Wooldridge.  To  prepare  this  substance  an  organ  rich  in  cells,  such  as 
the  thymus,  is  minced  and  extracted  with  water  or  normal  salt    solution.       After 

*  By  the  Germans  the  term  '  protcid  '  is  often  applied  to  this  group.  In  English, 
however,  the  term  '  proteid  '  has  been  generally  used  for  the  shnple  protein  known 
to  the  Germans  as  '  Eiweisskorper.'  On  account  of  the  confusion  which  has  risen 
from  this  double  use  of  the  term  '  proteid,'  I  have  attempted  to  avoid  it  altogether  in 
this  volume. 


102  PHYSIOLOGY 

separating  the  cells  by  means  of  the  centrifuge,  the  clear  fluid  is  decanted  off  and 
acidified  with  acetic  acid.  A  precipitate  is  produced  consisting  of  '  tissue  fibrinogen.' 
This  substance  is  soluble  in  excess  of  acid  and  is  easily  soluble  in  alkalies.  All  the 
tissue  fibrinogens  are  highly  unstable  bodies  and  undergo  changes  in  the  mere  act  of 
precipitation  and  re-solution.  When  injected  into  the  blood  they  cause  intravascular 
clotting.  On  digestion  with  gastric  juice  they  yield  a  precipitate  of  nuclein,  and  this 
precipitate  contains  a  large  proportion  of  the  lecithin  present  in  the  original  substance. 
In  the  nucleoproteins  nucleic  acid  is  combined  with  proteins  in  two  degrees,  a  large 
portion  of  the  protein  being  separable  by  gastric  digestion,  while  the  remainder  needs 
stronger  reagents  for  its  dissociation.  The  relation  of  the  two  portions  -of  the  nucleo- 
protein  may  be  represented  therefore  by  the  following  schema  : 

Nucleo-protein 
Protein  Nuclein 


Protein  Nucleic  acid 

(generally  histone 
or  protamine) 

By  various  means,  all  of  wliich  involve  hydrolysis,  the  nucleic  acid  may 
be  broken  up  into  its  proximate  constituents.  These  differ  according  to 
the  source  of  the  nucleic  acid.  Whatever  the  source,  the  disintegration 
products  belong  to  closely  alUed  groups  of  substances.  These  may  be 
grouped  as  follows  : 

(1)  Pliosflioric  Acid.  The  proportion  of  phosphorus  varies  within  but 
narrow  hmits  in  the  different  nucleic  acids,  the  average  being  about  10  per 
cent.  It  is  probable  that  the  phosphoric  acid  represents,  so  to  speak,  the 
combining  medium  for  the  groups  contained  in  the  nucleic  acid  molecule,  as 
is  the  case  with  the  various  groups  which  make  up  the  lecithin  molecule. 

(2)  The  Purine  Bases.  Among  the  products  of  disintegration  of  nucleic 
acid  we  find  constantly  one  of  the  bases  adenine,  C5H5N5,  and  guanine 
(C'sHgNgO).  These  substances,  with  the  products  of  their  oxidation,  xan- 
thine, C5II4N4O2,  hypoxanthine,  C5H4N4O,  have  long  been  known  to  be 
ch)sely  alhed  to  uric  acid,  C5H4N4O3,  but  their  true  relationships  have  only 
been  thoroughly  known  since  the  researches  of  Fischer  on  this  group. 
According  to  Fischer  they  can  be  all  regarded  as  derivatives  of  the  body 
purine,  iN=«CB: 

I  I 

II  II  >H« 

3X 4(J ]^9     /^ 

Each  group  in  this  purine  ring  is  generally  designated  with  a  number  indicated 

in  the  structural  formula,  in  order  that  it  may  be  possible  to  represent  the 

position  of  any  substituted  groups  in  its  derivatives.     Uric  acid  itself  is 

2-f)-8-trioxypurine  with  the  following  formula  : 

HN— CO 

I       I 
00     C— NH^ 

I    II         >co 

HN— C— NH/ 


THE  PROTEINS  •  103 

It  can  be  synthetised  by  fusing  together  in  a  sealed  tube  trichlorolactamide 
and  urea.     Thus  : 

NHg     CONH2  NH— CO 

II  II 

CO   +  CHOH  +  NH2  =    CO      C— NH  +  NH^Cl.  +  2HC1 

II  /CO  I  II  /CO 

NH,     CCI3  NH2"  NH— O-NH-^ 

The  relation  of  xanthine,  hypoxanthine,  guanine,  and  adenine  to  uric  acid 

is  shown  by  the  following  formulse  : 

NH— CO  HN CO 

II  II 

CO      C— NH.  CO— C^NH 

I  II  >C0  I         II  )CH 

NH— C— NH^  HN C— N    ^ 

Uric  acid  Xanthine 

2-6-8-trioxypurine  2-6-dioxypurine 


HN— CO 

N 

=  C.NH2 

NH— CO 

1          1 

HC     C  — NHx 

II      11             >H 
N— C  — N  ^ 

HC 

II 
N- 

C— NHx 

-    O-N    ^ 

I  1 
NHgC        O-NHx 

II  11           >CH 
N—  C^-N    ^ 

Hypoxanthine  Adenine  Guanine 

6-oxypurine  6-amino-puriae  2-amino  6-oxypurine 

Closely  allied  to  this  group  of  bodies  are  the  chief  constituents  of  tea, 
coffee,  and  cocoa,  namely  caffeine,  which  is  trimethvl  diox^^urine,  and 
theobromine,  which  is  dimethyl  dioxypurine.  From  the  structural  formulae 
given  it  will  be  seen  that  the  purine  radical  contains  two  nuclei.  The 
nucleus  N C 

C    C 

I      I 
N— C 

is  spoken  of  as  the  pyrimidine  nucleus,  pyrimidine  having  the  formula 

iN=  «CH 

I       I 
''HC     ''CH 

I       II 
»N— "CH 

The  other  is  the  radical  which  we  have  met  vnth.  already  in  histidine,  a 

•  lisintegration  product  of  proteins,  namely  iminazol  : 

HC— NH 
II  >CH 

HC— N   ^ 

Besides  the  purine  bases  proper,  we  find  among  the  disintegration  products 

of  nucleic  acid  a  series  of  bases  derived  from  the  pyrimidine  ring.      These 

are  uracil,  thymine,  and  cytosine. 

Uracil  is  2-6-dioxypyrimidine,  NH — CO 

I         I 
CO—  CH 

NH— CH 


104  PHYSIOLOGY 

Thymine  is  5-methyl  uracil,    NH— CO 

1         I 
CO      C.CH3 

I    II 

NH— CH 

while  CYTOSiNE  is  6-amino-2-oxypyrimidine, 

N    ^C.NHs 

I  I 

CO      CH 

I  II 

NH— CH 

Besides  these  two  groups  of  nitrogenous  compounds  derived  from  the 
purine  and  pyrimidine  rings,  many  nucleic  acids  yield  on  hydrolysis  a  carbo- 
hydrate. Thus,  Hammarsten  has  isolated  a  pentose,  from  the  nucleo- 
proteins  of  the  pancreas.  It  is  supposed  that  the  nucleic  acid  of  the  thymus 
gland  contains  a  hexose,  since  it  is  possible  to  spht  off  from  it  Isevuhnic  acid, 
which  is  one  of  the  first  products  of  the  decomposition  of  a  hexose.  The  com- 
plex constitution  of  the  nucleic  acids  and  nucleoproteins  may  be  rendered 
clearer  from  the  following  schema  : 


on  digestion  yields 


Nucleo -protein 


nuclein         proteoses  and  peptones 
dissolved  in  alkali  and  precipitated 
with  hydrochloric  acid  yields 


nucleic  acid  acid  derivatives  of  protein,  histones 

or  protamines 
hydrolysed  yields 


phosphoric  acid 


reducing  sugar 
pentose  or 
hexose 


purine  bases 
adenine 
guanine 


pyrimidine  bases 
uracil 
thymine 
cytosine 


It  must  not  be  imagined,  however,  that  all  these  disintegration  products 
are  present  in  all  nucleic  acids.  Thus  the  nucleic  acid  derived  from  the 
pancreas,  the  so-called  guanyhc  acid,  yields  of  the  purine  bases  only  guanine, 
and  of  the  pyrimidine  bases  only  thymine  and  uracil,  and  every  variety  is 
met  with  as  we  analyse  the  nucleic  acids  of  different  origin.  The  fact  that 
nucleic  acid  is  a  characteristic  and  necessary  constituent  of  all  nuclei  adds 
interest  to  the  divergence  of  its  constituent  radicals  from  those  which  dis- 
tinguish the  proteins  of  the  cell  protoplasm.  Further  importance  is  lent  to 
this  section  of  the  chemistry  of  the  body  by  the  close  relationship  which  we 
shall  have  to  study  later  between  the  nuclein  metabolism  of  the  body  and 
the  production  and  excretion  of  uric  acid. 

(c)  The  Glycoproteins.  In  the  glycoproteins  the  prosthetic  group  is 
represented  by  a  carbohydrate  radical,  generally  containing  nitrogen,  such 
as  glucosamine  or  galactosamine.    They  are  spht  into  their  two  constituents. 


THE  PROTEINS  105 

protein  and  carbohydrate  radical,  on  prolonged  boiling  with  dilute  mineral 
acids  or  by  the  action  of  alkaUes.  They  may  be  divided  into  the  two  main 
groups  of  mucins  and  mucoids. 

The  mucins  play  a  large  part  in  the  animal  kingdom  as  protective  agents. 
They  form  the  shmy  secretion  which  covers  the  inner  surface  of  the  mucous 
membranes  and  the  outer  surface  of  many  marine  animals,  and  is  secreted 
either  by  the  goblet  cells  of  the  epithelium  or  by  special  groups  of  cells 
collected  together  to  form  a  mucous  gland.  They  may  be  precipitated  from 
their  solutions  or  semi-solutions  by  the  addition  of  acids,  and  after  precipita- 
tion need  the  addition  of  alkalies  for  their  re-solution.  They  are  not  coagu- 
lable  by  heat.  The  presence  of  their  protein  moiety  causes  them  to  give 
the  various  typical  protein  tests,  such  as  the  xanthoproteic,  Millon's,  the 
biuret  reaction,  and  so  on.  Prolonged  boiling  with  acids  sphts  the  molecule, 
with  the  production  of  acid  metaprotein  and  albumoses  and  glucosamine. 
From  the  mucin  of  frogs'  eggs  a  similar  treatment  results  in  the  production  of 
galactosamine. 

With  the  mucins  may  be  classified  certain  bodies  wliich  have  been  derived  from 
ovarian  cysts,  namely,  pseudomucin  and  paramucin.  Pseudomucin  occurs  as  a  con- 
stituent of  the  colloid  material  from  ovarian  tumours.  It  forms  slimy  solutions  wliich 
do  not  coagulate  by  heat  and  are  not  precipitated  by  acetic  acid.  It  is  precipitated 
Ijy  alcohol,  the  precipitate  being  soluble  in  water  even  after  standing  a  long  time  under 
the  ak'oliol.  On  boiling  with  acid  it  gives  a  reducing  substance.  Paramucin  differs 
from  the  above  in  reducing  Fehling's  solution  before  boiling  with  acids.  Otherwise 
it  resembles  jiseudomucin.  Leathes,  in  investigating  this  body,  isolated  from  it  a 
reducing  substance  which  apparently  was  an  amino-derivative  of  a  disaccharide, 
|)cnha])s  in  combination  with  glycuronic  acid. 

The  mucoids  include  a  number  of  substances  which  may  be  extracted 
from  various  tissues  by  the  action  of  weak  alkalies,  e.g.  from  tendons,  bone, 
and  cartilage.  The  best  studied  example  of  this  group  is  the  chondromucoid 
which,  with  collagen,  forms  the  ground  substance  of  cartilage.  Chondro- 
mucoid is  especially  rich  in  sulphur  and  gives  protein  by  long  treatment  with 
weak  alkali.  On  boiling  for  a  short  time  with  acid  it  is  decomposed  into 
sulphm-ic  acid  and  chondroitin,  and  this  latter,  on  further  action  of  the  acid, 
is  converted  into  a  substance  chondrosin,  which  is  certainly  an  amino- 
derivative  of  a  polysaccharide  containing  the  elements  of  glycuronic  acid  and 
an  amino-disaccharide.  Chondroitin-sulphuric  acid  occurs  not  only  in 
cartilage  but  also  in  bone,  yellow  elastic  tissue,  white  fibrous  tissue,  and  as  a 
constant  constituent  of  the  lardacein  or  amyloid  substance  wliich  occurs  as  a 
deposit  in  the  middle  coat  of  the  blood-vessels  as  the  result  of  syphihs  or 
long-continued  suppuration,  and  gives  rise  to  the  condition  known  as  '  lar- 
daceous  disease."  Another  example  of  this  class  of  nuicoids  is  ovomucoid, 
which  is  a  constituent  of  egg-white.  In  order  to  prepare  ovonuicoid  the 
globulin  and  albumin  are  precipitated  by  boiling  diluted  egg-white.  From 
the  iiltrate  ovomucoid  can  then  be  thrown  down  by  alcohol.  A  similar  body 
has  ))een  prepared  from  blood  serum.  Both  these  mucoids  yield  a  large 
amount  of  reducing  substance  on  hydrolysis.  Thus  from  100  grm.  of  ovo- 
mucoid it  is  possible  to  prepare  30  grm.  of  glucosamine. 

4* 


106  PHYSIOLOGY 

(10)  THE  ALBUMINOIDS  OR  SCLERO-PROTEINS.     Under  this  heading 
are  grouped  a  number  of  diverse  substances  which  play  an  important  part 
in  building  up  the  framework  of  the  body.     Their  value  as  skeletal  tissue 
seems  to  be  determined  by  their  insoluble  character.     On  this  account  it  is 
practically  impossible  to  speak  of  purifying  them.     In  every  case  we  can 
simply  take  the  residue  of  a  skeletal  tissue  which  is  left  after  extraction  of 
the  soluble  constituents.     When  broken  down  by  the  action  of  strong  acids 
they  yield  a  series  of  disintegration  products  which  are  included  among  those 
we  have  already  studied  as  the  disintegration  products  of  proteins.     Their 
difference  from  the  proteins  which  are  employed  in  metabohsm  for  their 
nutritive  value  is  caused  either  by  the  absence  of  certain  groups  common 
to  all  the  nutritive  proteins,  by  the  presence  of  an  excess  of  one  or  two  groups, 
or  by  the  presence  of  certain  polypeptides  which  present  considerable  resist- 
ance to  the  action  of  digestive  ferments.     This  class  plays  the  part  in  the 
animal  economy  which  in  the  vegetable  kingdom  is  filled  by  the  anhydrides 
of  the  hexoses  and  pentoses,  e.g.  the  celluloses,  Hgnin,  the  pentosanes,   &c. 
Collagen  forms  the  main  constituent  of  white  fibrous  tissue  and  the  ground 
substance  of  bone  and  cartilage.     It  is  insoluble  in  water,  hot  or  cold,  and  in 
trypsin.     Under  the  action  of  acids  or  when  subjected  to  prolonged  boihng 
with  water,  especially  under  pressure,  it  is  converted  into  gelatin,  which  is 
soluble  in  hot  water,  forming  a  colloidal  solution  hquid  at  high  temperatures, 
but  setting  to  a  jelly  when  cold.     When  subjected  to  acid  hydrolysis  it  gives 
a  series  of  amino-acids  from  which  tyrosine  and  tryptophane  are  wanting. 
On  this  account  gelatin  does  not  give  any  reaction  either  with  Millon's 
reagent  or  with  glyoxyhc  acid.     On  the  other  hand,  there  is  a  preponderance 
of  such  groups  as  glycine  and  phenylalanine,  and  it  is  probable  that  glycine, 
phenylalanine,  and  leucine  are  joined  together,  perhaps  with  other  amino- 
acids,  to  form  a  polypeptide  which  is  not  attacked  by  digestive  ferments,  and 
therefore  determines  the  resistance  of  the  original  collagen  molecule  to  solu- 
tion.    Gelatin  is  precipitated  by  tannic  acid,  but  not  by  acetic  acid.     It  is 
dissolved  with  hydrolysis  by  gastric  juice  or  by  pancreatic  juice,  whereas 
collagen,  its  anhydride,  is  imafEected  by  the  latter.     On  prolonged  boihng  in 
water  it  is  converted  into  a  modification  which  does  not  form  a  jelly  on 
cooling.     Under  the  action  of  formaldehyde  it  is  converted  into  an  insoluble 
modification  which  does  not  melt  on  warming. 

Reticulin.  This  name  has  been  applied  to  the  tissue  which  forms  the  supporting 
network  of  adenoid  tissue,  and  has  also  been  described  in  the  spleen,  the  mucous  mem- 
brane of  the  intestine,  liver,  and  kidneys.  It  differs  from  collagen  in  resisting  chgestion 
by  gastric  juice,  and  also  in  containing  phosphorus  in  organic  combination.  According 
to  Halliburton  there  is  no  essential  difference  between  reticulin  and  collagen. 

The  keratins  are  produced  by  the  modification  of  epithehal  cells  and 
form  the  horny  layer  of  the  skin  as  well  as  the  main  substance  of  hairs, 
wool,  nails,  hoofs,  horns,  and  feathers.  They  are  distinguished  by  their 
insolubihty  in  water,  dilute  acids  or  alkahes,  and  in  the  higher  animals 
pass  through  the  ahmentary  canal  unchanged.  Although  differing  in  their 
elementary  composition,  according  to  the  tissue  from  which  they  are  pre- 


THE  PROTEINS 


107 


pared,  they  are  all  distinguished  by  the  very  large  amount  of  sulphur  present 
in  their  molecule.  The  greater  part  of  this  sulphur  is  in  the  form  of  cystine, 
of  which  as  much  as  10  per  cent,  can  be  extracted  from  keratin.  They  also 
yield,  on  acid  hydrolysis,  tyrosine  in  larger  quantities  than  is  the  case  with  the 
ordinary  proteins. 

Neurokeratin,  which  forms  the  basis  of  the  neuroghal  framework  of  the 
central  nervous  system,  must  be  grouped  by  its  general  behaviour  as  well  as 
by  its  origin  \\^th  the  keratins.  It  resembles  the  other  members  of  this  class 
in  its  insolubility  and  in  its  high  content  in  sulphm-.  It  is  extracted  from 
nervous  tissues  by  boiling  these  with  alcohol  and  ether  and  then  submitting 
the  tissue  to  prolonged  tryptic  digestion,  which  leaves  the  neurokeratin 
unaffected. 

Elastin  is  a  constant  constituent  of  the  connective  tissues,  where  it  forms 
the  elastic  fibres.     In  some  locaHties,  as  in  the  Hgamentum  nuchse,  practically 


Fibroin 

Keratin 

Keratin 

Keratin 

of 

Elastin 

from 

from 

from 

Gelatin 

sUk 

horn 

horsehair 

feathers 

Glycine  .... 

36-0 

25-75 

0-45 

4-7 

2-6 

16-5 

Alanine 

21-0 

6-6 

1-6 

1-5 

1-8 

0-8 

Amino-valerianic  acid 

0-0 

1-0 

4-5 

0-9 

0-5 

10 

Proline  .... 

|. resent 

1-7 

5-2 

Leucine .... 

1-5 

^  21-4 

15-3 

71 

8-0 

21 

Phenylalanine 

1-5 

3-9 

1-9 

0-0 

0-0 

0-4 

Glutaroic  acid 

0-0 

0-8 

17-2 

3-7 

2-3 

0-88 

Aspartic  acid 

present 

present 

2-5 

0-3 

11 

0-56 

Cystine  .... 

— 

— 

7-5 

— 

— 

Serine    .... 

1-6 



11 

0-6 

0-4 

0-4 

Tyrosine 

10-5 

0-34 

3-6 

3-2 

3-6 

0-0 

Tryptophane  . 

— 

— 

— 

— 

— 

0-0 

Lysine    .... 

traces 

— 

0-2 

11 

— 

2-75 

Arginine 

1-0 

0-3 

2-7 

4-5 

— 

7-62 

Histidine 

small 
amount 

— 

— 

0-6 

— 

0-4 

Oxyproline 

— 

• — 

— 

— 

30 

the  whole  tissue  is  made  up  of  these  fibres.  Elastin  is  insoluble  in  water, 
alcohol,  or  ether,  or  in  dilute  acids  and  alkahes.  It  is  slowly  dissolved  on 
■prolonged  treatment  with  gastric  juice,  but  is  practically  unaffected  in  the 
alimentary  canal.     It  gives  the  xanthoproteic  and  Millon's  tests. 

Other  members  of  this  group  are  fibroin,  which  forms  the  main  j  substance 
of  silk,  spongin,  the  homy  framework  of  sponges,  conchiolin,  the  ground 
substance  of  shells,  and  perhaps  the  amyloid  substance  or  lardacein  which  we 
have  already  mentioned  in  connection  with  the  mucoids.  All  these  sclero- 
proteins  present  considerable  differences  in  their  quahtative  and  quantitative 
composition  in  aniino-acids.  Their  proximate  composition  is  shown  in  the 
Table  given  above  (Abderhalden). 

We  have  finally  to  mention  a  miscellaneous  collection  of  bodies  which  are 
aUied  to  the  proteins  and  are  distinguished  by  their  extreme  insolubility. 


108  PHYSIOLOGY 

They  are  often  designated  as  albmnoids.  Of  their  composition  we  know 
practically  nothing.  Under  this  name  are  grouped  such  substances  as  those 
forming  the  membrana  propria  of  glands,  the  sarcolemma  of  striated  muscle, 
the  albumoid  of  the  crystalhne  lens,  the  ground  substance  of  the  chorda 
dorsahs,  the  organic  basis  of  fish  scales,  and  many  similar  substances.  In 
every  case  the  substance  is  characterised  necessarily  according  to  its  place 
of  origin,  httle  or  nothing  being  known  as  to  its  chemical  composition. 


SECTION  VI 
THE  MECHANISM  OF  ORGANIC  SYNTHESIS 

THE  ASSIMILATION   OF  CARBON 

The  building  up  of  protoplasm  from  the  material  which  is  available  at  the 
earth's  surface  must  be  an  endothermic  process.  The  food  presented  to  the 
plant  contains  the  necessary  elements,  but  as  a  rule  in  a  state  of  complete 
oxidation.  The  energy  of  the  hving  plant,  as  of  animals,  is  derived  almost 
entirely  from  the  oxidation  of  its  constituents.  The  building  up  of  un- 
organised into  organised  material  must  therefore  be  effected  at  the  expense 
of  energy  supplied  from  without.  The  source  of  this  energy  is  the  sun's  rays. 
The  machine  for  the  conversion  of  solar  radiant  energy  into  the  chemical 
potential  energy  of  protoplasm  is  the  green  leaf.  Here  a  deoxidation  of  the 
carbon  dioxide  of  the  atmosphere  takes  place,  with  the  production  of  carbo- 
hydrates, generally  in  the  form  of  starch.  The  formation  of  starch  must  be 
regarded  as  the  first  act  in  the  life-cycle,  since  this  substance  serves  as  a 
source  of  energy  to  the  already  formed  protoplasm  in  its  work  of  building  up 
all  the  other  constituents  of  the  living  cell.  It  is  the  solar  energy  captured 
by  the  green  leaf  which  is  utihsed  by  all  plants  devoid  of  chlorophyll,  as  well 
as  by  the  whole  animal  kingdom. 

There  are  one  or  two  exceptions  to  this  statement.  Thu.s  the  bacterium  nitrc- 
somonas,  described  by  Winogradsky,  grows  on  a  medium  devoid  of  all  organic  con- 
stituents, and  derives  the  energy  for  its  constructional  activity  from  that  set  free  in 
the  conversion  of  ammonia  into  nitrites.  The  sulphur  bacteria  apparently  derive 
their  energy  from  the  decomposition  of  hydrogen  sulphide  and  the  liberation  of 
sulphur. 

The  fundamental  importance  of  this  process  of  assimilation  for  the  whole 
of  physiology  justifies  some  accomit  of  the  researches  which  have  been 
directed  to  the  elucidation  of  its  mechanism.  The  production  of  oxygen  by 
the  green  plant  was  disovered  by  Priestley  in  1772,  and  a  few  years 
later  Ingenhaus  showed  that  this  production  occurred  only  in  the  light  and 
was  effected  only  by  green  plants.  De  Saussure  (180-4)  pointed  out  that  the 
essential  process  concerned  was  a  setting  free  of  the  oxygen  from  the  carbon 
dioxide  of  the  atmosphere,  and  recognised  that  the  co-operation  of  water 
was  also  necessary.  Mohl  in  1851  observed  the  formation  of  starch  grains 
in  the  chlorophyll  corpuscles,  and  regarded  these  as  the  first   products   of 

109 


110  PHYSIOLOGY 

assimilation.  The  organs  of  carbon  dioxide  assimilation  are  the  chloroplasts. 
These,  which  are  responsible  for  the  green  colour  of  plants,  are  generally 
small  oval  bodies  embedded  in  the  cytoplasm,  but  sometimes,  as  in  spirogyra, 
may  have  the  form  of  spiral  bands.  In  a  plant  which  has  been  kept  for  some 
time  in  the  dark,  or  in  an  atmosphere  free  from  carbon  dioxide,  they  present 
no  enclosed  granules.  Within  three  to  five  minutes  after  exposure  to  hght 
in  the  presence  of  carbon  dioxide,  starch  granules  make  their  appearance 
within  them,  and  grow  rapidly,  assuming  the  typical  laminated  structure. 
Engelmann  has  pointed  out  a  means  by  which  it  can  be  proved  that  the 
chloroplasts  carry  out  this  process  without  the  co-operation  of  the  rest  of  the 
cytoplasm.  Certain  bacteria  have  a  great  avidity  for  oxygen  and  present 
movements  only  in  the  presence  of  this  gas.  If  a  filament  of  spirogyra  be 
placed  in  a  suspension  of  these  bacteria  and  be  examined  under  a  microscope, 
the  bacteria  will  be  seen  to  congregate  in  the  immediate  neighbourhood  of  the 
chlorophyll  bands.  The  same  phenomenon  is  observed  in  the  case  of 
chlorophyll  corpuscles  isolated  by  breaking  up  the  cells  in  which  they  were 
contained.  These  corpuscles  therefore  take  up  carbon  dioxide  and  water, 
and  form  carbohydrate  and  oxygen,  as  follows  : 

n(6C02  +  5H2O)  =  (CgHioOs),  +  n{QO,) 

The  whole  structure  of  the  green  leaf  is  directed  to  the  furthering  of  this 
process.  Its  cells  contain  chlorophyll  corpuscles,  which  change  their  position 
according  to  the  intensity  of  the  illumination.  A  free  supply  of  air  to  all 
the  cells  is  provided  by  means  of  the  stomata  on  the  under  surface  of  the 
leaf.  Horace  Brown  has  shown  that  the  rate  at  which  carbon  dioxide  diffuses 
through  such  fine  openings  is  as  great  as  if  the  whole  leaf  were  an  absorbing 
surface.  We  get,  therefore,  optimum  absorption  of  carbon  dioxide  by  the 
leaf,  with  the  maximum  protection  of  the  absorbing  tissue  and  the  necessary 
hmitation  of  loss  of  water  by  transpiration. 

In  Adew  of  the  very  small  amount  of  carbon  dioxide  in  the  atmosphere, 
the  extent  of  the  assimilatory  process  is  remarkable.  One  square  metre  of 
leaf  of  the  catalpa  can  lay  on  1  grm.  of  sohd  per  hour,  using  up  for  this  pur- 
pose 784  ccm.  carbon  dioxide.  The  rapidity  of  assimilation  is  increased 
within  Mmits  by  increasing  the  intensity  of  the  hght  falhng  on  the  plant, 
though  an  over- stimulation  of  the  process  is  prevented  by  the  movements  of 
the  chloroplasts  just  mentioned.  It  is  also  increased  by  raising  the  per- 
centage of  carbon  dioxide  in  the  atmosphere  supplied  to  the  leaf.  The 
optimum  percentage  of  carbon  dioxide  will  of  course  vary  with  the  other 
conditions  of  the  leaf.  In  certain  experiments  Kreusler  found  the  optimum 
to  be  about  1  per  cent.  Taking  the  amount  of  assimilation  in  normal  air  with 
•03  per  cent,  carbon  dioxide  at  100,  the  assimilation  in  an  atmosphere  con- 
taining 1  per  cent,  was  237,  and  was  not  increased  by  raising  the  percentage 
of  carbon  dioxide  to  7  per  cent.  Owing  to  the  decomposition  of  the  organic 
matter  of  the  soil,  the  percentage  of  carbon  dioxide  near  the  ground  is  always 
greater  than  in  the  higher  strata  of  the  atmosphere — a  fact  which  is  taken 


THE  MECHANISM  OF  ORGANIC  SYNTHESIS  111 

advantage  of  by  the  low-growing  plants  and  herbage.  Other  necessary  con- 
ditions of  assimilation  are  the  presence  of  water  and  the  maintenance  of  a 
certain  external  temperature.  The  absorption  of  the  sun's  rays  by  the  leaf 
raises  the  temperature  of  the  later  above  that  of  the  surrounding  medium, 
and  so  quickens  the  process  of  assimilation. 

The  assimilation  of  carbon  dioxide,  the  formation  of  starch,  and  the 
evolution  of  oxygen  will  go  on  in  the  isolated  chloroplast.  In  the  absence 
of  chlorophyll,  as  in  an  etiolated  leaf,  the  formation  of  starch  will  take  place 
if  the  plant  be  supplied  with  a  sugar  such  as  glucose,  and  this  conversion 
represents  the  main  function  of  the  leucoplasts  present  in  all  the  cells  of  the 
reserve  organs  of  plants.  In  the  absence  of  chlorophyll  no  decomposition  of 
carbon  dioxide  takes  place,  so  that  this  pigment  is  evidently  essential  for 
the  utilisation  of  the  sun's  energy.  Chlorophyll  may  be  extracted  from 
leaves  by  means  of  absolute  alcohol.  A  solution  is  thus  obtained  which  is 
green  by  transmitted  and  red  by  reflected  light,  i.e.  chlorophyll  is  a  fluorescent 
substance.  It  presents  four  absorption  bands,  the  chief  being  an  intense 
black  band  between  Fraunhofer's  lines  B  and  C.  If  the  chlorophyll  is  the 
means  of  conversion  of  the  solar  into  chemical  energy,  the  conversion  must 
take  place  at  the  expense  of  the  Ught  which  is  absorbed  by  the  pigment. 
One  would  expect,  therefore,  the  process  of  assimilation  to  be  most  pio- 
iiounced  in  those  parts  of  the  spectrum  corresponding  to  the  absorption 
bands — an  expectation  which  has  been  realised  by  experiment. 

As  to  the  exact  chemical  changes  effected  by  these  absorbed  rays  physio- 
logists are  still  undecided.  There  can  be  no  doubt  that  an  early  product  of 
the  process  is  a  hexose,  which  is  rapidly  converted  into  cane  sugar  or  into 
starch.  It  was  suggested  by  Baeyer  in  1870  that  carbon  dioxide  was 
reduced  to  formaldehyde,  which  later  by  condensation  yielded  sugar.  We 
know  that  formaldehyde  easily  polymerises  to  form  a  mixture  of  hexoses, 
but  until  recently  no  evidence  had  been  brought  forward  of  its  presence  as 
an  lutei'mediate  product  in  the  assimilatory  process.  For  most  plants, 
indeed,  formaldehyde  is  extremely  poisonous,  though  certain  algae,  as  well 
as  the  water-plant,  Elodea,  can  stand  a  solution  containing  -001  per  cent, 
formaldehyde.  Bokorny  stated  that  spirogyra  could  form  starch  out  of  such 
derivatives  of  formaldehyde  as  sodium  oxymethyl-sulphonate,  or  from 
methylal.  The  difficulty  in  these  cases  is  that  possibly  a  spontaneous 
formation  of  sugar  from  the  formaldehyde  had  taken  place  in  the  solution  and 
that  the  plants  were  using  up  the  sugar  rather  than  the  formaldehyde  as  the 
source  of  their  starch. 

One  nnist  assume,  with  Timiriazeft',  that  the  function  of  chlorophyll  in 
the  process  of  assimilation  is  that  of  a  sensitiser.  Just  as  the  addition  of 
eosin  to  the  emulsion  used  for  coating  photographic  plates  will  render  these 
sensitive  to  the  red  and  green  parts  of  the  spectrum,  i.e.  will  excite  change  in 
the  silver  salt  when  light  from  these  parts  of  the  spectrum  falls  upon  it,  so 
the  chlorophyll  serves  as  a  means  by  which  the  absorbed  solar  energy  can  be 
utilised  for  the  production  of  chemical  change  in  the  chloroplast.     Attempts 


112  PHYSIOLOGY 

have  been  made  to  imitate  this  process  outside  the  plant.  Thus  Bach  passed 
a  stream  of  carbon  dioxide  through  a  1  -5  per  cent,  solution  of  a  fluorescent 
substance,  uranium  acetate,  in  sunhght.  As  a  result  there  was  a  precipitate 
of  uranium  oxide  and  peroxide,  with  the  formation  of  traces  of  formaldehyde. 
Usher  and  Priestley,  on  treating  a  solution  of  carbon  dioxide  with  1-5  per 
cent,  uranium  acetate  or  sulphate  in  bright  sunlight,  obtained  uranium 
peroxide  and  formic  acid,  but  no  formaldehyde.  The  formation  of  peroxides 
in  these  conditions  suggests  that  the  first  change  in  the  chloroplast  may  be 
as  follows  : 

CO2  +  3H2O  =  2H2O2  +  CH2O 

Such  a  reaction  must  be  regarded  as  reversible  since  the  hydrogen  per- 
oxide first  formed  would  tend  to  oxidise  the  formaldehyde  again.  Moreover 
it  would  have  a  destructive  influence  on  the  chlorophyll  itself,  which  is  easily 
oxidised.  In  order,  therefore,  that  the  reaction  should  go  on  in  one  direction 
only,  i.e.  that  of  assimilation,  means  must  be  present  in  the  chlorophyll  cor- 
puscles for  the  removal  of  both  hydrogen  peroxide  and  formaldehyde  as  soon 
as  they  are  formed.  The  removal  of  the  hydrogen  peroxide  can  be  efiected 
by  a  catalase,  which  is  fairly  widely  distributed  in  plants  and  has  been  shown 
by  the  last-named  authors  to  be  present  in  the  chloroplasts.  In  order  to 
demonstrate  the  production  of  the  first  result  of  assimilation,  i.e.  formalde- 
hyde, the  further  stages  in  its  conversion  must  be  stopped  by  kilhng  the  plant 
and  the  catalase  it  contains.  They  therefore  placed  leaves,  which  had  been 
boiled,  in  water  saturated  with  carbon  dioxide  and  exposed  them  to  bright 
sunlight.  The  leaves  were  bleached  by  the  oxidation  of  the  chlorophyll,  and 
some  substance  of  an  aldehydic  nature  was  produced,  as  shown  by  the 
red  colour  obtained  on  placing  them  in  rosanihne,  previously  decolorised 
with  sulphurous  acid. 

Two  proofs  were  brought  forward  that  this  substance  was  formaldehyde  : 

(a)  Some  of  the  bleached  leaves  were  soaked  for  twelve  hours  in  aniline  water.  The 
chloroplasts  under  the  microscope  were  seen  to  contain  crystals  resembling  methylene 
aniline. 

(b)  The  leaves  were  distilled  in  a  current  of  steam.  The  distillate  was  shown  to 
contain  formaldehyde  by  the  formation  of  methylene  aniline  crystals  on  treatment 
with  aniline,  and  by  the  preparation  from  it  of  the  characteristic  tetrabrome  derivative 
of  hexamethylenetetramine. 

Usher  and  Priestley  conclude  that  the  first  products  of  the  photolysis 
of  carbonic  acid  are  hydrogen  peroxide  and  formaldehyde.  Both  these 
substances  are  rapidly  removed  from  the  reaction.  The  hydrogen  peroxide 
is  broken  up  by  the  catalase  into  water  and  oxygen  which  is  turned  out  by  the 
plant.  The  formaldehyde  is  at  once  polymerised  in  the  protoplasm  of  the 
chloroplast  with  the  formation  first  of  a  hexose  and  then  of  starch.  The 
formaldehyde,  if  not  removed  in  this  way,  destroys  the  catalase.  The 
hydrogen  peroxide,  if  not  broken  up  by  the  catalase,  destroys  the 
chlorophyll. 


THE  MECHANISM  OF  ORGANIC  SYNTHESIS  1 13 

The  relations  between  the  various  factors  in  this  process   may  be  dia- 
grammatically  expressed  thus  : 

Carbon  dioxide  +  Water 


(//  7iot  removed,  destroys)  ->     Chlorophyll 


^ 


Hydrogen  peroxide  +  Formaldehyde 

/ 
^(//  not  removed,  foisons) 

Enzyme  Living  protoplasm 

Oxygen  Carbohydrates 

In  thus  reducing  certain  of  the  stages  in  the  assimilation  of  carbon 
to  phenomena  which  can  be  imitated  outside  the  Hving  organism  we  have 
made  considerable  strides  in  the  '  understanding  '  of  the  process.  The  stage 
for  which  the  vitality  of  the  chloroplast  is  absolutely  essential  is  the  formation 
of  starch  from  formaldehyde.  Outside  the  body,  our  polymerisation  of 
formaldehyde  results  in  the  formation  of  a  mdxture  of  sugars  which  are  optic- 
ally inactive.  The  same  process,  in  the  hving  cell,  leads  to  the  production 
of  optically  active  sugars  which  are  connected  stereochemically  and  mutually 
convertible  one  into  the  other,  e.g.  fructose  and  glucose.  The  derivatives  of 
protoplasm,  containing  asymmetric  carbon  atoms,  are  in  the  same  way 
optically  active,  and  it  seems  that  the  asymmetry  of  the  protoplasmic 
molecule  conditions  a  corresponding  asymmetry  in  the  substance  which  it 
builds  on  to  itself.  The  protoplasm  furnishes,  so  to  speak,  a  mould  in  which 
polymerisation  of  formaldehyde  can  result  only  in  the  production  of  sugars 
of  certain  definite  stereochemical  configurations. 

Few,  if  any,  chemical  reactions  are  pure.  Nearly  all  are  attended  with 
by-reactions,  so  that  the  yield  of  end  product  never  attains  100  per  cent,  of 
the  theoretical  yield.  Even  if  the  above  mechanism  be  regarded  as  the 
chief  one,  it  is  probable  that  side  reactions  take  place  at  the  same  time,  so  that 
we  may  have  the  formation  of  substances  such  as  glyoxylic  acid  and  other 
derivatives  of  the  fatty  acid  series.  Such  by-products  might  play  an  im- 
portant part  in  the  other  synthetic  activities  of  the  cell,  and  especially  in  the 
formation  of  fats  and  proteins. 

THE   FORMATION   OF  PROTEINS 

Our  knowledge  of  the  mechanism  by  which  proteins  are  synthetisod 
in  plants  is  still  more  incomplete  than  that  of  the  synthesis  of  carbohydrates, 
and  we  are  reduced  in  most  cases  to  a  discussion  of  the  possible  ways  in 
which,  from  our  knowledge  of  the  chemical  behaviour  of  the  constituents  of 
the  protein  molecule,  we  might  conceive  of  its  formation.  We  can  at  any 
rate  state  the  problems  which  have  to  be  solved  and  study  the  conditions 
under  which  the  synthesis  of  protein  is  possible  in  plants  and  in  animals. 


114  PHYSIOLOGY 

We  know  that  plants  are  independent  of  any  organic  food  for  building 
up  their  various  constituents,  whether  carbohydrate,  protein,  or  iat,  pro- 
vided only  that  they  possess  chlorophyll  corpuscles  and  so  are  able  to  utihse 
the  energy  of  the  sun's  rays.  Most  plants  will  grow  in  the  dark  if  supphed 
with  sugar  and  with  combined  nitrogen  either  in  the  form  of  ammonia  or  of 
nitrates.  The  higher  plants  are  especially  dependent  on  the  presence  of 
nitrogen  in  the  latter  form,  and  it  is  on  this  account  that  the  nitrifying  bac- 
teria of  the  soil  acquire  so  great  an  importance  for  agriculture.  From  the 
carbon  dioxide  of  the  atmosphere  or  from  the  hexose  formed  by  the  assimila- 
tion of  carbon,  and  from  nitrogen,  in  the  form  either  of  ammonia  or  nitrates, 
together  with  inorganic  sulphates,  the  plant  cell  is  able  to  build  up  all  the 
various  types  of  protein  which  are  distributed  throughout  the  vegetable 
kingdom.  Our  study  of  the  disintegration  products  of  proteins  has  shown 
that  this  class  of  bodies  contains  a  large  number  of  the  most  diverse  groups, 
having  as  a  common  character  the  possession  of  nitrogen  in  their  molecule, 
generally  as  an  NHg  or  NH  group.  These  disintegration  products  can  be 
classified  as  follows  : 

(a)  Open  chain  amino-acids. 

(6)  HeterocycHc  compounds,  including : 

(1)  P}Trol  derivatives. 

(2)  Pyi-imidine  derivatives. 

(3)  Iminazol  derivatives. 

These  two  last  groups  co-exist  in  all  the  purine  compounds. 

{c)  Benzene  derivatives. 
[d)  Indol  derivatives. 

The  first  step  in  the  synthesis  of  proteins  is  probably  the  formation  of  these 
constituent  groups.  Just  as  in  digestion  the  protein  molecule  is  taken  to 
pieces  with  the  formation  of  the  difierent  amino-acids,  so  in  the  synthetic 
action  of  protoplasm  the  reverse  process  of  dehydration  occurs,  resulting 
in  a  couphng  up  of  the  different  groups,  as  has  been  effected  by  Fischer  in  the 
case  of  the  polypeptides.  Wherever  transport  of  protein  from  one  part  of  the 
organism  to  another  is  necessary  the  protein  is  carried,  not  in  its  original 
form,  but  in  the  hydrolysed  condition  of  amino-acids.  Thus  the  germination 
of  seeds  which  contain  rich  stores  of  protein  is  accompanied  by  a  liberation 
of  proteolytic  ferments  -wdthin  the  cells  of  the  seeds,  and  the  breakdown 
of  the  reserve  protein  into  its  constituent  amino-acids.  As  amino-acids  it 
is  transported  into  the  growing  tip  and  leaves  of  the  seedhng,  analysis  of  the 
latter  showing  a  very  large  percentage  of  nitrogen  in  the  form  of  amino-acids. 
This  is  especially  the  case  if  the  synthetic  functions  of  the  gromng  tip  are 
hindered  by  interference  with  assimilation,  as,  e.g.  by  keeping  the  plant  in  the 
dark.  Under  these  circumstances,  asparagine  may  form  as  much  as  25 
per  cent,  of  the  total  dried  weight  of  the  seedhng.  In  animals  the  greater 
part  of  the  protein  of  the  food  is  broken  down  into  its  constituent  amino- 
acids  in  the  intestine.     These  are  absorbed  and  probably  carried  to  the 


THE  MECHANISM  OF  ORGANIC  SYNTHESIS  115 

different  organs  of  the  body,  where  they  are  resynthetised,  generally  in 
different  proportions  from  those  of  the  original  protein,  into  the  protein 
specific  for  the  organ  or  tissue.  The  same  process  of  hydrolysis  and 
subsequent  synthesis  occurs  whenever  the  transport  of  protein  is  neces- 
sary from  one  organ  to  another.  We  shall  later  on  have  to  discuss  the 
possibihty  of  synthesis  of  the  different  amino-acids  in  animals.  AVe  need, 
therefore,  at  present  only  deal  with  the  possible  methods  by  which,  from  the 
glucose  or  substances  produced  in  the  assimilation  of  carbon  and 
from  the  ammonia  or  nitrates  derived  from  the  soil,  the  plant  is  able 
to  make  the  different  groups  which  go  to  the  building  up  of  the  protein 
molecule. 

All  the  amino-acids  contain  the  NHj  group  in  the  «  position.  We  can 
therefore  consider  them  as  formed  by  the  interaction  of  an  «-oxyacid  and 
ammonia.     Thus : 


CH3 

CH3 

CH.OH  +  NH3 

= 

CH.NH2  +  H-P 

COOH 

COOH 

lactic  acid 

alanine 

This  particular  example,  namely,  the  formation  of  alanine,  may  occur 
at  the  expense  of  the  glucose  produced  as  the  first  product  of  assimilation 
of  carbon  dioxide.  If  a  solution  of  glucose  together  with  lime  be  exposed  to 
sunlight  for  a  considerable  time  it  undergoes  decomposition  with  the  forma- 
tion of  lactic  acid.     Thus  : 

CeHi^Os        =        2C3He03 

glucose  lactic  acid 

This  change  of  glucose  to  lactic  acid  under  the  catalytic  influence  of  the 
alkaline  calcium  hydrate  probably  occurs  by  means  of  a  shifting  of  the 
elements  of  the  water,  a  process  which  in  many  long  chains  seems  to  occur 
with  considerable  facility,  and  is  dependent  on  the  spatial  configuration  of 
the  molecule  involved.  Thus  the  change  of  sugar  to  lactic  acid  is  readily 
eft'ected  by  means  of  many  micro-organisms  in  the  case  of  glucose,  fructose, 
and  mannose,  but  with  considerable  difficulty  in  the  case  of  galactose.  In 
the  three  former  sugars  the  atoms  lound  th(^  two  middle  carbon  atoms  of  the 
chain  are  disposed  thus  : 

OH.C.H  H.C.OH 

I  ^^^  I 

H.C.OH  OH.C.H 


116  PHYSIOLOGY 

When  either  of  these  arrangements  reacts  with  water,  thus  : 

CH2OH 


CH2OH 
CHOH 
OH.C.H 


HOOH 

I 
CHOH 

COH 


OH 


+ 


H 


CHOH 
COH  +  H2O 

CH2OH 
CHOH 
COH 


we  obtain  two  molecules  of  glyceric  aldehyde,  which  then  by  a  further 
shifting  of  the  OH  and  H  groups  becomes 

CH3 

CH.OH 

COOH 

lactic  acid 

Lactic  acid  with  ammonia  and  some  dehydrating  agent  will  give  amino- 
propionic  acid  or  alanine.  The  formation  of  the  higher  amino-acids  in- 
volves a  process  of  reduction  of  the  sugar  first  formed  in  the  chlorophyll- 
granules.  It  is  possible,  however,  that  the  starting-point  for  the  amino-acid 
synthesis  may  be,  not  a  hexose  itself,  but  some  other  substances,  formed, 
so  to  speak,  as  by-products  in  the  assimilation  of  sugar  from  carbon  dioxide. 
We  have  seen  reason  to  believe  that  the  first  result  of  the  action  of  the  sun's 
rays  within  the  chlorophyll  corpuscle  is  formaldehyde.  This  substance  in 
the  presence  of  calcium  carbonate  when  exposed  to  the  hght  gives  a  mixture 
of  glyceryl  aldehyde  and  dihydroxyacetone.  If  we  can  assume  that  acetone 
is  formed  from  the  latter  by  a  process  of  reduction,  we  might  possibly  derive 
leucine  from  an  interaction  of  this  substance  with  lactic  acid  and  ammonia. 
Thus  : 

CH3       CH3 


CH;,  CH5, 


CO -F  CH.OH  +  NH,  +  H, 


CH,    COOH 


\ch/ 


CH, 


+  2HoO 


CH.NH, 


COOH 


THE  MECHANISM  OF  ORGANIC  SYNTHESIS  117 

As  an  intermediate   product    in  the  synthesis  of  starch,   glyoxylic  acid 

CHO 

I  has  been  described  as  occurring  in  the  green  parts  of  plants.     This 

COOH 

substance  with  ammonia  gives  formyl  glycine,  and  by  the  splitting  oft  of 
formic  acid,  glycine  or  amino-acetic  acid.  Why  nitrates  are  necessary  for 
certain  forms  of  plants  is  not  at  present  understood.  In  the  proteins  nitrogen 
always  occurs  in  an  unoxidised  form  as  NH  or  NHg,  and  the  nitrates  taken 
up  from  the  soil  must  therefore  undergo  reduction  before  they  can  be  built 
into  the  protein  molecule.  It  is  supposed  that  they  may  pass  through  a  series 
of  reductions,  namely  : 

HNO3  HNO2  HNO  H2N— OH 

nitric  acid  nitrous  acid  hyponitrous  acid  hydroxylamine 

and  that  the  latter  substance  then  reacts  with  formaldehyde  or  other  sub- 
stance derived  from  the  carbon  dioxide  assimilation  to  form  amino-com- 
pounds.  In  general  we  may  say  that  the  probable  mechanism  of  formation 
of  amino-acids  is  the  production  of  a-oxyacids,  which  then  react  with 
ammonia  to  form  the  amino-acids  of  the  protein  molecule  ;  but  of  the 
exact  steps  in  this  process  we  are  at  present  ignorant.  Knoop's  work  would 
point  to  the  ketonic  acids  as  forming  one  step,  and  as  interacting  with 
ammonia,  A\ath  simultaneous  reduction,  to  form  amino-acids. 

The  pyrrol  ring  which  occurs  in  prohne  and  in  oxyproUne  may  possibly 
be  derived  from  an  open  chain  amino-acid,  and  it  has,  in  fact,  been  suggested 
that  the  proUne  fomid  in  the  products  of  the  acid  digestion  of  proteins  is 
derived  from  ornithine  by  a  process  of  condensation  with  the  loss  of  ammonia. 
Thus  : 

CH2NH2.CH2.CH2.CH.NH2COOH  becomes 
CH,.CH<,.CH,.CH.COOH 


or,  as  it  is  generally  written 


NH 
CHo— CH., 


CH      CH.COOH 

2 


NH 

Its  pie-existence  in  the  protein  molecule  is,  however,  practically  assured,  and 
it  plays  an  important  part  in  the  building  up  both  of  chlorophyll  and  of 
hsematin,  the  prosthetic  group  of  haemoglobin. 

CH— NH 
Iminazol  ||  ')CH 

CH— N    -^ 

occurs  in  histidine  (which  is  iminazol  alanine),  and  can  be  formed  fairly 
readily  by  the  action  of  certain  catalytic  agents  on  a  mixture  of  glucose  and 
ammonia.     Thus,  if  a  solution  of  glucose  with  ammonia  and  zinc  oxide  be 


118  PHYSIOLOGY 

exposed  to  light,  methyl  imiuazol  is  formed  in  large  quantities.  Windaus 
and  Knoop  imagined  that  in  this  process  glyceric  aldehyde  and  formaldehyde 
are  first  formed,  and  that  these  then  interact  with  ammonia  to  form  methyl 
iminazol. 

CH3 

C    — NH 

11  >H 

CH— N    ^ 

It  is  interesting  to  note  that  if  we  attach  to  this  compound  carbamide 
or  urea  we  obtain  a  body  belonging  to  the  class  of  purines.  Xanthine, 
for  instance,  would  have  a  formula 

NH— CO 

CO      C— NH 

I         II  >CH 

NH— CH— N^ 

Thus  by  the  action  of  simple  catalytic  agencies  on  sugar  and  ammonia 

we  can  obtain  the  iminazol  nucleus,  and  by  easy  transitions  pass  through 

this  to  the  purine  nucleus  with  its  contained  ring,  the  pyrimidine  nucleus, 

found  in  the  bases  cytosine,  uracil,   &c.,  which  occur  in  the  nucleins. 

With  regard  to  the  formation  of  the  aromatic  constituents  of  the  protein 

molecule,  i.e.  those  containing  the  benzene  and  indol  rings,  we  have  at 

present  very  Uttle  indication  even  of  the  lines  along  which  it  might  be 

possible  to  prosecute  our  researches.     It  has  been  suggested  that  inosite  may 

represent  some  stage  in  the  formation  of  the  benzene  ring  from  the  open  chain 

found  in  the  carbohydrates.     Inosite  has  the  same  formula  as  glucose, 

namely,  CgHigOe,  but  is  a  saturated  ring  compound  : 

CHOH 


CHOH 
CHOH 


CHOH 
CHOH 


CHOH 

and  may  be  expected  to  be  formed  as  a  result  of  polymerisation  of  formalde- 
hyde. We  have  no  evidence,  however,  of  the  possibihty  of  such  a  formation, 
and  the  relations  of  this  substance  with  the  benzene  compounds  are  by  no 
means  intimate.  It  is  of  such  universal  occurrence,  "both  in  plants  and 
animals,  that  it  is  difficult  to  refrain  from  the  suspicion  that  it  may  play  some 
part  as  an  intermediate  stage  between  the  fatty  and  the  aromatic  series. 

Since  plants  are  able  to  manufacture  all  these  varied  substances  out  of 
the  products  of  assimilation  of  carbon  and  ammonia  or  nitrates,  they  must 
also  find  no  difiiculty  in  transforming  one  amino-acid  into  another,  and  we 
know  that  most  plants  can  procure  their  nitrogen  from  a  solution  of  a  single 
amino-acid  as  well  as  from  a  nutrient  fluid  containing  the  nitrogen  in  the  form 


THE  MECHANISM  OF  ORGANIC  SYNTHESIS  119 

of  ammonia.  In  animals  the  power  of  transforming  one  amino-acid  into 
another,  of  one  group  into  another,  is  probably  strictly  limited.  So  far  as 
we  know,  nearly  all  the  amino-acids  utilised  in  the  building  up  of  the  animal 
proteins  are  derived  directly  from  those  contained  in  the  food.  On  the 
other  hafid,  we  have  evidence  in  the  animal  body  of  synthesis  of  the  purine 
bodies,  and  therefore  of  the  pyrimidine  and  iniinazol  rings.  The  hen's  egg 
at  the  beginning  of  incubation  contains  very  Uttle  nuclein,  nearly  the  whole 
of  its  phosphorus  being  present  in  the  form  of  phosphoproteins  and  lecithin. 
As  incubation  proceeds  these  substances  disappear,  their  place  being  taken 
by  the  nucleins  which  form  the  chief  constituent  of  the  nuclei  of  the  developing 
chick.  In  the  same  way  the  ovaries  and  testes  of  the  salmon  are  formed 
during  their  sojourn  in  fresh  water  at  the  expense  of  the  skeletal  muscles, 
especially  those  of  the  back.  Here  again  there  is  a  transformation  of  a  tissue 
poor  in  purine  bases  into  a  tissue  which  consists  almost  exclusively  of  nucleins 
and  protamines.  Whether  in  this  case  there  is  a  direct  conversion  of  the 
niono-amino-acids  of  the  muscle  proteins  into  the  diamino-acids  and  bases 
typical  of  protamines,  we  do  not  know.  It  is  more  probable  that  only 
diamino-acids  and  bases  previously  existing  in  the  muscle  are  utilised  for  the 
formation  of  the  generative  glands,  the  other  amino-acids  being  oxidised 
and  utilised  for  the  ordinary  energy  requirements  of  the  animal. 

THE   SYNTHESIS  OF  FATS 

In  some  plants  fat  globules  have  been  stated  to  appear  as  the  first  products 
of  the  assimilation  of  carbon  dioxide  under  the  influence  of  sunlight,  but 
there  is  no  doubt  that  as  a  rule  the  formation  of  fats  as  reserve  material  in 
seeds  or  fruits  occurs  at  the  expense  of  carbohydrates.  In  the  higher  animals, 
too,  although  a  certain  amount  of  the  fat  of  the  body  is  derived  from  the  fat 
taken  up  with  the  food,  the  organism  can  also  manufacture  neutral  fat  out 
of  the  carbohydrates  presented  to  it  in  its  food.  The  problem,  therefore, 
of  the  synthesis  of  the  fats  is  the  problem  of  the  conversion  of  a  sugar  such 
as  glucose  into  glycerin  and  the  fatty  acids.  Although  this  conversion 
is  apparently  so  easily  effected  by  the  Hving  organism,  it  is  one  which  from  the 
chemical  standpoint  involves  considerable  difficulties.  On  account  of  the 
fact  that  the  higher  fatty  acids  consist  largely  of  oleic  and  stearic  acids,  i.e. 
acids  containing  eighteen  carbon  atoms  in  their  chain,  it  has  been  thought 
that  the  synthesis  might  be  brought  about  by  the  linking  together  of  three 
molecules  of  a  hexose.  Such  a  change  would  involve  a  series  of  difficult 
chemical  transformations.  For  instance,  no  less  than  sixteen  out  of  the 
eighteen  oxygen  atoms  present  in  the  three  glucose  molecules  would  have 
to  be  dislodged  in  order  to  convert  the  chain  into  stearic  acid.  Moreover, 
although  these  two  acids  contain  a  multiple  of  six  carbon  atoms,  a  whole 
array  of  fats  are  foimd  both  in  plants  and  animals  which  could  not  be  derived 
by  a  simple  aggi-egation  of  glucose  molecides,  and  it  is  worthy  of  note  that,  of 
all  the  fatty  acids  which  occur  in  nature,  all  those  with  more  than  five  carbon 
atoms  contain  an  even  number  of  carbon  atoms.  Thus  in  milk,  in  addition 
to  the  three  common  fats,  tristearin,  tripalmitin,  and  triolein,  we  find  the 


120 


PHYSIOLOGY 


glycerides  of  caproic,  capiylic,  capric,  lauric,  and  myristic  acids,  i.e.  acids 
with  6,  8,  10,  12,  and  14  carbon  atoms.  In  all  cases  these  acids  are  the 
normal  acids  with  straight  unbranched  chains.  It  seems  probable  that  in 
the  transformation  of  carbohydrate  into  fatty  acid  the  latter  is  built  up,  not 
by  six  carbon  atoms,  but  by  two  carbon  atoms  at  a  time.  It  has  been 
suggested  by  Magnus  Levy  and  by  Leathes  that  the  transformation  may 
occur  by  way  of  lactic  acid.  We  have  seen  already  that  glucose  and  the 
sugars  of  analogous  composition  may  be  converted  under  the  influence  either 
of  sunlight  or  of  micro-organisms  into  lactic  acid.  Lactic  acid  breaks  down 
with  readiness  into  aldehyde  and  formic  acid. 


CH, 


CH. 


CHOH     =      CHO+H 


COOH  COOH 

Aldehyde  undergoes  condensation  to  form  aldol. 


CH. 


CHO 


CH3 
CHOH 


CH, 


CHO 

aldehyde  aldol 

Aldol  reacts  with  water  and  undergoes  a  shifting  of  its  OH  and  H  groups, 
in  a  manner  with  which  we  are  already  familiar  as  occurring  in  the  conversion 
of  glucose  into  lactic  acid,  forming  butyric  acid.  We  may  represent  the 
reaction  in  the  following  way,  placing  the  water  molecules  opposite  those 
groups  of  the  aldol  molecule  with  which  they  react : 

CH3 


H       HO  :CH 


H 


OH 


gives 


CH2 

0  c  |h    oh 

CH3 

CH^ 

i 

CH2 

COOH 


+  2H,0 


THE  MECHANISM  OF  ORGANIC  SYNTHESIS  121 

It  will  be  seen  that  although  water  must  enter  into  reaction  there  is  no 
addition  of  water  to  the  aldol  in  order  to  form  the  butyric  acid. 

It  has  been  suggested  that  similar  reactions  might  account  for  the  forma- 
tion of  the  higher  fatty  acids,  in  which  case  one  molecule  of  acetic  aldehyde 
would  be  added  to  the  fatty  acid  in  order  to  build  up  the  acid  which  is  next 
highest  in  the  series.  Although  certain  of  the  higher  acids  have  been  pre- 
pared in  this  way,  proof  is  still  wanting  that  a  continuous  series  of  syn- 
theses may  be  effected  by  the  continuous  addition  of  aldehyde.  Such  a 
li)^othesis  is,  however,  more  probable  tban  the  direct  conversion  of  three 
molecules  of  sugar  into  one  molecule  of  stearic  acid.  The  latter  change 
would  be  associated  with  a  very  great  absorption  of  energy,  whereas  a  con- 
tinuous building  up  of  fatty  acids  by  the  addition  of  aldehyde  obtained 
through  lactic  acid  from  the  disintegi-ation  of  hexose  molecules  only  requires 
a  small  expenditure  of  energy,  which  could  be  obtained  by  the  combustion 
of  the  formic  acid  formed  as  a  by-product  in  the  process.  If  we  suppose  that 
the  synthesis  of  the  higher  fatty  acids  from  sugar  is  carried  out  in  this  way, 
the  energy  equations  would  be  as  follows  (Leathes)  : 

1  g.  mol.  glucose       )  ^/2  g.  mols.  aldehyde  +  2  g.  mols.  formic  acid. 

677-2  cals.  J  \  2  x  275-5  +  2  x  61-7 

=  674-4  cals. 

2  g.  mols.  aldehyde  ^  ,        / 1  g-  r>iol.  aldol      )  f  1  §•  ^o^-  butjTic  acid. 

551  cals.     "        /■      ^t         546-8  cals.     /      ^\         517-8  cals. 

Or,  tracing  the  same  change  on  as  far  as  palmitic  acid : 

4  g.  mols.  glucose     "j  fl  g.  mol.  palmitic  acid  +  8  g.  mols.  formic  acid. 

2708  cals.  /      ^\         2362  cals.  +  494  cals. 

=  2856  cals. 

In  the  first  stage  of  the  synthesis,  the  reaction  leading  to  butyric  acid,  the 
net  result  would  be,  supposing  the  formic  acid  to  be  oxidised,  that  some  160 
calories,  or  nearly  25  per  cent,  of  the  whole  energy,  would  be  rendered  avail- 
able for  other  purposes.  In  the  latter  stages  leading  to  pabnitic  acid  some 
of  the  energy  derived  from  the  oxidation  of  the  formic  acid  Avould  be  required 
for  effecting  the  synthesis,  and  only  about  12-5  per  cent,  of  the  original 
amount  contained  in  the  sugar  would  be  set  free.  It  is  worth  noting  that 
in  the  butyric  fermentation  of  sugar  by  micro-organisms  there  is  a  production 
first  of  lactic  acid,  and  this  substance  then  disappears  to  give  place  to  butyric 
acid.  At  the  same  time  carbonic  acid  and  hydrogen  are  evolved,  both  gases 
being  derived  from  the  decomposition  of  the  formic  acid.  In  the  process  a 
certain  amount  of  caproic  acid  is  always  produced,  and  the  crude  butyric 
acid  of  fermentation  is  used  as  the  source  from  which  commercial  caproic 
acid  is  derived. 

Attempts  to  produce  the  higher  fatty  acids  by  the  condensation  of  successive 
molecules  of  aldehyde  have  so  far  only  resulted  in  the  production  of  branched  chains 
of  carbon  atoms,  whereas  the  nornuil  fatty  acids  of  the  body  are  straight  chains  ;  though 
Raper  has  sliown  that  the  normal  caproic  acid  may  be  formed  by  the  condensation 
of  aldol  with  itself.  Miss  Smedley  has  suggested  that  a  more  probable  line  of  synthesis 
lies  through  pyruvic  acid.     Pyruvic  acid,  which  may  be  produced  iu  the  body  fi'om 


122  PHYSIOLOGY 

lactic  acid,  and  so  from  carbohydrate,  is  fermented  by  yeast  with  the  production  of 
acetaldehyde  and  carbon  dioxide,  by  means  of  a  ferment  carboxylase.  If  we  assume 
the  existence  of  a  similar  ferment  in  the  cells  of  the  body,  it  would  split  this  acid  into 
aldehyde  and  002-  Aldehyde,  however,  combines  with  a  molecule  of  pyruvic  acid  to 
form  a  higher  keto=acid,  which  might  either  be  oxidised  to  the  fatty  acid  containing  one 
carbon  atom  less,  or  might  be  again  transformed  by  enzymes  into  an  aldehyde  capable 
of  reacting  with  another  molecule  of  pyruvic  acid.  These  changes  are  represented  in  the 
following  equations  : 

CH3CO.COOH  =  CH3CHO  +  CO2 
CH3CHO  +  CH3CO.COOH  =  CH3CHOH.CH2.CO.COOH 
CH3CHOH.CH2.CO.COOH  +-0  =  CH3CHOH.CH2COOH  +  CO2 

/3-oxyacids  would  thus  be  a  normal  stage  in  the  building  up  as  well  as  in  the  breaking 
down  of  fatty  acids. 

The  glycerin  which  enters  into  the  formation  of  the  ordinary  neutral 
fats  can  be  synthetised  by  both  plants  and  animals,  and  there  is  every 
ground  for  believing  that  it,  hke  the  fatty  acids,  may  be  derived  from 
carbohydrates.  We  have  already  seen  that  in  the  conversion  of  glucose 
into  lactic  acid  the  first  step  is  the  formation  of  glyceric  aldehyde, 

CH2OH  CH2OH 

CHOH  CHOH 

CHOH  CHO 

*'CH0H*  OH^OH 

CHOH  CHOH 

CHO  CHO 

and  it  is  easy  to  understand  how  by  a  process  of  reduction  the  aldehyde 
is  converted  into  the  corresponding  alcohol,  namely,  glycerin.  The  synthesis 
of  the  neutral  fat  from  glycerin  and  fatty  acid  is  a  change  which  can  be 
accomplished  by  many  ferments.  It  is  one  involving  practically  no  absorp- 
tion or  expenditure  of  energy.  The  change  is  a  reversible  one,  and  we  find 
both  in  plants  and  animals  that  a  hydrolysis  of  neutral  fat  into  fatty  acid 
and  glycerin  always  occurs  when  a  transport  of  the  fat  is  required,  while 
the  laying  down  of  fat  as  a  store  of  energy  is  always  preceded  by  a  resynthesis 
of  the  neutral  fat.  We  shall  have  occasion  to  deal  in  greater  detail  with  these 
questions  when  we  have  to  discuss  the  formation  and  fate  of  the  fat  in  the 
animal  body. 


CHAPTER  IV 
THE   ENERGETIC   BASIS   OF  THE   BODY 

SECTION  I 

THE   ENERGY   OF    MOLECULES    IN   SOLUTION 

RvERY  vital  act  involves  at  the  same  time  a  transformation  of  the  material 
liasis  of  the  living  cell  and  a  transformation  of  energy.  The  ultimate 
source  of  the  energies  displayed  by  the  animal  organism  is  the  chemical 
energy  of  the  substances  taken  in  as  food.  In  all  the  changes  undergone  by 
either  matter  or  energy  in  the  body  there  is  neither  destruction  nor 
creation.  The  living  organism  may  therefore  be  regarded  in  one  sense  as  a 
)nachine,  that  is  to  say,  a  system  for  the  conversion  of  one  form  of  energy 
into  another.  Thus  the  steam-engine  converts  the  potential  energy  of  over- 
heated steam  into  mechanical  work  ;  a  gas-engine  the  chemical  energy  of  an 
explosive  mixture  of  gases  into  heat  and  mechanical  energy  ;  in  a  battery 
there  is  a  transformation  of  chemical  into  electrical  energy  ;  in  a  dynamo,  of 
mechanical  into  electrical  energy,  and  so  on.  In  the  living  cell  the  chemical 
energy  of  the  food  may  undergo  conversion  into  any  of  the  other  forms 
mentioned  above,  i.e.  heat,  work,  electrical  difference  of  potential,  or  it  may 
be  used  for  the  production  of  other  chemical  substances  possessing  perhaps 
as  nmch  potential  energy  as  or  more  than  the  food-stuffs  themselves. 

Protoplasm,  which  is  the  seat  of  all  these  changes  in  both  plants  and 
animals,  is  active  only  within  fairly  narrow  limits  of  temperature,  approxi- 
mately between  5°  and  40°  C.  In  consistence  it  is  slimy  and  wet,  water 
forming  from  70  to  95  per  cent,  of  its  bulk.  No  substance  introduced  into 
the  protoplasm  has  any  influence  on  it,  unless  it  be  soluble,  and  the  first 
stage  in  the  preparation  of  food-stuifs  for  assimilation  always  consists  in  a 
process  of  solution.  The  sole  source  of  energy  to  the  body  being  that  con- 
veyed with  the  food,  it  follows  that  all  the  energy  with  which  we  have  to 
deal  is  the  energy  of  molecules  in  watery  solution,  the  playgiound  of  whose 
activities  is  a  jelly-like  mass  of  colloidal  material,  heterogeneous  yet  struc- 
turally continuous.  It  is  important,  therefore,  at  the  outset  to  inquire  into 
the  nature  of  this  energy  and  the  methods  by  which  it  may  be  measured. 

OSMOTIC  PRESSURE.  If  we  place  two  gas  jars  together,  mouth  to 
mouth,  as  in  Fig.  19,  the  upper  jar  containing  hydrogen  and  the  lower  jar 
some  heavier  gas,  such  as  oxygen  or  carbon  dioidde,  within  a  very  short  time 

123 


124 


PHYSIOLOGY 


fc4 


the  gases  will  have  become  intimately  mixed,  and  each  jar  will  contain  an 
equal  amomit  of  both  gases.  We  say  that  each  gas  has  difiused  into  the  other, 
and  ascribe  the  diffusion  to  the  movement  of  the  gaseous  molecules.  In 
closed  vessels  the  rapidly  moving  molecules  are  continually  impinging  on 
the  walls  of  the  vessels  and  rebounding,  and  it  is  this  bombardment  by  the 
gaseous  molecules  which  is  responsible  for  the  pressure 
exerted  by  a  gas  on  its  containing  walls.  If  we  double  the 
amount  of  gas  in  a  given  space,  we  double  the  amount  of 
molecules  which  strike  a  unit  area  of  the  wall  in  unit  tune, 
and  therefore  double  the  pressure  exerted  by  the  gas  on  the 
vessel  wall.  In  this  way  we  may  explain  the  law  of  Boyle 
that  the  pressure  of  a  gas  is  inversely  proportional  to  its 
volume,  or  the  product  of  pressure  and  volume  at  a  given 
temperature  is  a  constant,  PV  =  C,  or  since  the  energy  of 
the  molecules  is  proportionate  to  the  absolute  temperature, 
PV  =  RT,  the  famiUar  gas  equation. 

The  molecules  of  substances  in  solution  behave,  within 
the  limits  of  the  solution,  in  a  manner  precisely  similar  to  the 
free  molecules  of  a  gas.  Thus,  if  a  vessel  be  half  filled  with 
a  10  per  cent,  solution  of  sugar  and  be  then  filled  up  by 
carefully  pouring  distilled  water,  so  as  to  form  a  distinct 
layer  on  the  heavier  sugar  solution,  the  sugar  at  once  begins 
to  move  upwards  into  the  distilled  water.  In  consequence 
of  the  resistance  offered  to  the  movement  of  the  sugar 
molecules  through  the  water,  this  process  of  diffusion  is  slow, 
but  if  the  vessel  be  left  undisturbed  and  free  from  any 
agitation  for  two  or  three  months  the  sugar  will  be  found 
to  spread  gradually  throughout  the  liquid,  so  that  at 
the  end  of  this  time  all  parts  of  the  fluid  contain  a  uniform  amount  of 
sugar. 

This  process  of  difiusion,  hke  that  of  gases,  must  be  ascribed  to  a  con- 
tinuous translatory  movement  of  the  dissolved  molecules.  Since  the  mole- 
cules possess  mass  and  are  endowed  with  a  velocity,  it  is  evident  that  they 
can  exercise  a  pressure  on  any  membrane  or  dividing  surface  which  tends  to 
hinder  their  free  passage  within  the  hmits  of  the  solvent.  Thus  if  we  take 
a  pig's  bladder  containing  a  20  per  cent,  solution  of  dextrose  and  immerse 
it  in  distilled  water,  water  will  pass  in  and  distend  the  bladder  to  such  an 
extent  that  it  may  burst  from  the  rise  of  pressure  in  its  interior.  This 
swelUng  of  the  bladder  is  due  to  the  fact  that  the  molecules  of  sugar  pass 
through  it  only  with  difficulty,  and  therefore  in  their  passage  outwards 
towards  the  confines  of  the  water  exert  a  pressure  on  the  walls,  driving  them 
apart  and  so  causing  a  distension  of  the  bladder.  It  is  impossible,  however, 
by  this  means  to  obtain  the  full  osmotic  pressure  due  to  the  pressure  exerted 
by  the  sugar  molecules,  since  the  bladder  wall  itself  is  not  absolutely  im- 
permeable to  sugar.  If  we  imagine  the  sugar  solution  confined  in  a  cyhnder 
and  covered  with  a  layer  of  distilled  water,  the  movement  of  the  sugar 


Fig.  19. 


THE  ENERGY  OF  MOLECULES  IN  SOLUTION 


125 


molecules  will  cause  them  to  wander  from  the  lower  to  the  upper  part,  and 
this  process  of  diffusion  will  cease  only  when  the  concentration  has  become 
the  same  in  all  parts  of  the  solution.  Supposing,  however,  the  two  fluids  are 
separated  by  a  piston,  p  (Fig.  20),  which  is  '  semi-permeable,'  i.e.  allows  free 
passage  to  water,  but  not  to  the  dissolved  sugar,  the  molecules  of  sugar  will 
now  exert  a  pressure  on  the  piston  similar  to  that  exerted  on  the  walls  of  the 
containing  vessel,  and  will  tend  to  drive  it  upwards.  The  force  which  it  is 
necessary  to  apply  to  the  piston  to  prevent  its  upward  movement  will  be  the 
measure  of  the  osmotic  pressure  of  the  sugar  in  the  solution.  If  the  piston 
be  pressed  down  with  a  greater  force,  the  sugar  molecules  alone  are  pressed 
together,  since  water  can  pass  freely  through  the  surface  of  the  piston,  and 
the  sugar  solution  is  therefore  rendered  more  concentrated.  Since  force 
nmst  be  applied  to  the  piston  in  order  to  press  it  down,  work 
is  done  in  the  process,  so  that  the  concentration  of  any  solution 
involves  the  performance  of  an  amount  of  work  determined  by 
the  initial  and  final  osmotic  pressures  of  the  solution.  If, 
on  the  other  hand,  a  weight  be  apphed  to  the  piston  which  is 
less  than  the  osmotic  pressure  exerted  by  the  sugar  solution, 
the  piston  with  its  weight  ^^A\\  be  moved  upwards,  and  the 
solution  will  undergo  dilution  until  its  osmotic  pressure  exactly 
balances  the  weight  on  the  piston.  We  see  that  the  osmotic 
pressure  of  a  solution  represents  a  certain  amount  of 
potential  energy,  which  can  be  utiUsed  in  an  osmotic 
machine,  such  as  that  represented  in  the  diagram,  for  the  performance 
of  work. 

THE  MEASUREMENT  OF  THE  OSMOTIC  PRESSURE.  By  a  method 
differing  but  httle  from  the  one  just  sketched  out,  Pfeffer  succeeded  directly 
in  measuring  the  Osmotic  pressure  of  certain  solutions.  For  this  purpose 
Pfeffer  took  advantage  of  the  fact,  discovered  by  Traube,  that  various  pre- 
cipitates, if  deposited  in  the  form  of  membranes,  were  impermeable  to  the 
substances  producing  them  as  well  as  to  some  other  dissolved  substances, 
though  allowing  a  free  passage  of  water.  Thus,  if  a  drop  of  a  concentrated 
solution  of  potassium  ferrocyanide  suspended  to  a  glass  rod  be  introduced 
carefully  into  a  more  dilrrte  solution  of  copper  sulphate,  it  will  be  observed 
that  at  the  junction  of  the  drop  and  the  surrounding  fluid  there  is  a  brown 
membranous  precipitate  of  copper  ferrocyanide.  In  consequence  of  the  greater 
concentratioir  of  the  fluid  in  the  drop,  a  constant  passage  of  water  takes 
place  from  without  inwards  through  the  membrane,  and  the  drop  therefore 
grows  continually  in  size,  sometimes  sending  out  branches  as  a  result  of 
slight  currents  in  the  fluid  set  up  by  accidental  vibrations.  Sugar  intro- 
duced into  such  a  drop,  although  quickening  its  rate  of  growth,  does  not  pass 
out  into  the  surrounding  copper  sulphate  solution,  nor  is  there  any  passage 
of  copper  sulphate  inwards  or  potassium  ferrocyanide  outwards.  Pfeft'er  con- 
ceived the  idea  of  depositing  such  a  semi-permeable  membrane  within  the 
interstices  of  a  clay  cell.  Strengthened  in  this  way,  it  is  able  to  afford  a 
resistance  to  pressure,  and  therefore  to  permit  of  the  contained  fluid  reaching 


126 


PHYSIOLOGY 


its  full  osmotic  pressure.  For  this  purpose  a  porous  jar  carefully  cleansed 
and  containing  a  solution  of  sugar  mixed  with,  a  little  copper  sulphate  is 
dipped  into  a  weak  solution  of  potassium  ferrocyanide.  A  semi-permeable 
membrane  of  copper  ferrocyanide  is  thus  produced  in  the  pores  of  the  filter, 
and  this,  while  allowing  the  passing  of  water,  is  impermeable  to  the  sugar. 
The  tube  is  then  fitted  with  a  cork  provided  with  a  closed  mercurial  mano- 
meter and  is  immersed  in  distilled  water,  when  it  is  found  that  water  passes 
into  the  cell  until  the  pressure  within  the  latter  is  equal  to  the  osmotic 
pressure  of  the  dissolved  substances.  By  this  means  Pfeffer  obtained  the 
following  results  with  a  1  per  cent,  solution  of  cane  sugar  at  different  tem- 
peratures : 


Temp.  °C. 

Pressure  in  atmospheres 

Calculated 

6-8 
13-7 
22-0 
32-0 
36-0 

Atm. 
0-664 
0-691 
0-721 
0-716 
0-746 

Atm. 
0-665 
0-681 
0-701 
0-725 
0-735 

It  is  always  possible  to  calculate  the  pressure  of  a  gas  when  its  nature, 
its  mass,  and  its  volume  are  known.  By  Avogadro's  hypothesis,  equal 
volumes  of  gases  at  the  same  pressure  contain  equal  numbers  of  molecules. 
On  this  account  the  molecular  weight  of  any  gas  can  be  reckoned  directly 
from  its  density.  The  figures  obtained  by  Pfeffer  show  that  the  same 
laws  apply  to  the  osmotic  pressure  of  substances  in  solution  as  to  the  pressure 
of  gases  in  their  free  state.  It  is  therefore  possible  to  reckon  the  osmotic 
pressure  which  would  be  exerted  by  1  per  cent,  sugar  in  solution  at  a  given 
temperature. 

This  calculation  is  carried  out  as  follows  :  A  gramme  molecule  of  any  gas  at  0°  C.  and 
760  mm.  Hg  has  a  volume  of  22-4  litres,  therefore  342  grammes  of  cane  sugar  (the 
molecular  weight  of  CVaHaoOn  =  342),  if  it  could  be  converted  into  a  gas  at  0°  C.  and 
760  mm.  Hg,  would  have  a  volume  of  22-4  litres.     One  gramme  of  sugar  therefore  at 

22-4 

the  same  temperature  and  pressure  would  have  a  volume  of  ^ — —  litres  =  65-5  c.c.      In 

PfefEer's  experiment  the  gramme  of  sugar  was  dissolved  in  100  grammes  of  water, 
making  a  total  volume  at  0°  C.  of  100-6  c.c.     The  gaseous  pressure  of  .the  sugar  molecules 


65-5 

in  this  solution  will  therefore  amount  to  —  0-651  atmosphere 

100-6  ^ 


At  a  temperature 
of  6-8  the  pressure  would  be  0-667  atmosphere,  as  against  the  observed  0-664  atmosphere. 


Pfefier's  method  is  difficult  to  carry  out  and  is  not  applicable  to  all 
dissolved  substances,  since  the  cupric  ferrocyanide  membrane  is  permeable 
for  many  substances,  such  as  potassium  nitrate  or  hydrochloric  acid.     Other 


THE  ENERGY  OF  MOLECULES  IN  SOLUTION 


127 


indirect  methods  have  therefore  been  apphed  to  the  comparison  of  the 
osmotic  pressures  of  different  solutions. 

DETERMINATION  OF  THE  OSMOTIC  PRESSURE  BY  PLASMOLYSIS.  Solu- 
tions which  have  the  same  osmotic  pressure  are  spoken  of  as  isosmotic  or  isotonic. 
The  method  of  plasmolysis,  which  we  owe  to  the  botanist  De  Vries,  coasists  essentially 
in  the  comparison  of  the  osmotic  pressure  of  solutions  with  that  of  the  cell  sap  of  certain 
plant  cells,  and  depends  on  the  fact  that  the  '  primordial  utricle,'  the  layer  of  protoplasm 
enclosing  the  cell  sap,  while  freely  permeable  to  water,  is  impermeable  to  a  large  number 
of  salts  and  other  crystalloids,  such  as  sugar.  It  is  therefore,  so  far  as  concerns  these 
substances,  'semi-permeable.'  The  cells  which  have  been  most  used  for  this  purpose 
are  the  cuticular  cells  on  the  mid-rib  of  the  lower  surface  of  the  leaves  of  tradescantia 
discolor.  If  some  of  these  cells  are  brought  into  a  concentrated  salt  solution,  which  is 
'  hypertonic  '  as  compared  with  the  cell  sap,  water  passes  out  of  the  cell  into  the  salt 
solution,  until  the  contents  of  the  cell  attain  a  molecular  concentration  equal  to  that 
of  the  surrounding  medium.  The  protoplasmic  layer  therefore  shrinks,  leaving  a  space 
between  it  and  the  cell  wall  (Fig.  7,  p.  23).  If  the  outer  solution  has  a  smaller  molecular 
concentration  than  the  cell  sap,  water  passes  into  the  cell  and  causes  here  a  rise  of 
pressure  which  simply  presses  the  protoplasm  still  more  closely  against  the  cell  wall.  If 
we  determine  the  concentration  of  the  salt  solution  at  which  the  shrinkage  of  the  proto- 
plasm, the  plasmolysis,  just  occm's,  and  another  smaller  concentration  at  which  plas- 
molysis is  absent,  we  know  that  the  concentration  of  the  cell  sap  lies  between  those 
of  the  two  salt  solutions.  Thus,  if  plasmolysis  occurs  in  a  solution  containing  0-6 
per  cent,  sodium  chloride  and  is  absent  in  a  solution  containing  0-59  per  cent,  of  the 
same  salt,  the  concentration  of  the  cell  sap  must  be  about  equivalent  to  a  0-595  jjer  cent. 
NaCl  solution.  Solutions  of  different  salts,  in  which  plasmolysis  just  occurs,  must  also 
be  isotonic  wdth  one  another.  Thus  a  1-01  per  cent,  solution  of  KNO3  is  found  to  be 
isotonic  with  a  0-58  per  cent.  NaCl  solution. 

DETERMINATION  BY  HAMBURGER'S  BLOOD-CORPUSCLE  METHOD.  The 
limiting  external  layer  of  red  blood-cori:)uscles  resembles  the  primordial  utricle  of 
plant  cells  in  being  impermeable  to  a  number  of  dissolved  substances.  If,  therefore, 
it  be  placed  in  a  solution  of  smaller  concentration  than  the  corpuscle  contents,  it  mil 
swell  up  and,  since  it  has  no  supporting  cell  wall,  the  increase  in  size  will  go  on  until 
the  corpuscle  bursts,  and  its  contained  red  colouring-matter,  haemoglobin,  passes  into 
solution  in  the  surrounding  fluid.  If  the  corpuscles  be  then  allowed  to  settle  or  be 
centrifuged,  the  fact  that  haemolysis  has  occurred  is  shown  by  the  red  colour  of  the 
clear  supernatant  fluid.  With  a  given  sample  of  blood,  the  concentration  of  a  potassium 
nitrate  solution  is  found  at  which  the  first  traces  of  haemolysis  occur.  In  order  to 
determine  the  osmotic  pressure  of  a  solution,  saj^,  of  sugar  or  of  sodium  chloride,  these 
are  also  added  in  various  dilutions  to  blood  corpuscles  until  we  get  solutions  in  which 
haemolysis  just  occurs.  These  solutions  will  then  be  isotonic  with  the  first  determined 
])otassium  nitrate  solutions.  As  an  example  of  this  method  may  be  adduced  the 
following  results  : 


Concentration 
of  the  solution 

in  which  the 

blood  corpuscles 

do  not  lose 

hfemoglobin 

Concentration 
of  the  solution 

in  which  the 
blood  corpuscles 

begin  to  lose 
hsemoglobin 

Mean 
concentration 

Potassium  nitrate 

Per  cent. 
I  04 

Per  cent. 
0-9f. 

Per  cent. 
lOt) 

Sodium  chloride 

0-60 

0-56 

0-585 

Cane  sugar 

6-29 

5-63 

5-96 

Potassium  iodide 

1-71 

1-67 

1-64 

Sodium  iodide     . 

1-54 

1-47 

1  -605 

Potassium  bromide      . 

1-22 

113 

M7 

128  PHYSIOLOGY 

OSMOTIC  PRESSURE  OF  ELECTROLYTES.  It  will  be  noticed  in  the 
last  Table  that  the  isotonic  solutions  of  different  salts  contain  these  salts 
in  the  proportion  of  their  molecular  weights,  i.e.  each  solution  contains  the 
same  number  of  molecules  of  dissolved  salt.  For  the  term  isotonic  we 
might  therefore  employ  equimolecular.  When,  however,  these  salts  are 
compared  with  solutions  of  sugar,  it  is  found  that  the  osmotic  pressures  of 
the  salt  solutions  are  double  or  nearly  double  those  of  equimolecular  solu- 
tions of  sugar.  The  osmotic  pressure  of  a  sugar  solution  is  equal  to  the 
pressure  which  its  molecules  would  exert  if  they  occupied  the  same  space 
in  a  gaseous  form.  A  dilute  salt  solution  therefore  acts  as  if  every  one  of  its 
molecules  were  doubled.  This  deviation  of  salt  solutions  from  solutions  of  sugar 
is  bound  up  with  the  power  of  the  former  to  conduct  an  electric  current.  A 
sugar  solution  conducts  electricity  little  better  than  pure  water.    On  the  other 


2    3    4     5       6       7 
H   ■    II     ■       11      ■ 


V/////////////////////////^//////////////////////////////////^^ 


Fig.  21.  Diagram  to  illustrate  Barger's  method  of  determining  osmotic 
pressure.  The  upper  figure  shows  the  capiUary  tube  with  nine  alter- 
nate drops  of  cane  sugar  and  the  substance  under  investigation. 

hand,  the  smallest  trace  of  salt  added  to  distilled  water  enormously  increases 
its  conducting  power.  As  Arrhenius  has  shown,  this  increase  of  the  osmotic 
pressure  of  a  salt  solution  is  determined  by  the  dissociation  which  all  these 
salts  undergo  in  watery  solution.  A  dilute  solution  of  sodium  chloride  con- 
tains, not  the  molecule  NaCl,  but  an  equal  number  of  the  ions  Na  and  CI,  Na 
carrying  a  positive  charge  while  the  CI  ions  carry  a  negative  charge.  As 
regards  osmotic  pressure  and  various  other  properties,  each  of  these  charged 
ions  acts  as  a  whole  molecule.  It  is  the  existence  of  these  ions  which  confers 
on  the  salt  solution  the  power  of  conducting  electricity — a  power  the  exercise 
of  which  is  attended  with  a  dissociation  (an  electrolysis)  of  the  salt  into  its 
constituent  ions,  the  electro-positive  ion  being  deposited  at  the  negative 
pole  while  the  electro-negative  ion  is  deposited  at  the  positive  pole.  The 
molecular  weight  of  NaCl  is  58-5.  The  molecular  weight  of  glucose  is  180. 
If  there  were  no  dissociation,  a  0-58  per  cent,  solution  of  NaCl  would  be 
isotonic  or  isosmotic  with  a  1  -8  per  cent,  solution  of  glucose.  On  account  of 
the  ionic  dissociation  or  ionisation,  it  is  actually  isosmotic  with  a  glucose 
solution  of  about  3-5  per  cent. 


THE  ENERGY  OF  MOLECULES  IN  SOLUTION 


129 


INDIRECT  METHODS  OF  MEASURING  OSMOTIC  PRESSURE.  Equi- 
molecular  solutions  have  the  same  osmotic  pressures.  Since  the  osmotic 
pressure  of  a  solution  is  therefore  directly  dependent  on  the  number  of 
molecules  it  contains  in  unit  space,  any  method  which  will  give  us  informa- 
tion as  to  the  number  of  molecules  present  will  also  enable  us  to  determine 
the  osmotic  pressure.  Other  properties  of  solutions  which,  like  the  osmotic 
pressure,  are  fmictions  of  the  number  of  molecules 
present,  are  vapour-tension,  boihng-point,  freezing- 
point.  The  presence  of  a  substance  in  solution  in 
water  diminishes  its  vapour-tension  at  any  given 
temperature,  raises  its  boihng-point,  and  depresses 
its  freezing-point,  and  the  extent  of  the  deviation 
from  distilled  water  is  proportional  to  the  number 
of  dissolved  molecules  present.  The  determination 
of  the  rise  of  boihng-point,  though  much  employed 
by  chemists,  is  of  very  httle  value  in  physiology, 
OTAing  to  the  fact  that  nearly  all  the  fluids  of  the  body 
are  seriously  modified  in  character  by  a  rise  of  tem- 
perature to  100°  C.  On  the  other  hand,  Barger  has 
suggested  an  ingenious  method  in  which  the  altera- 
tion of  vapour-tension  is  made  the  basis  of  a  method 
for  determining  the  osmotic  pressure  of  small  quan- 
tities of  fluids  at  ordinary  temperatures.  And  this 
}nethod  may  find  important  appHcations  in  phy- 
siology. 

BARGER'S  METHOD.  Drops  of  the  fluid,  the  vapour- 
tension  of  which  it  is  desired  to  ascertain,  are  drawn  up 
into  a  tube  (1-5  mm.  in  diameter),  so  as  to  alternate  with 
small  drops  of  cane  sugar  solution  of  kno^vii  content  (Fig.  21 ). 
Water  in  a  state  of  vapoiu:  will  pass  from  the  solution  of 
which  the  vapour-tension  is  the  higher.  By  observing  the 
edge  of  a  drop  under  a  magnification  of  65  diams.,  it  can 
he  easily  seen  whether  it  has  grown  or  diminished  in  size. 
If  the  edge  of  the  drop  remains  stationary,  it  shows  that  the 
vapour-tension  and  the  osuiotic  pressure  of  the  two  fluids 
.".re  equal.  A  scries  of  trials  is  made  with  different 
strengths  of  salt  solution  until  this  equality  is  established. 
In  this  method  only  minimal  quantities  of  material  are 
required,  and  the  determination  of  the  aqueous  tension  is 
made  at  ordinary  temperatui'es. 

The  method,  however,  which  is  of  greatest  value 
in  physiology  is  the  measurement  of  the  depression  of  freezing-point. 
The  depression  of  freezing-point  can  be  converted  directly  into  osmotic 
pressure  by  multiplying  the  depression  of  freezing-point  observed  by  the 
factor  122-7.  Thus  a  1  per  cent,  solution  of  sodium  chloride  with  A  =0-61 
will  have  an  osmotic  pressure  of  0-61  x  122-7  =  74-84:7  metres  of  water. 

The  determination  is  carried  out  in  a  Beckmann's  apparatus  with  a  thermometer 
reading  to  ^i^°  C.  (Fig.  22).     A  solution  freezes  at  a  lower  temperature  than  pure 


Fig.  22.  Beckmann's 
apparatus  for  determina- 
tion of  freezing-point. 


130  PHYSIOLOGY 

water,  and  the  depression  of  freezing-point  is  proportional  to  the  number  of  molecules 
present.  Thus  the  freezing-point  of  a  1  per  cent,  solution  of  NaCl  is  —0-61°  C.  The 
depression  of  freezing-point  is  generally  represented  by  the  Greek  letter  A-  This 
method  has  the  advantage  that  the  fluids  are  in  most  cases  in  no  wise  altered  by  the 
process  of  freezing,  and  it  can  be  applied  to  solutions  containing  coagulable  proteins 
which  would  be  irretrievably  altered  by  any  considerable  rise  of  temperature. 

Every  substance  in  solution  possesses,  therefore,  a  certain  amount  of 
potential  energy  in  the  form  of  osmotic  pressure.  This  pressure  is  inde- 
pendent of  the  nature  of  the  substance  dissolved  and  is  determined  merely 
by  its  molecular  concentration.  It  can  be  used  as  a  driving  force  for  the 
movement  by  diffusion  of  the  molecules  themselves,  or,  by  the  use  of 
appropriate  mechanisms  or  '  machines,'  for  the  performance  of  mechanical 
work,  or,  as  will  be  seen  later,  for  the  production  of  electrical  differences 
of  potential. 

In  addition  to  this  osmotic  or  volume  energy  every  molecule  in 
solution  can  be  regarded  as  endowed  with  a  chemical  energy,  which  is 
dependent  not  only  on  the  number  of  molecules  present,  but  also  on  the 
nature  of  the  molecules.  In  the  case  of  electrolytes  and  of  substances 
which  are  susceptible  of  ionisation,  the  potential  or  intensity  of  the  chemical 
energy  of  each  molecule  is  capable  of  measurement.  On  the  other  hand, 
the  chemical  energy  of  a  substance  such  as  glucose  cannot  be  definitely 
expressed  apart  from  consideration  of  the  conditions  under  which  it  is 
present.  If  we  take  the  whole  course  of  transformations  undergone  by 
glucose  in  the  body,  we  may  speak  of  it  as  having  a  potential  energy, 
which  is  measured  by  the  total  heat  energy  given  out  by  this  substance  on 
its  complete  combustion  with  oxygen  to  carbon  dioxide  and  water.  In 
the  intermediate  changes  which  it  undergoes  during  its  metabohsm  in  the 
cells  of  the  body,  this  energy  is  probably  set  free  by  degrees,  but  its  chemical 
energy  in  any  given  phase  cannot  be  measured  unless  the  conditions  and 
the  end  results  of  the  chemical  changes  which  it  is  undergoing  are  known. 
This  chemical  energy  may  be  utiUsed  for  the  production  of  heat,  for  the 
performance  of  chemical  work  in  the  building  up  of  other  substances,  or 
by  the  multiphcation  of  the  number  of  molecules  in  a  solution,  for  the 
production  of  increased  osmotic  pressure,  which  in  its  turn  may  be  con- 
verted into  the  energy  of  movement  either  of  masses  or  of  molecules. 


SECTION  II 

THE  PASSAGE  OF  WATER  AND  DISSOLVED 
SUBSTANCES   ACROSS   MEMBRANES 

We  have  already  seen  that  if,  in  a  solution,  the  concentration  of  the  dis- 
solved substance  or  solute  is  not  uniform,  there  is  a  movement  of  the  sub- 
stance from  the  place  of  higher  to  the  place  of  lower  concentration,  and 
this  movement  proceeds  until  the  concentration  is  equal  throughout  the 
fluid.  This  movement  of  dissolved  substances  through  a  fluid  is  spoken  of  as 
diffusion,  and  is  analogous  in  all  respects  with  the  process  by  which  the  inter- 
mixture of  gases  is  attained.  The  movement  in  the  case  of  dissolved  sub- 
stances, as  of  gases,  takes  place  from  the  region  of  higher  to  the  region  of  lower 
(osmotic)  pressure.  It  can  therefore  be  ascribed  to  differences  of  pressure, 
or  rather  to  the  factor  which  we  regarded  as  responsible  for  the  production  of 
the  pressure,  viz.  the  movement  of  the  molecules  themselves.  The  rate  of 
diffusion  is  not  the  same  for  all  substances.  In  gases  the  rate  varies  inversely 
as  the  square  root  of  the  density  of  the  gas.  Thus  hydrogen  (density  =  1) 
diffuses  four  times  as  rapidly  as  oxygen  (density  =  16).  We  find  similar 
differences  between  the  rates  of  diffusion  of  dissolved  substances — differ- 
ences which  also  are  determined  in  all  probabihty  by  the  weight  and 
size  of  the  individual  molecules,  although  the  relation  between  molecular 
weight  and  rate  of  diffusion  is  not  so  simple  as  the  ratio  between  these  two 
quantities  in  gases.  The  dift'usibihty  of  a  substance  is  given  by  its  diffusion 
coefficient.  The  amount  of  dissolved  substance,  which  diffuses  in  a  unit 
of  time  across  a  given  area  of  fluid,  is  proportional  to  the  difference  between 
the  osmotic  pressures  at  two  cross-sections  of  the  column  of  fluid  at  an  in- 
finitesimally  small  distance  apart.  If  we  take  a  cyhndrical  mass  of  solution 
which  is  one  centimetre  long  and  has  a  sectional  area  of  one  square  centimetre 
(Fig.  23),  and  maintain  a  constant 
difference  of  concentration  between  A 
and  B  =  I,  the  diffusion  coefficient 
is  the  amount  of  substance  which 
diffuses  in  a  unit  of  time  from  A  to 
B.  Thus  the  statement  that  the 
diffusion  co-efficient  of  urea  is  0-810 
at  7-5°  C.  denotes  that  if  A  be  con- 
tinually  filled    with    a    1    per   cent. 

solution    of    urea,    while  in   B    a    constant    current    of    distilled    water 
is  kept  up  so  as  to  maintain  the  concentration  at  zero,  in  the  course  of  a 

131 


132  PHYSIOLOGY 

day  0  -810  gramme  of  urea  will  pass  from  A  to  B  through  the  cyhnder  of  one 
centimetre  in  length  and  one  square  centimetre  in  cross-section.  The  deter- 
mination of  these  diffusion  coefficients  presents  many  difficulties.  The  task 
is,  however,  rendered  easier  by  the  fact,  first  ascertained  by  Graham,  that 
diffusion  of  salts  occurs  as  rapidly  through  a  sohd  jelly  of  gelatin  or  agar-agar 
as  through  water.  It  is  therefore  possible  to  make  the  plug  in  the  diagram 
soHd  by  the  admixture  of  one  of  these  two  substances,  and  to  maintain  a  con- 
stant concentration  on  the  two  sides  of  it  by  the  circulation  of  fluid  without 
affecting  the  rate  of  diffusion  through  the  cyhnder  by  setting  up  accidental 
currents. 

More  important  from  the  physiological  point  of  view  than  diffusion 
through  fluids  is  the  exchange  of  fluids  (water  and  dissolved  substances), 
which  may  take  place  across  membranes.  Such  processes  are  of  constant  oc- 
currence in  all  parts  of  the  body  and  are  concerned  in  such  functions  as  the 
formation  and  absorption  of  lymph,  the  absorption  from  and  secretion 
into  the  intestines,  absorption  from  serous  cavities,  and  so  on.  In  many 
of  these  functions  we  shall  have  to  consider  later  whether  the  transference 
across  the  membrane  is  determined  solely  by  the  nature  and  concentration 
of  the  fluids  on  the  two  sides  of  it  or  is  effected  by  the  active  intervention, 
involving  the  expenditure  of  energy,  on  the  part  of  living  cells  forming 
constituent  elements  of  the  membrane  itself.  It  is  worth  our  while,  there- 
fore, to  consider  at  some  greater  length  the  purely  physical  factors  which  may 
be  concerned  in  the  passage  of  water  and  dissolved  substances  across 
membranes. 

In  the  case  of  fluids  containing  only  one  substance  in  solution,  the  ex- 
change across  the  membrane  will  be  determined  entirely  by  the  osmotic 
pressures.  Thus,  if  two  watery  solutions,  with  the  same  osmotic  pressure, 
are  separated  by  a  membrane  through  which  diffusion  can  take  place,  no 
change  in  volume  occurs  on  either  side  of  the  membrane.  If  the  solutions 
on  either  side  of  the  membrane  are  of  unequal  osmotic  pressure,  water  passes 
from  the  side  where  the  pressure  is  lower  to  the  side  where  it  is  higher,  and 
there  is  a  simultaneous  passage  of  the  solute  from  the  side  of  greater  to  the 
side  of  less  concentration. 

If,  however,  the  solutions  on  the  two  sides  contain  dissimilar  substances, 
with  different  diffusion  coefficients,  the  conditions  are  more  comphcated, 
and  may  tend  even  to  produce  a  movement  of  fluid  in  apparent  opposition  to 
the  difference  of  osmotic  pressure.  Under  these  circumstances  the  nature 
of  the  membrane  itself  is  all-important.  We  may  therefore  shortly  consider 
the  various  modes  in  which  interchanges  may  take  place  across  membranes  of 
varying  permeabihty.  We  shall  see  that  the  close  analogy  which  exists 
between  substances  in  solution  and  gases,  when  deahng  with  '  semi- 
permeable '  membranes,  is  also  borne  out  by  experiment  when  used  to  predict 
the  behaviour  of  solutions  separated  by  such  permeable  membranes  as 
occur  in  the  body. 

The  simplest  case  is  that  in  which  two  fluids  are  separated  by  a  perfect 
semi-permeable  membrane  that  permits  the  passage  of  water  but  is  absolutely 


PASSAGE  OF  WATER  AND  DISSOLVED  SUBSTANCES      133 

impermeable  to  dissolved  siibstances.  In  this  case  the  transference  of  water 
from  one  side  to  the  other  depends  entirely  on  the  difference  of  osmotic 
pressure  between  the  two  sides. 

If  we  suppose  two  vessels,  A  and  B  (Fig.  24),  separated  by  such  a  mem- 
brane, A  containing  a  solution  of  a  and  B  a  solution  of  [3,  water  will  pass 
from  A  to  B  so  long  as  the  osmotic  pressure  of  [3  is  greater  than  the  osmotic 
pressure  of  the  solution  of  a.  If  B  be  subjected  to  a  hydrostatic  pressure 
greater  than  the  osmotic  difference  between  the  two  fluids,  water  will  pass 
from  B  to  A  until  the  force  causing  filtration  or  transudation  (the  hydrostatic 
pressure)  is  equal  to  the  force  causing 
absorption  into  B  (the  difference  of 
osmotic  pressures).  Under  no  circum- 
stance wdll  there  be  any  transference 
of  salt  or  dissolved  substance  between 
the  two  sides.  Such  semi-permeable 
membranes    as    this,    however,    rarely  Fig.  24, 

occur  in  the  body  over  any  extent  of 

surface.  The  external  layer  of  the  cell  protoplasm  may  resemble  the 
protoplasmic  pelhcle  of  plant  cells  in  possessing  this  '  semi-permeabihty  * ; 
but  in  nearly  all  cases  where  we  have  a  membrane  made  up  of  a  number 
of  cells,  it  can  be  shown  to  permit  the  free  passage  of  at  any  rate  a  large 
number  of  dissolved  substances. 

Let  us  now  consider  what  will  occur  when  the  two  solutions  A  and  B 
are  separated  by  a  membrane  which  permits  the  free  passage  of  salts  and 
water.  If  the  osmotic  pressure  of  B  be  higher  than  A  at  the  commencement 
of  the  experiment,  the  force  tending  to  move  water  from  A  to  B  will  be  equal 
to  this  osmotic  dift'erence.  But  there  is  at  the  same  time  set  up  a  dift'usion 
of  the  dissolved  substances  from  B  to  A  and  from  A  to  B.  The  result  of  this 
diffusion  must  be  that  there  is  no  longer  a  sudden  drop  of  osmotic  pressure 
from  B  to  A,  and  the  result  of  the  primary  osmotic  difference  on  the  move- 
ment of  water  willbe  minimised  in  proportion  to  the  freedom  of  diffusion  which 
takes  place  through  the  membrane.  Now  let  us  take  a  case  in  which  A 
and  B  represent  equimolecular  and  isotonic  solutions  of  a  and  [3.  It  is  evident 
that  the  movement  of  water  into  A  will  vary  as  A;;  —  Bp  *  =  0.  But 
diffusion  also  occurs  of  a  into  B  and  of  [3  into  A.  Now  the  amount  of  sub- 
stance diffusing  from  a  solution  is  proportional  to  the  concentration,  and 
therefore  to  its  osmotic  pressure,  as  well  as  to  its  diffusion  coefficient. 

Hence  the  amount  of  a  diffusing  into  B  will  vary  as  A  y.y.h  (when  h  is 
the  diffusion  coefficient). 

In  the  same  way  the  amount  of  ^  diffusing  into  A  will  vary  as  B/?.  (Bk'. 

Hence,  if  a^  is  greater  than  [3k',  i.e.  if  a  is  more  diffusible  than  [3,  the 
initial  result  nuist  be  that  a  greater  number  of  molecules  of  a  will  pass  into  B 
than  of  [3  into  A.  The  solutions  on  the  two  sides  of  the  membrane  will  thus 
be  no  longer  equimolecular,  but  the  total  number  of  molecules  of  x  -t-  (i  in 
B  will  be  greater  than  the  number  of  molecules  of  a  +  (i  in  A,  and  this  differ- 
*  Ap  =  osmotic  pressiu'e  of  A,  &c. 


134  PHYSIOLOGY 

ence  will  be  most  marked  in  the  layers  of  fluid  nearest  the  membrane.  The 
result,  therefore,  of  the  unequal  diffusion  of  the  two  substances  is  to  upset  the 
previous  equahty  of  osmotic  pressures.  The  layer  of  fluid  on  the  B  side  of 
the  membrane  will  have  an  osmotic  pressure  greater  than  the  layer  of  fluid 
in  immediate  contact  with  the  A  side  of  the  membrane,  and  there  will  thus  be 
a  movement  of  water  from  A  to  B.  Hence  if  we  have  two  equimolecular  and 
isotonic  solutions  of  different  substances  separated  by  a  membrane  permeable 
to  the  solutes,  there  will  be  an  initial  movement  of  fluid  towards  the  side  of 
the  less  diffusible  substance. 

We  have  an  exact  parallel  to  this  in  Graham's  famihar  experiment,  in 
which  a  porous  pot  filled  with  hydrogen  is  connected  by  a  vertical  tube  with 
a  vessel  of  mercury.  In  consequence  of  the  more  rapid  diffusion  outwards  of 
the  hydrogen  than  of  atmospheric  air  inwards,  the  pressure  within  the  pof 
sinks  below  that  of  the  surrounding  atmosphere  and  the  mercury  rises  several 
inches  in  the  tube. 

We  must  therefore  conclude  that,  even  when  the  two  solutions  on  either 
side  of  the  membrane  are  isotonic,  there  may  be  a  movement  of  fluid  from 
one  side  to  the  other  with  a  performance  of  work  in  the  process.  In  fact, 
osmosis  may  occur  from  a  fluid  having  a  higher  towards  a  fluid  having  a  lower 
osmotic  pressure.  If,  for  example,  equimolecular  solutions  of  sodium 
chloride  and  glucose  be  separated  by  a  peritoneal  membrane,  the  osmotic 
flow  will  take  place  from  the  fluid  having  the  higher  osmotic  pressure — 
sodium  chloride.*  We  might  compare  with  this  experiment  the  results  of 
separating  hydrogen  at  one  atmosphere's  pressure  from  oxygen  at  two 
atmospheres'  pressure  by  means  of  a  plate  of  graphite.  In  this  case  the 
initial  result  will  be  a  still  further  increase  of  pressure  on  the  oxygen  side 
of  the  diaphragm — a  movement  of  gas  against  pressure  taking  place  in 
consequence  of  the  greater  diffusion  velocity  of  hydrogen. 

So  far  we  have  considered  only  the  behaviour  of  solutions  when  separated 
by  a  membrane,  the  permeability  of  which  to  salts  is  comparable  to  that  of 
water  ;  so  that  the  passage  of  salts  through  the  membrane  depends  merely  on 
the  diffusion  rates  of  the  salts.  There  can  be  no  doubt,  however,  that  we 
might  get  analogous  movements  of  fluid  against  total  osmotic  pressure 
determined,  not  by  the  diflusibihty  of  the  salts,  but  by  the  permeabihty  of 
the  membrane  for  the  salts — a  permeability  which  may  depend  on  a  state 
of  solution  or  attraction  existing  between  membrane  and  salts.  We 
have  an  analogue  to  such  a  condition  of  things  in  the  passage  of  gases 
through  an  india-rubber  sheet.  If  two  bottles,  one  containing  carbonic  acid, 
the  other  hydrogen,  be  separated  by  a  sheet  of  india-rubber,  carbon  dioxide 
passes  into  the  hydrogen  bottle  more  quickly  than  hydrogen  can  pass  out 
into  the  carbon  dioxide  bottle,  so  that  a  difference  of  pressure  is  created,  and 
the  rubber  bulges  into  the  carbon  dioxide  bottle.  We  might,  in  the  same 
way,  conceive  of  a  membrane  which  permitted  the  passage  of  dextrose  more 

*  In  consequence  of  ionic  dissociation  of  the  sodium  chloride,  a  decinormal  solution 
of  this  salt  will  have  an  osmotic  pressure  nearly  twice  as  great  as  that  of  a  similar 
solution  of  the  non-ionised  glucose. 


PASSAGE  OF  WATER  AND  DISSOLVED  SUBSTANCES       135 

easily  than  that  of  urea.  The  importance  of  the  membrane  in  determining 
the  direction  of  the  osmotic  passage  of  fluid  is  well  illustrated  by  Raoult's 
experiments.  When  alcohol  and  ether  were  separated  by  an  animal  mem- 
brane, alcohol  passed  into  the  ether,  whereas  if  vulcanite  were  employed  for 
the  diaphragm,  the  osmotic  flow  was  in  the  reverse  direction,  and  an  enormous 
pressure  was  set  up  on  the  alcohol  side  of  the  diaphragm.  * 

The  next  point  to  be  considered  is  the  passage  of  a  dissolved  substance 
across  membranes,  in  consequence  of  differences  in  the  partial  pressure  of 
the  substance  in  question  on  the  two  sides  of  the  membrane.  Stress  has  been 
laid  by  Heidenhain  and  others  on  the  fact  that  in  the  peritoneal  cavity,  as 
well  as  from  the  intestine,  salt  may  be  taken  up  from  fluids  containing  a 
smaller  percentage  of  this  substance 
than  does  the  blood  plasma,  and 
they  regard  this  absorption  as  point- 
ing indubitably  to  an  active  inter- 
vention of  living  cells  in  the  process.  A  B 
This  argument  requires  examination. 
Let  us   suppose  the  two  vessels  A 

and  B  (Fig.  25)  to  be  separated  by  a     '  i^r'"25~ 

membrane  which  oft'ers  free  passage 
to  water  and  a  difficult  passage  to  salts.  Let  A  contain  0-5  per  cent, 
salt  solution  and  B  a  solution  isotonic  with  a  1  per  cent.  NaCl, 
but  containing  only  0-65  per  cent,  of  this  salt,  the  rest  of  its  osmotic 
tension  being  due  to  other  dissolved  substances.  If  the  membrane  were 
absolutely  '  semi-permeable,'  water  would  pass  from  A  to  B  until  the  two 
fluids  were  isotonic,  i.e.  until  A  contained  1  per  cent.  NaCl  (we  may  regard 
volume  B  as  infinitely  great  to  simphfy  the  argument).  If,  however,  the 
membrane  permitted  passage  of  the  dissolved  substances,  the  course  of 
events  might  be  as  follows  :  At  first  water  would  pass  out  of  A,  and  salt  would 
diffuse  in  until  the  percentage  of  NaCl  in  A  was  equal  to  that  in  B.  There 
would  now  be  an  equal  partial  pressure  of  NaCl  on  the  two  sides  of  the 
membrane,  but  the  total  osmotic  pressure  of  B  would  still  be  higher  than  A. 
Water  would  therefore  still  continue  to  pass  from  A  to  B  more  rapidly  than 
the  other  ingredients  of  B  could  pass  into  A.  As  soon,  however,  as  more 
water  passed  out  from  A,  the  percentage  of  NaCl  in  A  would  be  raised  above 
that  in  B.  The  extent  to  which  this  occurs  will  depend  on  the  impermeability 
of  the  membrane.  As  the  NaCl  in  A  reaches  a  certain  concentration  it  will 
pass  over  into  B,  and  this  will  go  on  until  equilibrium  is  estabhshed  between 
A  and  B.  Extending  this  argument  to  the  conditions  obtaining  in  the 
living  body,  we  may  conclude  that  neither  the  raising  of  the  percentage  of  a 

*  Here  we  have  a  possible  clue  to  the  explanation  of  some  phenomena  of  cell 
activity,  to  which  the  term  '  vital '  is  often  assigned.  In  the  swimming-bladder  of 
fishes,  for  instance,  we  find  a  gas  which  is  extremelj-  rich  in  oxygen,  and  tlie  oxygen 
is  said  to  have  been  secreted  by  the  cells  lining  the  bladder.  It  is,  however,  possible 
that  the  processes  here  may  be  analogous  to  Graham's  atmolysis,  and  that  the  bladder 
may  represent  a  perfected  form  of  Graham's  india-rubber  bag. 


136  PHYSIOLOGY 

salt  in  any  fluid  above  that  of  the  same  salt  in  the  plasma,  nor  the  passage 
of  a  salt  from  a  h5rpotomc  fluid  into  the  blood  plasma,  can  afiord  in  itself 
any  proof  of  an  active  intervention  of  cells  in  the  process. 

In  the  case  of  the  pleura,  for  example,  we  seem  to  have  a  membrane  which  is  very 
imperfectly  semi-permeable.  It  is  permeable  to  salts,  but  presents  rather  more 
resistance  to  their  passage  than  to  the  passage  of  water.  Hence  on  injecting  0-5  per 
cent.  NaCl  solution  into  the  pleural  cavity,  water  passes  from  the  pleural  fluid  into 
the  blood,  until  the  percentage  of  sodium  chloride  in  the  fluid  is  raised  perceptibly 
above  that  in  the  blood  plasma.  The  limit  of  the  resistance  of  the  pleural  membrane 
to  the  passage  of  salt  is,  however,  soon  reached,  and  then  salt  passes  from  pleural  fluid 
into  blood  ;  but  in  every  case  this  passage  is  from  a  region  of  higher  to  a  region  of 
lower  partial  pressure.  Hence  at  a  certain  stage  of  the  experiment  we  find  a  higher 
percentage  of  salt  in  the  pleura  than  in  the  blood-vessels,  although  the  total  amount 
of  salt  in  the  pleural  fluid  is  less  than  that  originally  put  in,  or,  in  other  words,  salt  has 
been  absorbed. 

We  have  already  seen  that  the  effective  osmotic  pressure  of  a  substance, 
i.e.  its  power  of  attracting  water  across  a  membrane,  varies  inversely  as  its 
difiusibihty,  or  as  the  permeabihty  of  the  membrane  to  it.  What,  then,  will 
be  the  effect  if  on  one  side  of  the  membrane  we  place  some  substance  in 
solution  to  which  the  membrane  is  impermeable  ? 

We  will  suppose  that  A  and  B  both  contain  1  per  cent.  NaCl,  but  that 
B  contains  in  addition  some  substance  x  to  which  the  membrane  is  im- 
permeable. Since  the  osmotic  pressure  of  B  is  higher,  by  the  partial  pressure 
of  X,  than  that  of  A,  fluid  will  pass  from  A  to  B  by  osmosis.  But  the  conse- 
quence of  this  passage  of  water  will  be  to  concentrate  the  NaCl  in  A,  so  that 
the  partial  pressure  of  this  salt  in  A  is  greater  than  in  B.  NaCl  will  therefore 
diffuse  from  A  to  B,  with  the  result  that  the  former  difference  of  total 
osmotic  pressure  will  be  re-estabhshed.  Hence  there  will  be  a  continual 
passage  of  both  water  and  salt  from  A  to  B,  until  B  has  absorbed  the  whole 
of  A.  This  result  will  be  only  delayed  if  the  osmotic  pressure  of  A  is  at  first 
higher  than  B,  in  consequence  of  a  greater  concentration  of  NaCl  in  A. 
There  may  be  at  first  a  flow  of  fluid  from  B  to  A,  but  as  soon  as  the  NaCi 
concentration  on  the  two  sides  has  become  the  same  by  diffusion,  the  power 
of  X  to  attract  water  from  the  other  side  will  make  itself  felt,  and  this  attrac- 
tion will  be  proportional  to  the  osmotic  pressure  of  x.  We  shall  have 
occasion  to  discuss  a  specific  instance  of  this  case  when  deahng  with  the 
mechanism  of  absorption  of  fluid  by  the  blood-vessels  from  the  connective 
tissue  spaces. 

A  more  famihar  example  is  afforded  by  the  process  known  as  dialysis. 
Many  animal  membranes,  all  of  which  are  colloidal  in  character,  and  others 
such  as  vegetable  parchment,  while  freely  permeable  to  salts,  are  impermeable 
to  dissolved  colloids.  If,  therefore,  a  fluid  containing  both  colloids  and 
crystalloids  in  solution,  e.g.  blood-serum,  be  enclosed  in  a  tube  of  vegetable 
parchment,  which  is  hung  up  in  a  large  bulk  of  distilled  water  (Fig.  26),  all 
the  salts  diffuse  out,  and  if  this  be  frequently  changed,  we  obtain  finally  a 
fluid  within  the  dialyser  free  from  salts  and  other  crystalloid  substances,  but 
containing  the  whole  of  the  colloidal  proteins  originally  present. 


PASSAGE  OF  WATER  AND  DISSOLVED  SUBSTANCES      137 

Thus  the  transference  of  fluids  and  dissolved  substances  across  membranes 
is  determined  not  only  by  the  osmotic  pressure  of  the  solutions,  but  also  by 
the  diffusion  coefficient  of  the  solutes  and  the  permeability  of  the  membrane. 
This  permeabiUty  may  be  of  the  same  character  as  the  permeabiHty  of  water, 
in  which  case  the  rates  of  passage  of  the  dissolved  substances  across  the 


Fig.  26.  Dialyser,  consisting  of  a  tube  of  parchment  paper  immersed  in  a  vessel 
through  which  a  constant  stream  of  sterile  distilled  water  can  be  passed. 
(Wf.obleski.) 

membrane  vary  as  their  diffusibiUties,  and  are  therefore  probably  some  func- 
tion of  their  molecular  weights.  On  the  other  hand,  the  membrane  may 
exhibit  a  certain  attraction  for,  or  power  of  dissolving,  some  of  the  solutes  to 
the  exclusion  of  others,  in  which  case  there  will  be  no  relation  between  the 
diffusibiUties  and  the  rates  of  passage  of  the  dissolved  substances. 

In  a  recent  paper  Bayliss  has  drawn  attention  to  certain  other  factors 
which  may  determine  permanent  inequaUty  of  distribution  of  a  salt  on  the 
two  sides  of  a  membrane  permeable  to  the  salt.  If  Congo  red,  which  is  a 
compound  of  an  indiflusible  colloid  acid  with  sodium,  be  placed  in  an  osmo- 
meter which  is  immersed  in  water,  a  certain  osmotic  pressure  is  developed. 
On  adding  sodium  chloride  either  to  the  inner  or  outer  fluid,  there  is  a  fall 
in  the  osmotic  ])i'cssure  if  time  be  allowed  for  equihbrium  to  be  estabhshed. 
At  this  ])()int  it  is  found  that  the  outer  fluid,  which  is  free  from  dye,  contains 
a  larger  percentage  of  sodium  chloride  than  the  inner  solution  of  dye.  This 
difference  is  permanent  and  is  more  marked  the  greater  the  concentration  of 
the  dye  salt.     In  the  following  Tabic  is  given  the  concentrations  of  the  two 

5* 


138  PHYSIOLOGY 

fluids  with  difierent  percentages  of  salt.  The  numbers  indicate  the  litres 
to  which  each  gramme  molecule  of  the  salt  is  diluted.  Apparently  the 
difference  depends  on  the  fact  that  the  non-dissociated  salt  must  be  equal  on 


Dye 

CWorine 

Inside 

Outside 

30 

30 

30 

100 

52 
465 
<5500 
32-9 

30 

73-6 

180 
29-5 

the  two  sides  of  the  membrane  and  that  the  dissociation  is  much  impeded 
on  the  inner  side  on  account  of  the  presence  there  of  another  salt  of  sodium. 
A  sodium  salt  of  any  other  indiffusible  substance,  e.g.  of  a  protein  such  as 
caseinogen,  would  behave  in  a  precisely  similar  fashion. 


SECTION  III 
THE  PROPERTIES   OF  COLLOIDS 

Although  the  chemical  changes  involved  in  the  various  vital  phenomena 
occur  between  substances  in  watery  solution,  the  solution  in  every  case  is 
bound  up  within  the  meshes  or  adsorbed  by  the  surfaces  of  a  heterogeneous 
mass  of  colloids.  The  complex  chemical  molecules  which  make  up 
protoplasm  itself  are  all  colloidal  in  character.  The  participation  of 
colloids  in  chemical  reactions  introduces  conditions  and  modes  of  reaction 
differing  widely  from  those  which  have  been  studied  in  watery  solutions. 
Our  knowledge  of  these  conditions  is  still  very  imperfect,  but  the  important 
part  played  by  colloids  in  the  processes  of  hfe  renders  it  necessary  to  discuss 
in  some  detail  their  properties  and  modes  of  interaction. 

The  term  colloid,  from  koWij,  glue,  was  first  introduced  by  Thomas 
Graham,  Professor  of  Chemistry  at  University  College  from  1836  to  1855. 
Graham  divided  all  substances  into  two  classes,  viz.  crystalloids,  including 
such  substances  as  salt,  sugar,  urea,  which  could  be  crystalhsed  with  ease, 
diffused  rapidly  through  water,  and  were  capable  of  diffusing  through  animal 
membranes  ;  and  colloids,  which  included  substances  such  as  gelatin  or 
glue,  gum,  egg-albumin,  starch  and  dextrin,  were  non-crystalUsable,  formed 
gummy  masses  when  their  solutions  were  evaporated  to  dryness,  diffused 
with  extreme  slo\\aiess  through  water,  and  would  not  pass  through  animal 
membranes.  The  process  of  dialysis  was  therefore  introduced  by  Graham 
for  the  separation  of  crystalloids  from  colloids.  Although  the  broad  dis- 
tinction drawn  by  Graham  between  colloids  and  crystalloids  still  holds  good, 
some  of  the  criteria  by  which  he  distinguished  the  two  classes  are  no  longer 
strictly  appUcable.  For  instance,  it  has  been  shown  that  many  typical 
colloidal  substances,  such  as  haemoglobin,  can  be  obtained  in  a  crystalUne 
form.  On  the  other  hand,  all  gradations  exist  between  substances,  such  as 
egg-albumin,  which  are  practically  indiifusible,  and  those,  such  as  connnon 
salt,  which  are  very  diffusible.  Graham  pointed  out  that  colloids  exist  under 
two  conditions  : 

(1)  In  a  state  of  solution  or  pseudo-solution,  in  which  they  form  sols,  and 
are  distinguished  as  hydrosols,  when  the  solvent  is  water  ;  and 

(2)  In  a  soHd  state,  in  which  a  relatively  small  amoimt  of  the  colloid 
sets  with  a  large  amount  of  a  fluid,  such  as  water,  to  form  a  jelly.  This 
solid  form  is  known  as  a  gel.  The  most  famihar  instance  is  the  jelly  which 
is  obtained  on  dissolving  a  little  gelatin  in  hot  water  and  allowing  the  mixture 

139 


140  PHYSIOLOGY 

to  cool.  Siich  a  jelly  is  known  as  a  hydrogel.  In  many  of  these  gels  the 
water  can  be  replaced  by  other  fluids,  such  as  alcohol,  without  any  alteration 
in  the  appearance  of  the  sohd,  which  is  then  known  as  an  alcogel.  An 
example  of  an  alcogel  is  the  jelly  which  can  be  made  by  dissolving  soap  in 
warm  alcohol  and  allowing  the  mixture  to  cool. 

A  number  of  these  colloidal  substances  can  be  shown  on  purely  chemical 
grounds  to  consist  of  monstrous  molecules.  Thus  the  molecular  weight 
of  haemoglobin  is  at  least  16,000,  and  one  must  ascribe  similar  high  molecular 
weights  to  such  substances  as  egg-albumin  and  globuhn.  Still  greater  must 
be  the  molecular  size  of  such  substances  as  the  cell  proteins,  which  may 
be  made  up  of  more  than  one  type  of  protein  built  up  with  various 
nucleins,  with  lecithin  and  cholesterin,  to  form  a  gigantic  complex,  to 
which  it  would  probably  not  be  an  exaggeration  to  ascribe  a  molecular 
weight  of  over  100,000.  This  chemical  complexity  is  not,  however,  a 
necessary  condition  of  the  colloidal  state,  as  is  shown  by  the  existence 
of  colloidal  sihca,  of  colloidal  ferric  hydrate  and  alumina,  and  even  of 
colloidal  metals. 

On  neutralising  a  weak  solution  of  sodium  silicate  or  water-glass  by  means  of  HCl, 
we  obtain  a  solution  which  contains  sodium  chloride  and  silicic  acid.  On  dialysing  this 
mixture  for  some  days  against  distilled  water,  the  whole  of  the  NaCl  passes  out,  and  a 
solution  of  silicic  acid  or  colloidal  silica  is  left  in  the  dialyser.  This  solution  can  be 
concentrated  over  sulphuric  acid.  When  concentrated  to  a  syrupy  consistence  it 
becomes  extremely  unstable.  The  addition  of  a  minute  trace  of  sodium  chloride 
or  other  electrolyte  to  the  solution  causes  it  to  set  at  once  to  a  solid  jelly  (gelatinous 
silica),  the  change  being  accompanied  by  an  appreciable  rise  of  temperature.  The 
change  is  irreversible,  in  that  it  is  not  possible  to  bring  the  silicic  acid  into  solution 
again  by  removal  of  the  electrolyte  by  means  of  dialysis.  If,  however,  it  be  allowed 
to  stand  with  weak  alkali  for  some  time,  it  gradually  passes  into  solution.  Analogous 
methods  are  employed  for  the  preparation  of  colloidal  FcgOs  and  AI2O3. 

Of  special  interest  are  the  colloidal  solutions  of  the  metals.  Faraday 
long  ago  pointed  out  that,  on  treating  a  weak  solution  of  gold  chloride  with 
phosphorus,  it  underwent  reduction  with  the  formation  of  metallic  gold. 
The  gold  was  not  precipitated,  but  remained  in  suspension  or  pseudo- 
solution,  giving  a  deep  red  *  or  a  blue  hquid,  according  to  the  con- 
ditions under  which  the  reaction  was  effected.  This  solution  was  homo- 
geneous in  that  it  could  be  filtered  without  change,  and  could  be  kept  for 
months  without  deposition  of  the  gold.  The  latter  was,  however,  thrown 
down  on  addition  of  mere  traces  of  impurity,  though  greater  stabihty  could 
be  conferred  on  the  solution  by  adding  to  it  a  little  '  jelly,'  i.e.  a  weak  solution 
of  gelatin.  In  1899  Bredig  showed  how  similar  hydrosols  might  be  prepared 
from  a  number  of  different  metals,  viz.  by  the  passage  of  a  small  arc  or 
electric  sparks  between  metallic  terminals  submerged  in  distilled  water. 
If,  for  example,  the  terminals  be  of  platinum,  the  passage  of  the  current 
is  seen  to  be  accompanied  by  the  giving  off  of  brown  clouds,  which  spread 
into  the  surrounding  fluid.  These  clouds  consist  of  particles  of  platinum 
of  all  sizes.  The  larger  settle  at  the  bottom  of  the  vessel,  the  smaller — 
*  Ruby  glass  is  a  colloidal  '  solid  '  solution  of  gold  in  a  mixture  of  silicates. 


THE  PROPERTIES  OF  COLLOIDS  Ul 

which  are  ultra-microscopic  in  size,  i.e.  from  5  /x/>i  to  40  /x/ot* — -remain  in  sus- 
pension, and  \ye  obtain  a  bro^vn  fluid  which  can  be  filtered  through  paper 
or  even  through  a  Berkefeld  filter  without  losing  its  colour.  It  may  be 
kept  for  months  without  any  deposit  taking  place.  The  addition  of  minute 
traces  of  electrolytes  precipitates  the  platinum  particles,  leaving  a  colourless 
fluid.  "We  shall  have  to  return  later  on  to  the  consideration  of  the  behaviour 
of  these  metalUc  sols. 

PROPERTIES  OF  GELS.  A  typical  hydrogel  is  the  firm  mass  in  which 
a  solution  of  gelatin  sets  on  coohng.  It  is  clear,  hyaUne,  apparently  structure- 
less, and  possesses  considerable  elasticity,  i.e.  resistance  to  deforming  force. 
It  may  be  regarded  as  formed  by  the  separation  of  the  warm  pseudo-solution 
of  gelatin  into  two  phases  :  first  a  solid  phase,  rich  in  gelatin  and  forming 
a  tissue  or  mesh  work,  in  the  interstices  of  which  is  embedded  the  second 
phase,  consisting  of  a  very  weak  solution  of  gelatin. 

If  the  process  be  observed  under  the  microscope,  according  to  Hardy,  minute  di'ops 
first  appear,  which,  as  they  enlarge,  touch  one  another  and  form  networks.  In  stronger 
solutions  the  first  structures  to  make  their  appearance  consist,  not  of  the  more  con- 
centrated iihase,  but  of  droplets  of  the  dilute  solution  of  gelatin  ;  the  stronger  solution 
collects  round  these  drops  and  solidifies  to  a  honeycomb  structure. 

In  many  cases  the  more  fluid  part  of  the  gel  is  practically  pure  water. 
In  such  a  case  immersion  in  alcohol  causes  a  diffusion  outwards  of  the  water, 
which  is  replaced  by  alcohol  with  the  formation  of  an  alco-gel.  In  a  dry 
atmosphere  the  gel  loses  water  and  becomes  shrivelled  and  dry,  but  in 
some  cases,  e.g.  gelatin,  it  can  resume  its  former  size  and  characters  on 
immersion  in  water.  Other  gels,  such  as  sihcic  acid  or  ferric  hydrate,  lose 
the  power  of  swelhng  up  after  drying.  The  change  in  them  is  therefore 
irreversible.  A  gel  adheres  to  the  last  traces  of  water  with  extreme  tenacity. 
In  consequence  of  its  structure,  it  presents  an  enormous  extent  of  surface 
on  which  adsorption  can  take  place.  At  this  surface  the  vapour-tension 
of  fluids  is  diminished,  as  well  as  the  osmotic  pressure  of  dissolved  substances. 
On  this  account  gelatin  must  be  heated  for  many  hours  at  a  temperature 
of  120°  0.  in  order  to  be  thoroughly  dried.  When  dry,  it,  as  well  as  other 
solid  colloids,  can  exert  a  considerable  amount  of  energy  when  caused  to 
swell  up  by  moistening.  This  energy  was  made  use  of  by  the  ancient 
Egyptians  in  the  quarrying  of  their  stone  blocks  by  the  insertion  of  wedges 
of  wood ;  water  was  poured  on  the  wood,  and  the  swelhng  of  the  wedges 
split  the  rock  in  the  desired  direction. "j" 

On  account  of  the  extent  of  surface  it  is  practically  impossible  to  wash 
out  the  inorganic  constituents  from  a  gel.  The  diminution  of  the  osmotic 
pressure  of  many  dissolved  substances  at  surfaces  causes  the  concentration 
at  the  surface  of  the  solid  phase  to  be  greater  than  that  in  the  surrounding 
medium.     Thus,  if  dry  gelatin  be  immersed  in  a  salt  solution  it  will  swell 

*  One  ft  is  one-thousandth  of  a  millimetre  ;  one  ^y^  is  one-thousandth  ^,  i.e.  onc- 
millionth  of  a  millimetre. 

t  According  to  Rodewald,  the  maximal  pressure  with  which  dry  starch  attracts 
water  amounts  to  2073  kilo,  per  sq.  cm. 


142  PHYSIOLOGY 

up,  but  the  solution  which  it  absorbs  will  be  more  concentrated  than  the 
solution  in  which  it  is  immersed,  so  that  the  proportion  of  salt  in  the  latter 
will  be  diminished.  When,  however,  equihbrium  is  estabhshed  between  a 
gel  and  the  surrounding  fluid,  it  is  found  to  present  no  appreciable  resistance 
to  the  passage  of  dissolved  crystalloids.  Thus  salt  or  sugar  diffuses  through 
a  column  of  sohd  gelatin  as  if  the  latter  were  pure  water.  On  the  other 
hand,  gels  are  practically  impermeable  to  other  colloids  in  solution.  This 
impermeabihty  is  made  use  of  in  the  separation  of  crystalloids  from  colloids 
by  dialysis,  membranes  used  in  this  process  being  generally  irreversible 
and  heterogeneous  gels  {i.e.  vegetable  parchment,  animal  membranes). 
Other  gels,  such  as  tannate  of  gelatin  or  copper  ferrocyanide,  are  not  only 
impermeable  to  colloids,  but  also  to  many  crystalloid  substances.  These 
membranes,  therefore,  were  used  by  Pfeffer  for  the  determination  of  the 
osmotic  pressure  of  such  crystalloids  as  cane  sugar. 

PROPERTIES  OF  HYDROSOLS.  Substances  such  as  dextrin  or  egg- 
albumin  may  be  dissolved  in  water  in  almost  any  concentration.  If  a 
solution  of  egg-albumin  be  concentrated  at  a  low  temperature,  it  becomes 
more  and  more  viscous  and  finally  sohd.  But  there  is  no  distinct  point 
at  which  the  fluid  passes  into  the  sohd  condition.  Such  solutions  are  known 
as  hydrosols.  Much  discussion  has  arisen  whether  they  are  to  be  regarded 
as  true  solutions  or  as  pseudo-solutions  or  suspensions.  The  chief  criterion 
of  a  true  solution  is  its  homogeneity.  In  a  solution  the  molecules  of  the 
solute  are  equally  diffused  throughout  the  molecules  of  the  solvent,  and 
it  is  impossible,  without  the  apphcation  of  energy,  to  separate  one  from 
the  other.  Thus  filtration,  gravitation  leave  the  composition  of  the  solution 
unchanged.  It  is  true  that,  by  the  employment  of  certain  kinds  of  mem- 
brane, e.g.  the  semi-permeable  copper  ferrocyanide  membrane,  it  is  possible 
to  separate  solute  from  solvent,  but  in  this  case  the  force  required  to  effect 
the  filtration  is  enormous  and  grows  with  every  increase  in  the  strength 
of  the  solution.  The  measure  of  the  force  required  is  the  osmotic  pressure 
of  the  solution,  and  it  becomes  natural  therefore  to  regard  the  possession 
of  an  osmotic  pressure  as  a  distinguishing  criterion  of  a  true  solution. 
Is  there  any  evidence  that  colloid  solutions  also  display  an  osmotic 
pressure  ? 

I  have  shown  that  it  is  possible  to  determine  the  osmotic  pressure  of 
colloidal  solutions  directly,  taking  advantage  of  the  fact  that  colloidal 
membranes,  while  permitting  the  passage  of  water  and  salts,  are  im- 
permeable to  colloids  in  solution. 

The  method  originally  adopted  was  as  follows  :  In  order  to  determine  the  osmotic 
pressure  of  the  colloidal  constituents  of  blood-serum,  150  c.c.  of  clear  filtered  serum  are 
filtered  under  a  pressure  of  30-40  atmospheres  through  a  porous  cell  which  has  been 
previously  soaked  with  gelatin.  The  first  10-20  c.c.  of  filtrate,  which  contain  the 
water  squeezed  out  of  the  meshes  of  the  gelatin  and  have  also  lost  salt  in  consequence 
of  absorption  by  the  gelatin,  are  rejected.  The  filtration  is  allowed  to  go  on  for  another 
twenty-four  hours,  when  about  75  c.c.  of  a  clear  colourless  filtrate  is  obtained,  perfectly 
free  from  all  traces  of  protein,  but  possessing  practically  the  same  freezing-point  as  the 
original  serum.     (Although  the  colloids,  if  they  possess  an  osmotic  pressure,  must 


THE  PROPERTIES  OF  COLLOIDS 


143 


also  cause  a  dei^ression  of  the  free  zing- jx)mt,  any  such  depression  would  be  within 
the  errors  of  observation,  since  a  pressure  of  45  mm.  Hg.  would  correspond  only  to 
0-005°  C.)  The  concentrated  serum  left  behind  in  the  filter  is  then  put  into  the  os- 
mometer, the  filtrate  being  used  as  the  inner  fluid.  The  construction  of  the  osmometer 
is  shown  in  the  diagram  (Fig.  27). 

The  tube  BB  is  made  of  silver  gauze,  connected  at  each  end  to  a  tube  of  solid  silver. 
Round  the  gauze  is  wTapped  a  piece  of  peritoneal  membrane,  as  in  making  a  cigarette. 
This  is  painted  all  over  with  a  solution  of  gelatin  (10  per  cent.)  and  then  a  second  layer 
of  membrane  applied.     Fine  thread  is  now  twisted  many  times  round  the  tube  to 


prevent  any  disturbance  of  the  membranes,  and  the  whole  tube  is  soaked  for  half  an 
hour  in  a  warm  solution  of  gelatin.  In  this  way  one  obtains  an  even  layer  of  gelatin 
between  two  layers  of  peritoneal  membrane  and  supported  by  the  wire  gauze.  The 
tube  so  prepared  is  placed  -ndthin  a  wide  tube,  AA,  which  is  provided  with  two  tubules 
at  the  top.  One  of  these,  0,  is  for  filling  the  outer  tube  ;  the  other  is  fitted  -nith 
a  mercurial  manometer,  M.  Two  small  reservoii's,  CC,  are  connected  -ndth  the  outer 
ends  of  BB,  by  means  of  rubber  tubes.  The  whole  apparatus  is  placed  in  a  wooden 
cradle,  DD,  pivoted  at  X,  and  provided  with  a  cover  so  that  it  may  be  filled  with  fluids 
at  different  temperatiu-es  if  necessary.  The  colloid  solution  is  placed  in  AA,  and  the 
reservoirs,  CC,  and  imier  tube,  BB,  are  filled  with  the  filtrate,  i.e.  with  a  salt  solution 
approximately  or  absolutely  isotonic  mth  the  colloid  solution.  The  apparatus  is  then 
made  to  rock  continuously  for  days  or  weeks  by  means  of  a  motor.  In  this  way  the 
fluid  on  the  two  sides  of  the  membrane  is  continually  renewed,  and  the  attainment 
of  an  osmotic  equilibrium  facilitated.  With  this  apparatus  I  found  that  the  colloids 
in  blood-serum,  containing  from  7  to  8  per  cent,  proteins,  had  an  osmotic  pressure  of 
25  to  30  mm.  Hg.,  which  would  correspond  to  a  molecular  weiglit  of  about  30,000. 

A  more  couvenieiit  form  of  osmometer  has  been  devised  by  B.  Moore, 
using  parchment  paper  as  the  membrane.  AVith  this  osmometer,  the 
existence  of  an  osmotic  pressure  in  colloidal  solutions  has  been  definitely 
established  both  by  Moore  in  the  case  of  haemoglobin,  proteins,  and  soaps, 
and  by  Bayliss  in  the  case  of  colloidal  dyes,  such  as  Congo  red.  The  osmotic 
pressure  of  haemoglobin  was  found  by  Hiifner  to  correspond  to  a  molecular 
weight  of  about  16,000,  i.e.  a  molecular  weight  already  deduced  from  its 
composition  and  its  combining  powers  with  oxygen.  Often,  however,  the 
osmotic  pressure  is  very  much  smaller  than  would  be  expected  from  the 
molecular  weiglit  of  the  substance,  owing  to  the  fact  that  colloids  in  solution 


144  PHYSIOLOGY 

may  be  in  many  different  conditions  of  aggregation.  Thus  the  molecule 
of  colloidal  sihca  must  be  many,  probably  thousands  of  times  larger 
than  the  molecule  as  represented  by  HgSiOg.  The  osmotic  pressure 
being  proportional  to  the  number  of  molecules  in  a  given  volume  of 
solution,  the  larger  the  aggregate  the  smaller  would  be  the  total  number 
of  molecules,  and  the  smaller  therefore  the  osmotic  pressure  of  the 
solution. 

It  is  in  consequence  of  the  huge  size  of  the  molecular  aggregates  that 
colloidal  solutions,  such  as  starch  or  glycogen,  and  probably  globulin,  display 
no  appreciable  osmotic  pressure.  We  cannot  divide  colloidal  solutions  into 
two  classes,  viz.  those  which  form  true  solutions  and  present  a  feeble  osmotic 
pressure,  and  those  which  only  form  suspensions  and  therefore  exert  no 
osmotic  pressure.  In  inorganic  colloids,  such  as  arsenious  sulphide,  Picton 
and  Linder  have  shown  that  all  grades  exist  between  true  solutions  and 
suspensions.  With  increasing  aggregation  of  the  molecules,  the  suspension 
becomes  coarser  and  coarser  until  finally  the  sulphide  separates  in  the  form 
of  a  precipitate. 

The  measurement  of  the  osmotic  pressure  of  the  colloids  of  serum  points 
to  their  having  a  molecular  weight  of  about  30,000.  Chemical  evidence 
shows  that  haemoglobin  has  a  molecular  weight  of  about  16,000,  and  we 
have  every  reason  to  beheve  that  the  much  more  complex  molecules  forming 
the  cell  proteins  may  have  molecular  weights  of  many  times  this  amount. 
When,  however,  we  arrive  at  molecular  weights  of  these  dimensions,  the 
disproportion  between  the  size  of  the  molecules  and  those  of  the  solvent, 
water,  becomes  so  great  that  a  homogeneous  distribution  of  the  two  sub- 
stances, solute  and  solvent,  is  no  longer  possible.  The  size  of  a  molecule 
of  water  has  been  reckoned  to  be  -7  x  10  ~  ^  mm.  A  molecule  10,000 
times  as  large  would  have  a  diameter  of  -7  X  10  "~  ^  mm.  =  -07 ^a,  a  size 
just  within  the  hmits  of  microscopic  vision.  Long  before  molecules  attained 
such  a  size  they  would  no  longer  react  according  to  the  laws  which  have 
been  derived  from  the  study  of  the  behaviour  of  the  almost  perfect  gases, 
but  would  possess  the  properties  of  matter  in  mass.  They  have  a  surface 
of  measurable  extent,  and  their  relations  to  the  molecules  of  water  or  solvent 
will  be  determined  by  the  laws  of  adsorption  at  surfaces  rather  than  by 
the  laws  of  interaction  of  molecules.  As  a  matter  of  fact  we  find  that  such 
solutions  present  an  amazing  mixture  of  properties,  some  of  which  betray 
them  as  mechanical  suspensions,  while  others  partake  of  the  nature  of  the 
chemical  reactions  such  as  those  studied  in  the  simpler  compounds  usually 
dealt  with  by  the  chemist. 

OPTICAL  BEHAVIOUR  OF  HYDROSOLS.  Nearly  all  colloidal  solu- 
tions present  what  is  known  as  the  Faraday-Tyndall  phenomenon.  When 
a  beam  of  hght  is  passed  through  an  optically  homogeneous  fluid,  the  course 
of  the  beam  is  invisible.  A  beam  of  sunlight  falling  into  a  dark  room  is 
rendered  visible  by  impinging  on  and  illuminating  the  dust  particles  in  its 
course.  Each  of  these  particles,  being  illuminated,  acts  as  a  centre  of  dis- 
persion of  the  Hght,  so  that  the  course  of  the  beam  is  apparent  to  a  person 


THE  PROPERTIES  OF  COLLOIDS  145 

standing  on  one  side  of  it.  Tyndall  showed  that,  if  the  particles  were 
sufficiently  minute,  the  light  dispersed  by  them  at  right  angles  to  the  beam 
was  polarised.  This  can  be  easily  tested  by  looking  at  the  beam  through 
a  NicoFs  prism.  If  the  prism  be  slowly  rotated,  it  will  be  found  that, 
while  at  one  position  the  hght  is  bright,  in  the  position  at  right  angles  to  this 
it  becomes  dim  or  is  extinguished.  The  production  of  the  Tyndall  pheno- 
menon may  therefore  be  regarded  as  a  test  for  the  presence  of  ultra-micro- 
scopic particles,  varying  in  size  from  5  to  50  yu/z.  The  phenomenon  is  perhaps 
too  sensitive  to  be  taken  as  a  proof  that  a  fluid  presenting  it  is  a  suspension 
rather  than  a  solution.  It  is  shown,  for  instance,  by  solutions  of  many 
bodies  of  high  molecular  weight,  such  as  rafiinose  (a  tri-saccharide)  or  the 
alkaloid  brucine  (Bayhss). 

A  particle  having  a  diameter  less  than  half  the  wave-length  of  hght, 
i.e.  about  300  X  or  -3  ^t,  cannot  be  clearly  distinguished  under  any  power  of 
the  microscope.  The  fact  that  an  ultra-microscopic  particle  may  serve 
as  a  centre  for  dispersal  of  light  may  be  used  for  rendering  such  particles 
visible  under  the  microscope.  For  this  purpose  a  strong  beam  of  hght  is 
passed  in  the  plane  of  the  stage  of  the  microscope  through  a  cell  containing 
the  hydrosol,  which  is  then  examined  under  a  high  power.  The  arrangement 
for  this  purpose  was  first  devised  by  Zsigmondy  and  Siedentopf.  On 
examining  with  this  apparatus  a  dilute  gold  sol,  we  see  a  swarm  of  dancing 
points  of  hght,  '  hke  gnats  in  the  sunhght,'  which  move  rapidly  in  all 
directions,  rendering  it  almost  impossible  to  count  their  number  in  the 
field.  The  coarser  particles  present  shght  oscillations  similar  to  those 
long  known  as  the  Brownian  movements.  The  smallest  particles  which 
can  be  seen  show  a  combined  movement,  consisting  of  a  translatory  move- 
ment, in  which  the  particle  passes  rapidly  across  the  field  in  one-sixth 
to  one- eighth  of  a  second,  and  a  movement  of  oscillation  of  much  shorter 
period.  The  representation  of  the  course  of  such  a  particle  is  given  in 
Fig.  28. 

The  size  of  the  smallest  particles  seen  in  this  way  may  amount  to  -005  //, 
Not  all  colloidal  solutions  show  these  particles  in  the  ultra-microscope. 
In  some  cases  this  is  due  simply  to  the  small  size  of  the  particles,  and 
the  addition  of  any  substance,  which  causes  aggregation  and  therefore 
increase  in  the  size  of  the  particles,  will  bring  them  into  view.  In  others 
the  absence  of  optical  inhomogeneity  may  be  due  to  the  coincidence  of 
the  refractive  indices  of  the  two  phases  of  the  hydrosol,  or  to  the  absence 
of  any  surface  tension  and  therefore  dividing  surfaces  between  the  two 
phases. 

ELECTRICAL  PROPERTIES  OF  COLLOIDS 

In  the  case  of  many  hydrosols  the  ultra-microscopic  particles  of  which 
they  are  composed  carry  an  electric  charge  which,  according  to  the  nature 
of  the  solution,  may  be  either  positive  or  negative.  On  this  account,  the 
particles  move  if  placed  in  an  electric  field,  and  the  direction  of  their  move- 
ment reveals  the  nature  of  their  change.     Thus  colloidal  ferric  hydrate  is 


146 


PHYSIOLOGY 


electro-positive  and  travels  from  anode  to  cathode.  Silicic  acid,  in  the 
presence  of  a  trace  of  alkah,  is  electro-negative,  and  the  same  is  true  of  a 
hydrosol  of  gold.  When  a  current  is  passed  through  these  hydrosols,  the 
colloidal  particles  travel  to  the  anode,  where  they  are  precipitated.  In 
certain  coUoids  the  charge  varies  according  to  the  conditions  under  which 
they  are  brought  into  solution.  If,  for  instance,  egg-white  be  diluted  ten 
times  with  distilled  water,  filtered  and  boiled,  no  precipitate  occurs,  but 

A. 


Fig.  28.     Movements  of  two  particles  of  india-rubber  latex  in  colloidal  solution,  recorded  by 
cinematograph  and  ultra -microscoiie.     (Hei>^ri.) 

■we  obtain  a  colloidal  suspension  of  albumin.  When  thoroughly  dialysed, 
this  protein  is  insoluble  in  pure  water,  but  is  soluble  in  traces  of  either  acid 
or  alkah.  In  acid  solution  the  protein  particles  carry  a  positive  charge, 
whereas  in  alkahne  solution  their  charge  is  negative.  The  charged  condi- 
tion of  these  particles  must  play  a  considerable  part  in  keeping  them  asunder 
and  therefore  in  preventing  their  aggregation  and  precipitation.  This  is 
shown  by  the  fact  that  any  agency  which  will  tend  to  discharge  them  will 
cause  precipitation  and  coagulation.  Among  such  agencies  is  the  passage 
of  a  constant  current,  just  mentioned.  To  the  same  action  is  due  the 
coagulative  or  precipitating  effects  of  neutral  salts.  Thus  any  of  the 
colloids  we  have  mentioned,  ferric  hydrate,  sihca,  gold,  or  boiled  albumen, 
are  thrown  down  by  the  addition  of  traces  of  neutral  salts,  and  it  is  found 
that  in  this  process  they  carry  with  them  some  of  the  ion  with  the  opposite 
charge  to  that  of  the  colloidal  particle.  Thus,  in  the  precipitation  of  the 
electro-positive  ferric  hydrate  the  acid  ion  of  the  salt  is  the  determining 
factor,  the  coagulative  power  increasing  rapidly  with  the  valency  of  the  acid. 
On  the  other  hand,  in  the  precipitation  of  a  gold  sol  the  electro -positive  ion 
is  the  effective  agent,  and  here  again  the  coagulative  effect  is  enormously 
increased  by  a  rise  in  valency.  This  is  shown  in  the  following  Tables, 
where  it  will  be  seen  that,  in  the  coagulation  of  gold,  barium  chloride,  with 
the  divalent  Ba",  is  seven  times  as  powerful  as  K2SO4,  containing  the 
univalent  K'.     On  the  other  hand,  in  the  precipitation  of  the  electro-positive 


THE  PROPERTIES  OF  COLLOIDS  147 

ferric  hydrate,  KgSOj,  with  a  divalent  SO./',  is  400  times  as  effective  as 
BaCla. 

Amount  of  Salt  xecessary  to  precipitate  Colloidal  Solutions 


To  coagulate  Fe203 

To  coagulate  Gold 

K2SO4    1  g  niol.  in  4,000,000  c.c 

BaCla  1  g.  mol.  in  500,000  c.c. 

MgSOi     >,       ,,    ^.  4,000,000     „ 

NaCl       „      „    „      72,000  .. 

BaCla       „       „    „        10,000     „ 

KpSOi     „     „    „     75,000    „ 

NaCI        „       „  „       30,000     „ 

The  presence  of  a  charge  is  not,  however,  a  necessary  condition  for  the 
stabiUty  of  a  colloidal  solution.  Thus  the  proteins  of  serum,  globuhn  in  a 
weak  sahne  solution,  or  gelatin,  present  no  drift  when  exposed  to  a  strong 
electric  field.  In  such  cases  one  must  assume  the  stabihty  of  the  solution 
to  be  determined  by  the  absence  of  any  surface  tension  between  the  two 
phases  in  the  solution,  or  between  the  particles  of  solute  and  the  solvent. 
Thus  no  force  is  present  tending  to  cause  aggregation  of  the  particles. 

The  charged  condition  of  a  colloidal  particle  makes  it  behave  in  an 
electric  field  in  much  the  same  way  as  a  charged  ion  of  an  electrolyte,  and 
this  similarity  extends  also  to  its  chemical  behaviour,  so  that  we  have  a 
class  of  compounds  formed  resembhng  in  many  respects  chemical  com- 
binations, but  differing  from  these  in  the  absence  of  definite  quantitative 
relations  between  the  reacting  substances.  This  class  of  continuously 
varying  chemical  compounds  has  been  designated  by  Van  Bemmelen  absorp- 
tion compounds.  Since,  however,  the  interaction  must  take  place  at  the 
surface  layer  bounding  the  charged  particles,  it  will  be  perhaps  better,  as 
Bayhss  has  done,  to  use  the  term  adsorption.  The  huge  molecules  or  aggre- 
gates of  molecules  which  distinguish  the  colloidal  state  form  a  system  with 
a  considerable  inertia,  so  that  we  have  a  tendency  to  the  estabhshment 
of  conditions  of  false  equihbrium.  Once  a  configuration  is  estabUshed,  it 
is  necessary,  in  consequence  of  the  inertia,  to  overstep  widely  the  conditions 
of  its  formation  in  order  to  destroy  it.  Thus  a  10  per  cent,  gelatin  solution 
sets  at  21°  C,  but  does  not  melt  until  warmed  to  29-6°  C.  Solutions  of  agar 
in  water  set  at  about  35°  C,  but  do  not  melt  under  90°  C.  A  gel  of 
gelatin  takes  twenty-four  hours  after  setting  to  attain  a  constant  melting- 
point. 

The  factors  involved  in  the  formation  of  adsorption  or  absorption  com- 
binations are  therefore  : 

(1)  Extent  of  surface.  In  a  colloidal  solution  this  must  be  enormous 
in  proportion  to  the  mass  of  substance  in  solution.  Thus  a  10  c.c.  sphere 
with  a  surface  of  22  sq.  cm.,  if  reduced  to  a  fine  powder  consisting  of  spherules 
of  -00000025  cm.  in  diameter,  will  have  a  surface  of  20,000,000  sq.  cm., 
i.e.  nearly  half  an  acre.  At  the  whole  of  this  surface  adsorption  may 
take  place,  invohnng  the  concentration  of  dissolved  electrolytes,  ions,  or 
gases. 

(2)  Chemical  nature  of  particle. 

(3)  Electric  charge  on  the  surface.     The  sign  of  this  may  be  determined 


148 


PHYSIOLOGY 


by  the  chemical  nature  of  the  colloid  and  its  relation  to  the  electrolytes  in 
the  surrounding  medium. 

Another  factor  which  may  determine  the  character  of  the  charge  on  the  particles 
has  been  pointed  out  by  Coehn.  This  observer  finds  that,  when  various  non-con- 
ducting bodies  are  immersed  in  fluids  of  different  dielectric  constants,  they  assume  a 
positive  or  negative  charge  according  as  their  own  dielectric  constants  are  higher  or 
lower  than  the  fluid  with  which  they  are  in  contact.  For  instance,  glass  (5  to  6)  is 
negative  in  water  (80)  or  alcohol  (26),  whereas  in  turpentine  (2-2)  it  is  positive.  In 
water,  as  Quincke  has  found,  nearly  all  non-conducting  bodies  take  on  a  negative  charge. 
Among  these  are  cotton-wool  and  silk.  Particles  of  these  in  water,  exposed  to  an 
electric  field,  move  towards  the  anode.    The  same  is  true,  as  Bayliss  has  shown,  of  paper. 

The  conditions  which  determine  the  formation  of  these  adsorption  com- 
pounds can  be  studied  in  their  simplest  form  on  the  adsorption  of  dyestufEs 
by  substances  such  as  paper.  If  we  take  a  series  of  solutions  of  a  dye, 
such  as  Congo-red,  in  progressively  diminishing  concentration,  and  place 
in  each  solution  the  same  amount  of  filter-paper,  we  find  that  a  part  of  the 
dye  is  taken  up  by  the  paper,  and  the  proportion  taken  up  is  larger  the  more 
dilute  the  solution.  This  relation  has  been  spoken  of  by  Bayhss  as  the  law 
of  adsorption.  This  is  illustrated  by  the  following  Table  of  results  of  such 
an  experiment : 


Concentration  of 

Proportion  of  dye 

Proportion  of  dye 

solution 

in  solution 

in  paper 

Initial                  Final 

Per  cent. 

Per  cent. 

0-014            0-0056 

40 

60 

0-012             0-0024 

20 

80 

0-010            0-0009 

9-3 

90-7 

0-008             0-0003 

4 

96 

0-006            0-00008 

1-3 

98-7 

0-004                — 

trace 

practically  all 

0-002                 — 

trace 

practically  all 

If  put  into  the  form  of  a  curve,  where  the  ordinates  represent  the  per- 
centage of  dye  left  in  solution,  and  the  abscissae  the  original  concentration 
of  the  solution,  the  curve  only  approaches  the  axis  {i.e.  zero  concentration) 
asymptotically.  In  other  words,  however  dilute  the  original  solution  may 
be,  there  will  always  be  a  certain  amount  of  the  dye  left  unabsorbed  by 
the  paper.  Similar  relations  are  found  to  exist  between  proteins  and  electro- 
lytes. By  continuously  washing  a  protein  or  gelatin  with  distilled  water, 
the  removal  of  electrolytes  becomes  slower  and  slower,  but  it  is  practically 
impossible  within  finite  time  to  get  rid  in  this  way  of  the  last  traces  of  ash. 

Although  the  chemical  behaviour  of  colloids  is  largely  determined  by 
surface  phenomena,  it  presents  at  the  same  time  analogies  with  more  strictly 
chemical  reactions,  since  it  is  conditioned  by  the  chemical  structure  of  the 
colloid  molecule  as  well  as  by  the  charge  carried  by  the  latter.  A 
good  example  of  these  adsorption  combinations  is  presented  by  globulin, 
the  behaviour  of  which  has  been  studied  by  Hardy.  This  may  be  obtained 
from  diluted  blood-serum  by  precipitation  with  acetic  acid.     Four  states 


THE  PROPERTIES  OF  COLLOIDS  149 

can  be  recognised  in  both  the  soKd  condition  and  in  solution,  viz.  globuhn 
itself,  compounds  with  acid  or  with  alkali,  and  compounds  with  neutral 
salt.  The  amount  of  acid  and  alkah  combining  with  the  globulin  is  in- 
determinate, the  effect  of  adding  either  acid  or  alkali  to  the  neutral  globulin 
being  to  cause  a  gradual  conversion  of  an  oqaqvie,  milky  suspension  into  a 
hmpid,  transparent  solution.  On  drying  HCl  globulin,  the  dried  solid  is 
found  to  contain  all  the  chlorine  used  to  dissolve  it.  The  acid  may  therefore 
be  regarded  as  being  in  true  combination.  Both  acid  and  alkah  globulins 
act  as  electrolytes,  the  globulin  being  electrically  charged  and  taking  part 
in  the  transport  of  electricity.  In  order  to  produce  the  same  extent  of 
solution,  the  concentration  of  the  alkah  added  must  be  double  that  of  the 
acid.  The  relation  of  globulin  to  acids  and  alkalies  is  similar  to  that  of  the 
so-called  amphoteric  substances,  such  as  the  amino-acids.  An  amino-acid, 
such  as  glycine,  can  react  as  a  basic  anhydride  with  other  acids,  thus  : 

.NH2  .NH2HCI 


CH/  +  HCl  -  CH< 


^COaH  CO2H 

or  as  an  acid  anhydride  with  bases  : 

CH2.NH,  CH2.NH., 

I  +NaHO-   I  +H2O 

COOH  COONa 

Like  these  too,  globulin  forms  soluble  compounds  with  neutral  salts.  An 
amphoteric  electrolyte  thus  acts  as  a  base  in  the  presence  of  a  strong  acid, 
and  as  an  acid  in  the  presence  of  a  strong  base. 

From  true  electrolytes,  colloidal  solutions  differ  in  the  fact  that  their 
particles  are  of  varying  size  according  to  the  conditions  in  which  they  exist 
and  carry  varying  charges  of  electricity,  whereas  an  ion  such  as  Na  or  CI 
has  a  mass  which  is  constant  for  the  ion  in  question,  and  always  carries 
the  same  electric  charge.  The  charged  particles  of  an  acid-  or  alkali-globulin 
may  be  distinguished  therefore  as  pseudo-ions. 

In  these  adsorption  combinations,  although  the  chemical  nature  of  the 
colloidal  molecules  is  concerned,  there  is  an  absence  of  definite  e(|ui]ibvium 
points,  such  as  we  are  accustomed  to  in  most  chemical  reactions.  The  inertia 
of  the  system  and  the  large  size  of  the  molecules  determine  the  occurrence 
of  false  equilibria  and  of  delayed  reaction,  so  that  the  condition  and  behaviour 
of  a  colloidal  system  at  any  moment  are  determined,  not  entirely  by  the 
quantitative  relations  of  its  components,  but  also  by  the  past  history  of  the 
system. 

COMBINATIONS  BETWEEN  COLLOIDS 
Besides  the  compounds  between  colloids  and  electrolytes,  combination, 
or  at  least  interaction,  takes  place  between  different  colloids.  Many  colloids 
are  precipitated  by  other  colloidal  solutions.  This  effect  is  always  found  to 
occur  when  the  colloidal  solutions  carry  different  charges.  Thus  ferric 
hydrate  in  colloidal  solution  is  precipitated  by  colloidal  silica  or  colloidal 


150  PHYSIOLOGY 

gold,  both  colloids  being  thrown  out  of  solution.  On  the  other  hand,  certain 
colloids  may  exercise  a  protective  influence  on  other  colloidal  solutions 
Thus,  as  Faraday  first  showed,  colloidal  gold  is  much  more  stable  in  the 
presence  of  a  httle  gelatin.  The  colloids  of  serum  can  dissolve  a  considerable 
amoimt  of  purified  globuhn.  Although  the  latter  in  solution  shows  a  drift 
in  the  electric  field,  the  resulting  solution  is  quite  unaffected  by  the 
passage  of  a  current  through  it.  In  these  cases  the  protective  colloids 
carry  no  charge,  but  the  same  protective  effect  may  be  observed  if  a  large 
excess  of,  e.g.  an  electro-positive  colloid  be  added  to  an  electro-negative 
colloid.  This  interaction  between  different  colloids  probably  plays  an 
important  part  in  many  physiological  phenomena.  We  have  reason  to 
beheve  that  the  reactions  between  toxin  and  antitoxin,  and  between  ferment 
and  substrate,  which  we  shall  study  later,  are  of  this  character,  and  that  the 
compounds  formed  belong  to  the  class  of  adsorption  combinations. 

THE  COAGULATION  OF  COLLOIDS 

Most  colloidal  solutions  are  unstable,  and  the  relations  between  the 
suspended  particle  or  molecule  and  the  surrounding  fluid  may  be  upset  by 
shght  changes  of  reaction  or  the  presence  of  minute  traces  of  salts.  As  a 
result  the  hydrosol  is  destroyed,  the  suspended  particles  aggregating  to 
form  larger  complexes.  These  aggregations  may  settle  to  the  bottom  of 
the  fluid  as  a  precipitate,  or  may  form  a  species  of  network,  the  result 
varying  according  to  the  nature  of  the  colloid  and  its  concentration.  Thus 
gelatin  changes  from  the  condition  of  hydrosol  to  hydrogel  with  fall  of 
temperature.  The  same  is  true  of  agar.  On  the  other  hand,  by  adding 
calcium  chloride  to  an  alkahne  solution  of  casein,  we  obtain  a  mixture  which 
sets  to  a  jelly  on  warming,  but  becomes  fluid  again  on  coohng.  Other  agen- 
cies may  lead  to  the  production  of  changes  which  are  irreversible.  Thus 
a  strong  solution  of  colloidal  silica  sets  to  a  sohd  jelly  on  the  addition 
of  a  trace  of  neutral  salt,  and  it  is  not  possible  to  reform  the  hydrosol, 
however  long  the  jelly  is  submitted  to  dialysis. 

Two  methods  of  bringing  about  coagulation  of  hydrosols  deserve  special 
mention.  The  first  of  these  is  heat-coagulation.  If  a  solution  of  egg- 
albumin  or  globulin  be  heated  in  neutral  or  shghtly  acid  medium  and  in  the 
presence  of  neutral  salt,  the  whole  of  it  is  thrown  down  in  an  insoluble  form. 
This  coagulated  protein  is  insoluble  in  dilute  acids  or  alkahes.  The  same 
coagulative  effect  of  heating  is  observed  in  the  metalhc  sols.  With  con- 
centrated solutions  of  protein,  heat  coagulation  results  in  the  formation  of  a 
gel,  i.e.  a  network  of  insoluble  protein,  containing  water  or  a  very  dilute 
solution  of  protein  in  its  meshes.  In  dilute  solutions  the  result  is  the  pro- 
duction of  a  flocculent  precipitate. 

Another  method  is  the  so-called  mechanical  coagulation.  If  a  solution 
of  globuhn  or  albumin  be  introduced  into  a  bottle,  which  is  then  violently 
shaken,  a  shreddy  precipitate  makes  its  appearance  in  the  solution,  and  this 
precipitate  increases,  so  that  by  prolonged  shaking  it  is  possible  to  throw 
down  80  or  90  per  cent,  of  the  dissolved  protein  in  the  coagulated  form. 


THE  PROPERTIES  OF  COLLOIDS  151 

Ramsden  has  shown  that  this  mechamcal  coagulation  is  a  surface  pheno- 
menon. It  depends  on  the  fact  that  a  large  number  of  substances  in  solution 
(viz.  any  which  lower  the  surface  tension  of  their  solutions)  undergo  concen- 
tration at  the  free  surface  of  the  fluid.  Such  substances  are  proteins,  bile- 
salts,  quinine,  saponin,  &c.  In  the  case  of  proteins  the  concentration  reaches 
such  an  extent,  and  the  molecules  at  the  surface  are  so  closely  packed 
together,  that  they  form  an  actual  solid  pelHcle,  which  hinders  the  movement 
of  any  object,  such  as  a  compass  needle,  suspended  in  the  surface.  When  the 
solution  is  violently  shaken,  new  surfaces  are  constantly  being  formed,  and 
as  the  older  surfaces  are  withdrawn  into  the  fluid,  the  solid  pelhcle  on  them 
is  rolled  up  into  a  fine  shred  of  coagulated  protein,  and  this  process  will  con- 
tinue until  there  is  no  protein  left  to  form  a  pellicle. 

We  must  conclude  that  colloidal  solutions,  although  differing  so  widely 
from  true  solutions  in  many  of  their  properties,  are  connected  with  these  by 
all  possible  grades.  In  a  solution  of  an  ordinary  crystalloid  or  electrolyte 
the  molecules  of  the  dissolved  substance  are  distributed  equally  and  homo- 
geneously among  the  molecules  of  the  solvent.  In  the  various  grades  of 
solution  a  colloid  solution  or  hydrosol  may  be  assumed  to  begin  when  the 
size  of  the  molecule  is  increased  out  of  all  proportion  to  that  of  the  molecules 
of  the  solvent.  The  '  dissolved  '  molecules  now  begin  to  have  the  properties 
of  matter  in  mass  and  to  present  surfaces  with  all  their  attendant  attributes. 
The  same  sort  of  solution  may  be  formed  with  smaller  molecules,  such  as 
Si02,  when  these  are  aggregated  together  with  adsorbed  water  into  huge 
molecular  complexes,  or,  as  in  metallic  sols,  by  the  division  of  the  sohd  metal 
into  ultra-microscopic  particles.  The  distinguishing  features  of  a  colloidal 
solution  are  due  to  this  lack  of  homogeneity,  and  to  the  fact  that  in  every 
solution  there  are  two  phases — a  fluid  phase,  and  a  second  phase,  which  is 
either  sohd  or  a  concentrated  or  supersaturated  solution  of  the  colloid.  The 
huge  size  of  the  molecules  and  the  development  of  surface  not  only  determine 
the  formation  of  adsorption  combinations,  but,  on  account  of  the  inertia  of 
the  system,  cause  a  delay  in  changes  of  state,  and  tend  to  the  formation  of 
false  equihbria  dependent  on  the  past  history  of  the  system. 

IMBIBITION 

All  colloids,  even  those  such  as  starch  or  gelatin,  which  are  insoluble 
in  cold  water,  exhibit  a  phenomenon,  viz.  '  Quellung  '  or  imbibition,  which 
in  many  cases  it  is  impossible  to  distinguish  from  the  process  of  solution. 
This  phenomenon,  which  was  long  ago  studied  by  Chevreul  and  has  lately 
been  the  subject  of  a  series  of  careful  experiments  by  Overton,  is  exhibited  by 
all  animal  tissues  and  all  colloids.  Thus  elastic  tissue  dried  in  vacuo  absorbs 
from  a  saturated  solution  of  common  salt  36-8  per  cent,  of  water  and  salt.  If 
dried  colloids  be  suspended  in  a  closed  vessel  over  various  solutions,  they 
will  take  up  water  in  the  form  of  vapour  from  the  solution,  and  the  osmotic 
pressure  of  the  solution  in  question  will  inform  us  as  to  the  amount  of  work 
which  would  be  necessary  in  order  to  separate  the  water  again  from  the 
colloids. 


152  PHYSIOLOGY 

Thus  it  lias  been  reckoned  that  to  press  out  water  from  gelatin  containing 
28-4  parts  of  water  to  100  parts  of  dried  gelatin  would  require  a  pressure  of 
over  two  hundred  atmospheres.  The  imbibition  pressure  of  colloids  in- 
creases rapidly  with  the  concentration  of  the  colloid  and  at  a  greater  rate  than 
the  latter.  In  this  respect,  however,  imbibition  pressure  resembles  osmotic 
or  indeed  gaseous,  pressure.  At  extreme  pressures  the  pressure  of  hydrogen 
rises  more  rapidly  than  its  volume  diminishes.  In  solutions  this  effect  is 
more  marked  the  larger  the  size  of  the  molecule.  Thus  a  6-7  per  cent, 
solution  of  cane  sugar  has  the  same  vapour-tension,  and  therefore  the  same 
osmotic  pressure,  as  a  -67  per  cent.  NaCl  solution.  A  67  per  cent,  cane-sugar 
solution  has,  however,  the  same  osmotic  pressure  as  an  18|  per  cent,  solution 
of  common  salt.  It  is  impossible  to  draw  any  hard  line  of  distinction  between 
imbibition  pressure  and  osmotic  pressure,  or  to  say  where  a  fluid  ceases  to  be 
a  solution  and  becomes  a  suspension.  All  grades  are  to  be  found  between  a 
solution  such  as  that  of  common  salt  with  a  high  osmotic  pressure  and  optical 
homogeneity,  and  a  solution  such  as  that  of  starch,  which  scatters  incident 
light  and  is  therefore  opalescent,  and  has  no  measurable  osmotic  pressure. 

The  close  connection  between  the  processes  of  imbibition  and  of  solution 
is  shown  also  by  the  fact  that  the  latter  occurs  only  in  certain  media,  the 
nature  of  the  media  being  dependent  on  the  chemical  character  of  the  sub- 
stances in  question.  Thus  all  the  crystalhne  carbohydrates — such  as  grape 
sugar  and  cane  sugar — are  easily  soluble  in  water,  only  slightly  soluble  in 
alcohol,  and  practically  insoluble  in  ether  and  benzol.  The  amorphous 
carbohydrates,  which  must  be  regarded  as  derived  by  a  process  of  condensa- 
tion from  the  crystalhne  carbohydrates — e.g.  starch,  cellulose,  gum  arable, 
&c.^ — have  a  strong  power  of  imbibition  for  water.  This  power  may  be 
hmited,  as  in  the  case  of  cellulose,  or  may  be  unlimited,  as  in  the  case  of 
gum  arable,  so  that  a  so-called  solution  results.  On  the  other  hand,  they 
swell  up  but  shghtly  in  alcohol,  and  are  unaffected  by  ether  and  benzol. 
In  the  same  way  proteins  all  take  up  water,  and  in  many  cases  form  a  so-called 
solution,  but  are  unaffected  by  ether  and  benzol — a  behaviour  which  is 
repeated  in  the  case  of  the  amino-acids,  out  of  which  the  proteins  are  built 
up,  and  which  are  easily  soluble  in  water,  but  are  practically  insoluble  in  ether 
and  benzol.  On  the  other  hand,  india-rubber  and  the  various  resins  take  up 
ether,  benzol,  and  turpentine  often  to  an  indefinite  extent,  while  they  are  un- 
touched by  water.  With  this  behaviour  we  may  compare  the  easy  solubility 
of  the  hydrocarbons,  the  aromatic  acids,  and  esters  in  ether  and  benzol,  and 
their  insolubility  in  water.  As  Overton  has  pointed  out,  the  power  of 
amorphous  carbohydrates  to  take  up  fluids  is  modified  by  alteration  of  their 
chemical  structure  in  the  same  direction  as  the  solubility  of  the  corresponding 
crystalline  carbohydrates.  Thus,  if  the  hydroxyl  groups  in  the  sugars  be 
replaced  by  nitro,  acetyl,  or  benzoyl  groups,  they  become  less  soluble  in 
water,  while  their  solubility  in  alcohol,  acetone,  &c.,  is  increased.  In  the 
same  way  the  replacement  of  the  hydroxyl  groups  in  cellulose  by  NO  2  groups 
diminishes  the  power  possessed  by  this  substance  of  taking  up  water,  but 
renders  it  capable  of  swelhng  up  or  dissolving  in  alcohol  and  acetone. 


SECTION  IV 

THE   MECHANISM   OF  CHEMICAL  CHANGES   IN 
LIVING   MATTER.    FERMENTS 

All  the  events  which  make  up  the  hfe  of  plants  and  animals  are  accompanied 
and  conditioned  by  chemical  changes  of  the  most  varied  character.  In  a 
previous  chapter  we  have  endeavoured  to  form  an  idea  of  the  ways  in  which 
some  of  the  synthetic  processes  that  occur  in  the  hving  body  may  be  effected. 
We  saw  that,  although  it  was  possible  to  imitate  in  many  respects  the  vital 
syntheses  by  ordinary  laboratory  methods,  the  imitation  fell  far  short  of  the 
process  as  it  actually  occurs  in  the  li^dng  cell,  both  in  completeness  of  the 
reaction  and  in  the  ease  wnth  which  it  could  be  effected.  We  can,  for 
instance,  by  passing  carbon  dioxide  over  red-hot  charcoal,  convert  it  into 
carbon  monoxide,  and  this  gas,  acting  on  dry  potassium  hydrate,  forms 
potassium  formate.  Formate  of  Hme,  on  dry  distillation,  gives  a  small 
proportion  of  formaldehyde  which,  under  the  influence  of  dilute  alkahes, 
will  condense  to  the  mixture  of  sugars  known  as  acrose.  The  green  leaf 
in  sunhght  absorbs  the  minimal  quantities  of  carbon  dioxide  present  in  the 
atmosphere  and  converts  it  almost  quantitatively  into  starch  wathin  a  few 
minutes,  and  this  change  is  effected  in  the  absence  of  any  concentrated 
reagents  and  at  the  ordinary  temperature  of  the  atmosphere.  Many  of  the 
chemical  transformations  effected  by  Hving  cells  we  have  so  far  been  quite 
unable  to  imitate.  The  problem  of  the  synthesis  of  camphor,  of  the  terpenes, 
of  starch,  of  cellulose,  is  still  unsolved,  and  even  in  the  case  of  those  sub- 
stances which  we  can  manufacture  outside  the  living  cell  our  methods  involve 
the  use  of  powerful  reagents  and  of  high  temperatures,  and  result  in  most 
cases  in  the  production  of  many  side  reactions,  besides  that  which  it  is  our 
special  object  to  imitate.  The  distinguishing  characteristics  of  the  chemical 
changes  wrought  by  the  living  cell  are  : 

(1)  The  rapidity  with  which  they  are  effected  at  ordinary  tempera- 
tures. 

(2)  The  specific  direction  of  the  process,  which  is  therefore  almost 
complete,  with  a  surprising  absence  of  the  side  reactions  which  interfere 
to  such  an  extent  with  the  yield  of  the  methods  employed  in  a  chemical 
laboratory. 

This  second  characteristic  may,  however,  be  regarded  as  a  consequence 
of  the  first,  since  an  increase  in  the  velocity  of  any  given  reaction  will  deter- 
mine a  preponderance  of  this  reaction  over  all  other  possible  ones.     A  funda- 

153 


154  PHYSIOLOGY 

mental  question,  therefore,  in  physiology  must  relate  to  the  manner  in  which 
the  cell  is  able  to  influence  the  velocity  of  some  specific  reaction. 

In  spite  of  the  enormous  diversity  of  chemical  reactions  occurring  in  the 
body,  they  may  be  divided  into  a  relatively  small  number  of  types.  Nearly 
all  the  reactions  are  reversible.  The  chief  types  of  chemical  change  are  as 
follows  : 

(1)  HYDROLYSIS.  In  most  cases  this  involves  the  taking  up  of  water 
and  a  decomposition  into  smaller  hiolecules.  Thus  the  proteins  are  broken 
down  in  the  intestine  into  their  constituent  amino-acids.  The  disaccharides, 
such  as  maltose  or  lactose,  take  up  one  molecule  of  water  and  giv6  rise  to 
two  molecules  of  monosaccharide.  The  fats  take  up  three  molecules  of 
water  with  the  formation  of  fatty  acid  and  glycerin.  Hippuric  acid  is  broken 
down  into  benzoic  acid  and  glycine.  The  reverse  change,  that  of  dehydra- 
tion, is  also  effected,  apparently  with  equal  facihty,  by  the  hving  cell,  the 
hexoses  losing  water  and  being  converted  into  a  complex  starch  or  glycogen 
molecule,  while  the  amino-acids  are  built  up  first  into  polypeptides,  and 
these  again  into  the  complex  proteins  of  the  cell.  Besides  the  reactions  in 
which  there  is  a  difierence  in  the  amount  of  free  water  on  the  two  sides  of 
the  equation,  it  seems  probable  that  hydrolysis  and  simultaneous  dehydrolysis 
at  different  parts  of  the  molecule  determine  a  number  of  chemical  transforma- 
tions, which  at  first  sight  seem  to  involve  a  simple  sphtting  of  the  molecule. 
An  example  of  such  a  process  is  afforded  by  the  conversion  of  glucose  into 
lactic  acid  described  on  p.  116. 

(2)  DEAMINATION.  This  process  involves  the  sphtting  off  of  an  NH2 
group  from  an  amino-acid  as  ammonia,  and  its  replacement  by  H  or  OH. 
Many  tissues  of  the  body  appear  to  have  this  power.  In  most  cases  the 
nature  of  the  change  in  the  remaining  fatty  moiety  of  the  molecule  has  not 
yet  been  ascertained.  If,  for  instance,  to  a  mass  of  liver  cells  some  amino- 
acid,  such  as  glycine,  alanine,  or  leucine,  be  added,  ammonia  is  set  free  in 
proportion  to  the  amount  of  amino-acid  which  was  added.  This  ammonia  is 
therefore  assumed  to  be  derived  from  the  amino-acid,  and  it  has  been  sug- 
gested that  here  also  the  process  of  sphtting  off  ammonia  is  a  hydrolytic  one 
and  that  the  NHg  gTOup  is  replaced  by  OH.     Thus — 

CH3  CH3 

CH.NH2  +  H2O  =  CH.OH  +  NH3 

COOH  COOH 

(alanine) 

Recent  work  by  Neubauer  tends  to  show  that  deamination  is  accompanied 
in  the  first  place  by  oxidation,  so  that  the  first  intermediate  product  formed 
is  not  an  a  oxy-acid,  but  an  a  ketonic  acid.  A  second  atom  of  oxygen  is 
then  taken  up,  and  carbon  dioxide  is  split  off,  with  the  production  of  the  next 
lower  acid  of  the  series. 


CHEMICAL  CHANGES  IN  LIVING  MATTER.    FERMENTS    155 
We  might  represent  these  changes  as  follows  : 

(1)  CH3  CH3 

I  I 

CHNH.  +  0  =  CO  +  NH3 

I  "  I 

COOH  COOH 

(2)  CH3 

I  CH3 

CO  +0=1  +  CO2 

I  COOH 

COOH 

.  Is  the  reverse  change  ever  effected  in  the  animal  body  ?  If  it  were 
possible  to  replace  the  OH  group  in  an  oxy-fatty  acid  by  NHg  or  the  0  in  an 
a  ketonic  acid  by  HNHg,  it  ought  also  to  be  possible  to  nourish  an  animal 
from  a  mixture  of  carbohydrates  and  ammonia,  or  at  any  rate  by  supplying 
him  with  a  mixture  of  the  appropriate  oxy-acids  or  ketonic  acids  and  am- 
monia. Until  recently  there  was  no  evidence  that  the  animal  body  is  able  to 
utilise  nitrogen,  except  in  organic  combination  as  amino-acids  or  the  complex 
aggregate  of  amino-acids  known  as  proteins.  In  the  plant  the  process 
of  synthesis  of  protein  from  ammonia  and  a  carbohydrate  such  as  hexose  is 
continuously  going  on,  and  it  is  probable  that  the  formation  of  amino-acid 
occurs  by  a  process  the  reverse  of  that  which  we  have  just  been  studying. 
Knoop  has  shown  that  the  same  reversed  change  may  occur  even  in  a 
mammal,  and  that  here  again  the  intermediate  substance  is  an  a  ketonic 
acid.  On  administering  benzylpyruvic  acid  (C6H5.CH2.CH2.CO.COOH) 
to  a  dog,  a  certain  amount  of  benzylalanine  (CeHg.CHa.CHa.CHNHg.COOH) 
appeared  in  the  urine.  The  first  phase  of  the  oxidative  deamination  of 
amino-acids  is  thus  a  reversible  one  and  may  be  represented  : 
R  R  R 

I  I    /OH  I 

CHNH,  +  0       ;=:         C(  ;=:        CO  +  NH3 

COOH  COOH  COOH 

(3)  DECARBOXYLATION.  Many  amino-acids  when  subjected  to  the 
agency  of  bacteria  lose  a  molecule  of  carbon  dioxide  and  are  converted  into 
a  corresponding  amine. 

For  instance,  lysine,  which  is  diamiiio-caproic  acid,  is  converted  into 
pentamethylene  diamine  or  cadaverine.     Thus  : 

CH.,.NH.,  CH,..XH., 

I  "   "  r  " 

CH.,  CHo 

I  I 

C'Ho  becomes  CHo 

I  I     " 

CH„  CH2 ' 

I  I     ^ 

CH.NH2  CH.2.NH2 

I 
COOH 


156  PHYSIOLOGY 

In  the  same  way  ornitliine  derived  from  the  breakdown  of  arginine  is  con- 
verted by  putrefactive  bacteria  into  tetra-methylene  diamine  or  putrescine. 
Other  examples  of  this  process  of  decarboxylation  are  : 

Isoamylamine  from  leucine,  (CH3)2.CH.CH2.CH2.NH2. 

[3  phenylethylamine  from  phenylalanine,  C6H5.CH2.CH2.NH2. 

Para-oxyphenylethylamine  from  tyrosine,  OH.C6H4.CH2.CH2.NH2. 

A  similar  process  has  been  supposed  to  take  place  as  a  step  in  the  suc- 
cessive oxidation  of  the  carbon  atoms  in  the  long  chain  fatty  acids  or  carbo- 
hydrates, but  a  thorough  study  of  this  process  as  it  occurs  in  the  higher 
animals  is  still  wanting,  and  its  very  existence  is  indeed  still  hypothetical. 
In  the  case  of  the  fats  the  oxidation  takes  place  chiefly  or  entirely  in  the 
P  position.  On  the  other  hand,  decarboxylation  certainly  takes  place  in 
substances  such  as  the  a  amino-acids,  where  the  first  oxidation  change  occurs 
in  the  a  group,  and  probably  closely  follows  this  oxidation  change.  The 
reverse  reaction,  namely,  the  insertion  of  the  group  CO.O  at  the  end  of  the 
long  carbon  chain,  is  not  known  to  take  place,  but  would  furnish  a  means 
by  which  the  organism  with  apparent  simphcity  could  build  up  long  carbon 
chains  and  so  imitate  the  process  which  in  the  laboratory  is  generally  effected 
by  attaching  a  ON  group  to  the  end  of  the  molecule.  In  the  case  of  the 
fats  the  building  up,  hke  the  oxidative  breakdown,  appears  to  occur  by 
two  carbon  atoms  at  a  time  ;  hence  all  the  fatty  acids  met  with  in  the  body 
have  an  even  number  of  carbon  atoms  in  their  chain. 

It  is  worthy  of  note  that  all  the  changes  which  we  have  been  considering 
— changes  which  not  only  account  for  the  greater  part  of  the  chemical  re- 
actions of  the  hving  body,  but  may  lead  to  the  production  of  the  most 
complex  substances  known — are  performed  with  httle  expenditure  or  evolu- 
tion of  energy.  This  is  evident  if  we  examine  the  heat  evolved  by  the 
total  combustion  of  one  gramme  molecule  of  the  initial  and  final  substances 
in  a  number  of  typical  reactions.  In  the  following  Table  these  are  given 
for  the  substances  involved  in  typical  instances  of  the  three  classes  of  chemical 
change  that  we  have  just  been  considering  : 


(1)  Hydrolysis 

Initial 
substance 

Heat  of  com- 
bustion per 
gram  molecule 

Final 
substance 

Heat 
of 

combustion 

Maltose 

.       1350 

2  Glucose     . 

1354 

Glucose 

677 

2  Lactic  acid 

659 

Hippuric  acid     . 

1013 

/  Glycine     . 
t  Benzoic  acid 

2351  1008 
773/  ^^^^ 

(2)  Dea] 

VIINATION 

Initial 

substance 

Heat  of 
combustion 

Final 
substance 

Heat  of 
combustion 

Alanine 

389-2 

Lactic  acid 

329-5 

Leucine 

855 

Caproic  acid 

837 

Aspartic  acid 

386 

Succinic  acid 

354 

CHEMICAL  CHANGES  IN  LIVING  MATTER.    FERMENTS    L57 


Initial 
substance 

Alanine 

Leucine 


(3)  Decarboxylation 

Heat  of  Final 

combustion  substance 


389 
855 


Ethylamine . 
Isoamylaniine . 


Heat  of 
combustion 

409 

867 


(4)  OXIDATION  AND  REDUCTION.  The  fourth  class  of  chemical 
reactions  differs  from  those  just  described  in  being  attended  with  a  very 
considerable  energy  change.  This  class  involves  the  processes  of  oxidation 
and  reduction.  In  almost  every  hving  cell  by  far  the  largest  amount  of 
the  energy  available  for  the  discharge  of  the  functions  of  the  cell  is  derived 
from  the  oxidation  of  the  food-stuffs,  and  even  in  the  plant  the  energy  is 
obtained  from  the  oxidation  of  the  food-stuffs,  built  up  in  the  first  instance 
at  the  cost  of  the  energy  of  the  sun's  rays.  If  we  take  the  final  changes 
in  the  food-stuffs,  the  very  large  evolution  of  energy  attending  their  oxida- 
tion is  at  once  apparent.  Thus  in  the  conversion  of  glucose  into  COg  and 
water  there  is  an  evolution  for  each  gramme  molecule  of  677  calories.  In 
the  combustion  of  glycerin  397  calories  are  evolved.  In  the  oxidation  of  a 
fat  such  as  trimyristin  there  are  6650  calories  evolved.  The  change  does 
not,  in  the  Hving  cell,  occur  all  at  once,  but  the  molecule  is  oxidised  step  by 
step.  In  each  step  the  heat  change  will,  however,  be  probably  greater  than 
the  heat  changes  in  the  other  types  of  chemical  change  which  we  have  been 
considering. 

Since  the  mechanism  of  oxidation  in  the  animal  body  will  have  to  be 
discussed  at  length  in  a  subsequent  part  of  this  work,  we  may  at  present 
confine  our  attention  to  the  other  types  of  chemical  change.  Of  these, 
all  which  involve  a  sphtting  of  a  large  molecule  into  smaller  ones  with  the 
taldng  up  of  one  or  more  molecules  of  water,  as  well  as,  in  all  probabihty, 
those  in  which  the  reverse  change  of  dehydration  and  synthesis  occur,  are 
effected  in  the  body  by  means  oi  ferments.  To  the  same  agency  are  also 
ascribed  the  process  of  deamination,  which  takes  place  in  many  organs  of 
the  body,  and,  though  with  less  certainty,  the  processes  which  involve 
decarboxylation. 

FERMENTS 
Under  the  name  ferments  we  include  a  number  of  substances  of  indefinite 
composition  whose  existence  is  chiefly  known  to  us  by  their  action  on  other 
substances.  A  ferment  has  been  defined  as  a  body  which  on  addition  to  a 
chemical  system  is  able  to  effect  changes  in  this  system  without  supplying 
any  energy  to  the  reaction,  without  being  used  up,  and  without  taking 
any  part  in  the  formation  of  the  end  products.  It  differs  therefore  from 
the  reacting  substances  in  the  absence  of  any  strict  quantitative  relation- 
ships between  it  and  the  substances  included  in  the  system  in  which  its 
effects  are  produced.  Minimal  quantities  of  ferment  can  induce  chemical 
changes  involving  almost  indefinite  quantities  of  other  substances,  the  only 
result  of  increasing  the  quantity  of  ferment  being  to  quicken  the  rate  of 
tlie  change.  Since  they  are  effective  in  minimal  doses  they  occur  in  living 
tissues  in  minute  quantities,  and  it  is  partly  due  to  this  fact  that  it  has 


158 


PHYSIOLOGY 


hitherto  proved  impossible  to  obtain  any  preparation  of  a  ferment  which 
could  be  regarded  as  a  pure  substance.  The  difficulty  in  their  isolation 
is  increased  by  the  fact  that  all  of  them  are  colloidal  or  semi- colloidal  in 
character,  and  present,  therefore,  the  tendency  common  to  all  colloids  of 
adhering  to  other  colloidal  matter  as  well  as  to  surfaces  such  as  those  pre- 
sented by  a  precipitate.  A  common  method  of  isolating,  or  rather  obtaining 
a  concentrated  preparation  of  a  ferment  is  to  produce  in  its  solution  an  inert 
precipitate  such  as  cholesterin  or  calcium  phosphate.  The  ferment  is 
carried  down  on  the  precipitate  and  may  be  obtained  in  solution  on  washing 
the  precipitate  with  water.  A  further  difficulty  in  their  preparation  hes 
in  the  unstable  character  of  many  members  of  the  group.  Although  they 
are  not  coagulated  by  alcohol,  they  are  nevertheless  gradually  changed,  so 
that  every  act  of  precipitation  of  a  ferment  tends  to  rob  it  of  some  of  its 
powers,  i.e.  of  the  only  characteristic  by  which  we  can  establish  its 
identity. 

Of  these  ferments  a  large  number  have  already  been  described  as  taking 
part  in  the  ordinary  chemical  processes  of  hfe.  So  wide  is  their  dominion 
in  cell  chemistry  that  many  physiologists  have  thought  that  the  whole  of 
hfe  is  really  a  continual  series  of  ferment  actions.  The  following  hst  repre- 
sents some  of  the  ferments  whose  existence  has  been  definitely  estabhshed 
in  the  animal  body.  The  greater  part  of  them  are  involved  in  the  processes 
of  digestion  in  the  ahmentary  canal.  The  preponderance,  however,  of 
digestive  ferments  in  the  hst  is  due  to  the  fact  that  we  know  more  about 
digestion  than  about  the  other  chemical  processes  taking  place  within  the 
cells  of  the  body. 

List  of  Ferments 


Ferment 

Converting 

Into 

Amylase    (of    saliva,    pancreatic 

Starch 

Maltose  and  dextrin 

juice,  liver,  blood  serum,  &c. ) 

Pepsin       ..... 

Proteins     . 

Proteoses   and   pep- 
tones 

Trypsin     ..... 

Proteins     . 

Peptones  and  amino- 
acids 

Enterokinase     .... 

Trypsinogen 

Trjrpsin 

Erepsin      ..... 

Proteoses 

Amino-acids 

Lipase  (of  pancreatic  juice,  liver, 

Neutral  fats 

Fatty       acid       and 

&c.) 

glycerin 

Maltase     .          .          .          ^          . 

Maltose 

Glucose 

Lactase     .          .          .          .''         . 

Milk  sugar 

Glucose  and  galactose 

Invertase  or  sucrase   . 

Cane  sugar 

Glucose    and    levu- 
lose 

Arginase    ..... 

Arginin 

Urea  and  ornithine 

Urease       ..... 

Urea 

Ammonium      carbo- 
nate 

Lactic  acid  ferment     . 

Glucose 

Lactic  acid 

Zymase  ( ?  present  in  the  body)    . 

Glucose 

Alcohol  and  COg 

Deaminating  ferment  (?),  v.  p.  154     Amino-acids 

Oxy-acids(?) 

r 


CHEMICAL  CHANGES  IN  LIVING  MATTER.    FERMENTS    159 

Many  other  ferments  will  probably  be  distinguished  with  increase  in 
our  knowledge  of  cellular  metaboUsm.  The  long  hst  which  is  here  given 
suffices  to  show  how  great  a  part  these  bodies  must  play  in  the  normal 
processes  of  hfe.  A  study  of  the  conditions  of  ferment  actions  is  therefore 
essential  if  we  would  form  a  conception  of  the  chemical  mechanisms  of  the 
living  cell. 

It  is  important  to  note  that  all  the  changes  wrought  by  ferments  can 
be  effected  by  ordinary  chemical  means.  Thus  the  disaccharides  can  be 
made  to  take  up  a  molecule  of  water  and  undergo  conversion  into  mono- 
saccharides. If  a  solution  of  maltose  be  taken  and  bacteria  be  excluded 
from  the  solution,  it  undergoes  at  ordinary  temperatures  practically  no 
change.  If  the  solution  be  warmed,  a  slow  process  of  hydration  takes  place 
which  is  quickened  by  rise  of  temperature,  so  that  if  the  solution  be  heated 
under  pressure  to,  say,  110°  C,  hydrolysis  occurs  T\dth  considerable  rapidity. 
If,  however,  a  little  maltase  be  added  to  the  solution,  the  change  of  maltose 
into  glucose  takes  place  rapidly  at  a  temperature  of  30°  C.  In  the  same 
way  a  solution  of  protein  may  be  kept  almost  indefinitely  without  undergoing 
hydrolysis,  which,  however,  can  be  induced  by  heating  the  solution  under 
pressure.  The  action  of  the  ferments  in  these  two  cases  is  to  quicken  a 
process  of  hydrolysis  which  without  their  presence  would  take  an  infinity 
of  time  for  its  accompUshment. 

In  this  respect  their  action  is  similar  to  that  of  acids,  and  indeed  of  a 
whole  class  of  bodies  which  are  spoken  of  as  catalysers  or  catalysts.  A 
catalyser  is  a  substance  which  will  increase  (or  diminish)  the  velocity  of  a 
reaction  without  adding  in  any  way  to  the  energy  changes  involved  in  the 
reaction,  or  taking  any  part  in  the  formation  of  the  end-products.  Since 
the  catalyser  is  unchanged  in  the  process,  a  very  small  quantity  is  able  to 
influence  reactions  involving  large  quantities  of  other  substances.  By 
adding  acids  to  a  watery  solution  of  the  food-stuffs,  the  process  of  hydrolysis 
is  quickened  in  proportion  to  the  strength  and  concentration  of  the  acid. 
The  effective  catalytic  agents  in  this  process  appear  to  be  the  hydrogen  ions 
of  the  free  acid.  There  are  many  other  bodies,  besides  the  free  acids,  which 
may  act  as  catalysers,  and  a  study  of  the  conditions  under  which  catalysis 
takes  place  may  throw  some  Ught  on  the  essential  nature  of  the  action  of 
ferments. 

The  velocity  of  almost  any  reaction  in  chemistry  can  be  altered  by  the 
addition  of  some  catalytic  agent,  and  there  are  few  of  the  ordinary  reactions 
in  which  catalysis  does  not  play  some  part.  Among  such  processes  we  may 
instance  the  action  of  spongy  platinum  on  hydrogen  peroxide.  Hydrogen 
peroxide  undergoes  slow  spontaneous  decomposition  into  water  and  oxygen. 
If  a  little  spongy  platinum  be  added  to  it,  it  is  at  once  seen  to  decompose 
rapidly  with  the  evolution  of  bubbles  of  oxygen,  and  the  action  does  not 
cease  until  the  whole  of  the  hydrogen  peroxide  has  been  destroyed.  Spongy 
platinum  is  able  in  the  same  way  to  quicken  a  very  large  number  of  chemical 
reactions.  Thus  sulphur  dioxide  and  oxygen  when  heated  together  will 
combine  very  slowly ;   the  combination  becomes  rapid  if  a  mixture  of  the 


160  PHYSIOLOGY 

two  gases  be  passed  over  heated  platinum.  The  same  reaction,  namely, 
the  combination  of  sulphur  dioxide  with  oxygen,  may  be  quickened  by  the 
addition  of  a  small  trace  of  nitric  oxide,  and  this  fact  is  made  use  of  in  the 
manufacture  of  sulphuric  acid  on  a  commercial  scale  by  the  ordinary  lead- 
chamber  process.  Hydrogen  peroxide  and  hydriodic  acid  slowly  interact 
with  the  formation  of  water  and  iodine.  This  reaction  may  be  quickened 
by  the  addition  of  many  substances,  among  which  we  may  mention  molybdic 
acid. 

There  is  moreover  a  specificity  in  the  action  of  catalysers,  though  not 
so  well  marked  as  with  ferments.  Whereas  all  the  disaccharides  are  con- 
verted by  acids  into  the  corresponding  monosaccharides,  a  ferment  such  as 
invertase  acts  only  on  cane  sugar,  and  has  no  action  on  maltose  or  lactose, 
each  of  which  requires  a  specific  ferment  (maltase,  lactase)  to  effect  their 
'  inversion.'  But  we  find  many  examples  of  a  restricted  action  even  among 
inorganic  catalysers.  Thus  potassium  bichromate  will  act  as  the  catalyser 
for  the  oxidation  of  hydriodic  acid  by  bromic  acid,  but  not  for  the  oxidation 
of  the  same  substance  by  iodic  acid.  Iron  and  copper  salts  in  minute  traces 
will  quicken  the  oxidation  of  potassium  iodide  by  potassium  persulphate, 
but  have  no  influence  on  the  course  of  the  oxidation  of  sulphur  dioxide 
by  potassium  persulphate.  Tungstic  acid  increases  the  velocity  of  oxida- 
tion of  hydriodic  acid  by  hydrogen  peroxide,  but  has  no  effect  on  the  velocity 
of  oxidation  of  hydriodic  acid  by  bromic  acid,  and  these  examples  may  be 
multiphed  to  any  extent.  One  cannot  therefore  regard  the  limitation  of 
action  of  the  ferments  as  justifying  any  fundamental  distinction  being 
drawn  between  the  action  of  this  class  of  substances  and  catalysts. 

Whereas  the  influence  of  most  catalysers  on  the  velocity  of  a  reaction 
increases  rapidly  with  rise  of  temperature,  in  the  case  of  ferments  this  in- 
crease occurs  only  up  to  a  certain  point.  This  point  is  spoken  of  as  the 
oftimum  temperature  of  the  ferment  action.  If  the  mixture  be  heated  above 
this  point  the  action  of  the  ferment  rapidly  slows  ofi  and  then  ceases.  This 
contrast,  again,  is  only  apparent.  The  ferments  are  unstable  bodies  easily 
altered  by  change  in  their  physical  conditions,  and  destroyed  in  all  cases 
at  a  temperature  considerably  below  that  of  boiUng  water.  Thus  ferment 
actions,  hke  catalytic  actions,  are  quickened  by  rise  of  temperature,  but 
the  effect  of  temperature  is  finally  put  a  stop  to  by  the  destruction  of  the 
ferment.  The  same  apphes  to  those  inorganic  catalysers  whose  physical 
state  is  susceptible,  like  that  of  the  ferments,  to  the  action  of  heat.  Thus 
the  colloidal  platinum  '  sol '  exerts  marked  catalytic  effects  on  various 
reactions,  e.g.  on  the  decomposition  of  hydrogen  peroxide  and  on  the 
combination  of  hydrogen  and  oxygen.  The  reaction  presents  an  optimum 
temperature,  owing  to  the  fact  that  the  colloidal  platinum  is  altered,  coagu- 
lated, and  thrown  out  of  solution  when  this  is  heated  to  near  boihng-point. 
We  may  therefore  employ  either  class  of  reactions  in  trying  to  form  some 
conception  of  the  processes  which  are  actually  involved. 

Very  many  theories  have  been  put  forward  to  account  for  this  action 
of  catalysers  or  of  ferments.     Many  of  them  are  merely  transcriptions  in 


CHEMICAL  CHANGES  IN  LIVING  MATTER.    FERMENTS     161 

words  of  the  processes  which  actually  occur,  and  fail  to  throw  any  hght 
on  their  real  nature.  The  essential  phenomena  involved  fall  directly  into 
two  classes.  In  the  first  class  we  must  place  those  which  are  determined 
by  the  influence  of  surface.  In  many  cases  the  combination  of  gases  can 
be  hastened  by  increasing  the  surface  to  which  they  are  exposed,  as  by 
passing  them  over  broken  porcelain  or  over  powdered  charcoal.  This  cata- 
lytic effect  is  certainly  connected  with  the  power  of  a  solid  to  condense 
gases  at  its  surface,  and  is  therefore  proportional  to  the  extent  of  surface 
exposed.  Thus  the  efficacy  of  platinum  in  hastening  the  combination  of 
hydrogen  and  oxygen  is  in  direct  proportion  to  its  fineness  of  sub-division, 
and  is  best  marked  when  the  metal  is  reduced  to  ultra-microscopic  dimen- 
sions, as  in  the  colloidal  solution  of  platinum.  Every  colloidal  solution 
must  be  regarded  as  presenting  an  enormous  surface  in  proportion  to  the 
mass  of  substance  in  solution.  There  is  therefore  a  direct  proportionality 
between  the  power  of  a  substance  to  condense  a  gas  on  its  surface  and  its 
power  to  quicken  the  velocity  of  chemical  changes  in  which  the  gas  is  in- 
volved. The  same  process  of  condensation  may  occur  with  dissolved  sub- 
stances. In  all  cases  where  the  presence  of  a  substance  in  solution  diminishes 
the  surface  tension  of  the  solvent,  there  is  a  diffusion  of  dissolved  substances 
into  the  surface,  i.e.  a  concentration  of  dissolved  substances  at  the  surface 
of  contact.  It  was  suggested  by  Faraday  that  the  catalytic  property  of 
surfaces  was  due  to  this  condensation  of  molecules,  and  the  consequent 
bringing  of  the  two  sets  of  molecules  within  each  other's  sphere  of  influence. 
Whether  this  is  the  sole  factor  involved  is  doubtful,  since  mere  compression 
of  gases  or  increased  concentration  of  solutions  does  not  in  the  majority 
of  cases  result  in  such  a  quickening  of  the  velocity  of  reaction  as  is  brought 
about  by  the  eft'ect  of  the  surface. 

It  is  possible  that  this  condensation  effect  or  adsorption  may  be  in  every 

case  combined  with  the  second  factor  which  we  must  now  consider,  namely, 

the  formation  of  intermediate  products.     If  we  boil  an  alkaline  solution 

of  indigo  with  some  glucose,  the  indigo  is  reduced  with  oxidation  of  the 

glucose.     The  mixture  therefore  becomes  colourless.     On  shaking  up  with 

air  the  colourless  reduction  product  of  the  indigo  absorbs  oxygen  from  the 

atmosphere,  and  is  re-transformed  into   indigo.     These  two  processes  can 

be  repeated  until  the  whole  of  the  glucose  is  oxidized,  and  the  process  can 

be  made  continuous  if  air  or  oxygen  be  bubbled  through  a  heated  solution 

of  glucose  containing  a  small  trace  of  indigo.     In  this  case  the  indigo  does 

not  add  to  the  energy  of  the  reaction.     It  appears  unchanged  among  the 

final  products  and  a  small  amount  may  be  used  to  eft'ect  the  change  of  an 

infinite  quantity  of  glucose.     It  therefore  may  be  said  to  act  as  a  ferment 

or  catalytic  agent.     Instead  of  an  alkaUne  solution  of  indigo,  we  may  use 

an  ammoniacal  solution  of  cupric  oxide  for  the  purpose  of  carrying  oxygen 

from  the  atmosphere  to  the  glucose.     This  is  reduced  to  cuprous  hydrate 

on  heating  with  the  sugar,  but  cupric  hydrate  can  be  at  otice  re-formed 

by  shaking  up  the  cuprous  solution  with  air.     It  has  been  thought  that  many 

or  all  of  the  catalvtic  reactions  occur  in  the  same  wav  by  two  stages,  i.e. 

6 


162  PHYSIOLOGY 

by  the  formation  of  an  intermediate  product.  Thus,  in  the  old  lead  chamber 
process  for  the  manufacture  of  sulphuric  acid,  the  nitric  oxide  may  be  sup- 
posed to  combine  with  the  oxygen  of  the  air  to  form  nitrogen  peroxide. 
This  interacts  with  sulphur  dioxide,  giving  sulphur  trioxide  and  nitric  oxide 
once  more.  The  nitric  oxide,  which  we  alluded  to  before  as  the  catalyser, 
may  in  this  way  be  regarded  as  the  carrier  of  oxygen  from  air  to  sulphur 
dioxide.  It  has  been  suggested  that  the  action  of  spongy  platinum  or 
colloidal  platinum  rests  on  the  same  process,  and  that  in  the  oxidation  of 
hydrogen,  for  instance,  PtO  or  PtOg  is  formed  and  at  once  reduced  by  the 
hydrogen  with  the  formation  of  water. 

There  is  a  certain  amount  of  experimental  evidence  in  favour  of  this  hypothesis. 
According  to  Engler  and  Wohler,*  platinum  black,  which  has  been  exposed  to  oxygen, 
in  virtue  of  the  gas  which  it  has  occluded,  has  the  power  of  turning  potassium  iodide, 
and  starch  blue.  This  power  is  not  destroyed  by  heating  to  260°  in  an  atmosphere  of 
CO2,  or  by  washing  with  hot  water.  On  exposure  of  the  platinum  black  to  hydrochloric 
acid,  a  certain  amount  is  dissolved,  and  the  substance  loses  its  effect  on  potassium 
iodide.  The  amount  dissolved  corresponds  with  the  amount  of  iodine  liberated  from 
potassium  iodide,  and  also  with  the  amount  of  oxygen  occluded,  the  (soluble)  platinum 
and  oxygen  being  in  the  proportions  necessary  to  form  the  compound  PtO. 

But  why  should  a  reaction  take  place  more  quickly  if  it  occurs  in  two 
stages  instead  of  one  ?  As  Ostwald  has  pointed  out,  the  formation  of  an 
intermediate  compound  can  be  regarded  as  a  sufficient  explanation  of  a 
catalytic  process  only  when  it  can  be  demonstrated  by  actual  experiment 
that  the  rapidity  of  formation  of  the  intermediate  compound  and  the  rapidity 
of  its  decomposition  into  the  end-products  of  the  reaction  are  in  sum  greater 
than  the  velocity  of  the  reaction  without  the  formation  of  the  intermediate 
body.  In  the  case  of  one  reaction  this  requirement  has  been  fulfilled.  The 
catalytic  effect  of  molybdic  acid  on  the  interaction  of  hydriodic  acid  and 
hydrogen  peroxide  has  been  explained  by  assuming  that  the  first  action 
which  takes  place  is  the  formation  of  permolybdic  acid,  and  that  this  then 
interacts  with  the  hydrogen  iodide  to  form  water  and  iodine.  Now  it  has 
been  actually  shown — (1)  that  permolybdic  acid  is  formed  by  the  action 
of  hydrogen  peroxide  on  molybdic  acid ;  (2)  that  permolybdic  acid  with 
hydriodic  acid  produces  water  and  iodine  ;  (3)  that  the  velocity  with  which 
these  two  reactions  occur  is  much  greater  than  the  velocity  of  the  inter- 
action of  hydrogen  peroxide  and  hydriodic  acid  by  themselves. 

Although  we  may  find  it  difficult  to  explain  why  a  reaction  should  occur  more 
quickly  in  the  presence  of  a  catalyser  by  the  formation  of  these  intermediate  bodies, 
certain  simple  analogies  may  help  us  to  comprehend  how  a  factor  which  introduces  no 
energy  can  yet  assist  the  process.  Thus  a  man  might  stand  to  all  eternity  before  a 
perpendicular  wall  twenty  feet  high.  Since  he  cannot  reach  its  top  at  one  jump,  he  is 
unable  to  get  there  at  all.  The  introduction  of  a  ladder  will  not  in  any  way  alter  the 
total  energy  he  must  expend  on  raising  his  body  for  twenty  feet,  but  will  enable  him 
to  attain  the  top.  Or  we  might  imagine  a  stone  perched  at  the  top  of  a  high  hill.  The 
passive  resistance  of  the  system,  the  friction  of  the  stone,  and  its  inertia  will  tend  to 
keep  it  at  rest,  even  though  it  be  on  a  sloping  surface  and  therefore  tending  to  slide 
or  roll  to  the  bottom.  If,  however,  it  be  rolled  to  a  point  where  there  is  a 
sudden  increase  in  the  rapidity  of  slope,  it  may  roll  over,  and  having  once  started 
*  Quoted  by  Mellor,  "  Chemical  Statics." 


CHEMICAL  CHANGES  IN  LmNG  MATTER.    FERMENTS        163 

its  downward  course,  its  momentum  will  carry  it  to  the  bottom.  The  amount  of 
energy  set  free  by  the  stone  in  its  fall  will  not  vary  whether  the  course  be  a  uniform 
one,  or  whether  it  falls  over  a  precipice  at  one  time  and  rolls  down  a  gentle  slope  at 
another.  It  is  evident  that  by  a  mere  alteration  of  the  slope,  or,  in  the  case  of  a  chemical 
reaction,  of  the  velocity  of  part  of  its  course,  a  change  in  the  system  may  be  initiated 
and  brought  to  a  conclusion  which  without  this  alteration  would  never  take  place. 

Since  the  action  of  ferments,  like  that  of  catalysts,  consists  essentially 
in  the  quickening  up  of  processes  which  would  otherwise  occur  at  an  in- 
finitely slow  velocity,  it  is  possible  that  in  their  case  also  the  formation 
of  an  intermediate  compound  may  be  involved  in  the  reaction.  Light  may 
be  thrown  upon  this  question  by  a  study  of  the  velocity  of  the  reaction  in- 
duced by  the  action  of  a  ferment. 

It  Ls  well  known  that  the  velocity  of  a  reaction  depends  on  the  number  of  molecules 
involved.  As  an  illustration,  we  may  take  first  the  case  of  a  reaction  involving  a 
change  in  one  substance.  If  arseniuretted  hydrogen  be  heated,  it  undergoes  decom- 
position into  hydrogen  and  arsenic.  This  decomposition  is  not  immediate,  but  takes 
a  certain  time,  and  the  velocity  with  which  the  change  occurs  depends  on  the  tempera- 
ture. At  any  given  temperature  the  amount  of  substance  changed  in  the  unit  of  time 
varies  with  the  concentration  of  the  substance.  If,  for  instance,  one-tenth  of  the  gas 
be  dissociated  in  the  first  minute,  in  the  second  minute  a  further  tenth  of  the  gas  will 
also  be  dissociated.  Thus,  if  we  start  with  1000  grammes  of  substance,  at  the  end 
of  the  first  minute  100  grammes  will  have  been  dissociated,  and  900  of  the  original 
substance  will  be  left.  In  the  second  minute  one-tenth  again  of  the  remaining  substance 
will  be  dissociated,  i.e.  90  grammes,  leaving  810  grammes.  In  the  third  minute  81 
grammes  will  be  dissociated,  leaving  729  grammes.  The  amount  changed  in  the 
unit  of  time  will  alwaj^s  bear  the  same  ratio  to  the  whole  substance  which  is  to  be 
changed,  and  will  therefore  be  a  function  of  the  concentration  of  this  substance.  Put 
in  the  form  of  an  equation,  we  may  say  that  </>,  the  amount  changed  in  the  unit  of  time, 
will  be  equal  to  KC,  where  K  is  a  constant  varying  with  the  substance  in  question  and 
with  the  temperature,  and  C  represents  the  concentration  of  the  substance.  The 
equation  <^  =  KC  applies  to  a  monomolecular  reaction. 

If  two  substances  are  involved,  the  equation  will  be  rather  different.  In  this  case 
the  amount  of  change  in  a  unit  of  time  will  be  a  function  of  the  concentration  of  each 
of  the  substances,  and  the  form  of  the  equation  will  be  (^  =  K(C^  x  Cj.).  In  the  case 
of  the  unimolecular  reaction,  halving  the  concentration  of  the  substance  will  halve  the 
amount  of  substance  changed  in  the  unit  of  time.  In  the  case  of  a  bimolecular  reaction, 
halving  each  of  the  substances  will  cause  the  amount  of  change  in  the  unit  of  time  to  be 
reduced  to  one-quarter  of  its  previous  amount.  If  now  either  a  unimolecular  or  a 
bimolecular  reaction  be  quickened  by  the  addition  of  a  catalyser  or  ferment,  and  the 
ferment  enter  into  combination  with  one  of  the  substances  at  some  stage  of  the  reaction, 
it  is  evident  that  our  equation  must  take  account  also  of  the  concentration  of  the 
ferment  or  catalyser.  In  the  case  of  the  catalytic  effect  of  molybdic  acid  on  the  inter- 
action between  hydrogen  peroxide  and  HI,  there  was  definite  evidence  of  a  reaction 
taking  place  between  the  molybdic  acid  and  the  peroxide,  resulting  in  the  formation 
of  an  intermediate  compound,  namely,  permolybdic  acid.  Brode  has  shown  that  the 
interaction  of  the  molybdic  acid  is  revealed  in  the  equation  representing  the  velocity 
of  the  reaction.     Without  the  addition  of  molybdic  acid  the  equation  would  be  : 

(^  =  K(C„20o   ^  Chi). 
After  the  addition  of  molybdic  acid,  the  equation  becomes  : 

0  =  K(C„202  +  y  C  molybdic  acid)CHi, 
when  y  is  another  constant  depending  on  the  molybdic  acid.     If  ferments  act  in  n, 
similar  way  by  the  formation  of  intermediate  compounds,  this  fact  should  be  revealed 
by  a  study  of  the  velocity  at  which  the  ferment  action  takes  place. 


164  PHYSIOLOGY 

Various  methods  may  be  adopted  for  the  study  of  the  velocity  of  ferment 
action.  If,  for  instance,  we  are  investigating  the  action  of  diastase  upon 
starch,  we  should  take  solutions  of  starch  and  of  diastase  of  known  concen- 
trations, keep  them  in  a  water  bath  at  38°  C,  and  at  a  certain  point  add, 
say,  20  c.c.  of  ferment  solution  to  every  100  c.c.  of  the  starch  solution. 
At  periods  of  five  or  ten  minutes  after  the  addition  had  been  made,  5  c.c. 
of  the  mixture  might  be  withdrawn  by  a  pipette  and  at  once  run  into  boiling 
Fehling's  solution.  The  precipitated  cuprous  oxide  would  be  dried  and 
weighed,  and  would  give  directly  the  amount  of  sugar  formed  by  the  action 
of  the  ferment.  After  obtaining  a  series  of  data  in  this  way,  a  curve  could 
be  drawn,  showing  the  amount  of  change  of  starch  which  had  occurred 
in  each  unit  of  time.  In  the  case  of  the  action  of  invertase  on  cane  sugar 
the  investigation  is  still  easier.  Since  the  change  from  cane  sugar  to  invert 
sugar  is  accompanied  by  a  change  in  the  rotatory  power  of  the  solution 
on  polarized  light,  it  is  only  necessary  to  put  the  mixture  of  ferment  and 
cane  sugar  into  a  polarimeter  tube,  which  is  kept  at  a  constant  temperature 
by  means  of  a  water  jacket,  and  read  off  at  intervals  of  a  few  minutes  the 
change  in  the  rotatory  power  of  the  solution.  From  this  change  can  be 
easily  calculated  the  percentage  of  cane  sugar  still  present,  and  there- 
fore the  total  amount  which  has  been  converted  into  fructose  and 
glucose. 

In  investigating  the  action  of  proteolytic  ferments,  as,  e.g.  that  of  trypsin 
on  caseinogen,  samples  are  taken  at  five-minute  intervals  and  run  into 
some  substance  such  as  trichloracetic  acid,  which  will  precipitate  all  the 
unchanged  protein,  but  will  leave  in  solution  the  products  of  hydration 
of  the  protein.  From  the  amount  of  nitrogen  in  the  filtrate  from  the  precipi- 
tate can  be  determined  the  total  amount  of  protein  which  has  undergone 
hydration  in  the  sample  under  observation.  Or  the  amount  of  albumoses 
and  peptones  present  in  each  sample  may  be  estimated  by  the  intensity  of 
the  biuret  reaction  which  can  be  obtained.  This  method,  however,  suffers 
from  the  drawback  that  the  albumoses  and  peptones,  at  any  rate  in  the 
action  of  trypsin,  are  formed  merely  as  a  stage  in  the  process,  and  the  in- 
tensity of  the  reaction  will  first  rise  to  a  maximum  and  then  gradually  dis- 
appear. A  very  convenient  method  is  that  employed  by  Henri  and  by 
Bayliss  in  the  investigation  of  the  kinetics  of  tryptic  action,  namely,  the 
determination  of  the  conductivity  of  the  solution.  In  the  disintegration 
of  the  molecule  caused  by  the  action  of  the  ferment,  there  is  a  continuous 
increase  in  the  conductivity  of  the  solution,  and  this  increase  can  be  regarded 
as  an  index  to  the  rate  of  change  in  the  substances  undergoing  disinte- 
gration. 

By  such  methods  it  has  been  found  that,  when  the  quantity  of  ferment 
employed  is  very  small  in  comparison  with  the  substrate  (the  substance 
acted  upon),  the  amount  of  change  in  a  given  time  is  proportional  to  the 
amount  of  ferment  present,  and  is  (within  limits)  independent  of  the  con- 
centration of  the  substrate.  This  is  well  shown  by  the  two  following  Tables 
representing  the  action  of  lactase  upon  lactose  (E.  F.  Armstrong)  : 


CHEMICAL  CHANGES  IN  LIVING  MATTER.     FERMENTS    165 


Proportions  Hydro lysed  in  100  c.c.  of  a  5  per  cent. 
Solution  of  Lactose 


Solutions  containing — 

lo  hours 

20  hours 

45  hours 

1  C.C.  lactase 
10  c.c.      „ 
20  c.c.      „ 

0-15 

1-6 

3-2 

2-2 
23-3 

45-8 

3-9 
38-6 

Amoitnt  op  Sugar  (Lactose)  Hydrolysed 


Solutions  containing — 

24  hours 

46  hours 

Proportion 

^Yeight 

Proportion 

Weight 

10  per  cent,  lactose 
20       „ 
30       „ 

U-2 
7-0 

4-8 

1-42 
1-40 
1-44 

22-2 
10-9 

7-7 

2-22 
2-18 
2-21 

Moreover,  if  we  take  only  the  earlier  stages  of  the  ferment  action,  it  is  found 
that,  with  small  proportions  of  ferment,  equal  amounts  of  substrate  are 
changed  in  successive  intervals  of  time  until  about  10  per  cent,  has  been 
hydrolysed.     This  is  shown  in  the  following  Table  : 


2  per  cent.  Lactose  with  Lactase 

Time 

Amount  hydrolysed 

^  hour 

3-2 

6-4 

1      „ 

9-6 

2  hours 

16-4 

3     „ 

20-8 

These  results  can  be  interpreted  only  by  assuming  that  the  first  stage  in 
the  reaction  is  a  combination  of  ferment  with  substrate.  It  is  only  this 
compound  which  represents  the  active  mass  of  the  molecules,  i.e.  the  molecules 
of  substrate  which  are  undergoing  change.  This  compound,  as  soon  as  it 
is  formed,  takes  up  water  and  breaks  down,  setting  free  the  hydrolyzed 
substrate  and  the  ferment,  which  is  at  once  ready  to  combine  with  a  further 
portion  of  the  substrate.  In  such  a  case  the  velocity  of  reaction  must  be 
directly  proportional  to  the  amount  of  ferment,  and  the  same  absolute 
quantity  of  substance  will  continue  to  be  changed  in  succeeding  units  of 
time.  Supposing,  for  instance,  we  had  a  load  of  bricks  at  the  bottom  of  a 
hill  which  had  to  be  transferred  to  the  top.  and  five  men  to  effect  the  trans- 
ference. The  rate  of  transference  would  be  directly  proportional  to  the 
number  of  men  employed  ;   we  could  double  the  rate  by  doubling  the  men. 


166 


PHYSIOLOGY 


Moreover,  the  number  of  bricks  carried  in  each  unit  of  time  would  be  the 
same.  Five  men  would  carry  as  many  bricks  in  the  second  ten  minutes 
as  they  would  in  the  first,  and  so  on.  On  the  other  hand,  the  velocity  with 
which  the  transference  was  effected  would  be  independent  of  the  number — 
that  is,  the  concentration — of  the  bricks  at  the  bottom  of  the  hill.  The 
active  mass  of  bricks  could  be  regarded  as  that  number  carried  at  any  moment 
by  the  transferring  factor,  namely,  the  men.  The  equation  of  change  would 
be  (^  =  KG,  where  G  is  the  concentration  of  the  ferment.  This  concen- 
tration is  always  being  renewed,  and  kept  constant  by  the  breaking  down 
of  the  intermediate  product,  so  that  the  rate  of  change  would  be  continuous 
throughout  the  experiment. 

On  the  other  hand,  when  the  amount  of  ferment  is  relatively  large,  the 
rate  of  change,  though  at  first  very  rapid,  tends  continuously  to  diminish. 
This  is  shown  by  the  following  Table  representing  the  rates  of  change, 
during  succeeding  intervals  of  ten  minutes,  in  a  caseinogen  solution  to  which 
a  strong  solution  of  trypsin  had  been  added  (BayUss)  : 
Velocity  of  Trypsin  Reaction 
N 


.  8  per  cent,  caseinogen 

+ 

2  c.c. 

10 

AmHO 

+ 

2 

c.c. 

2  per  cent 

tryps 

5in 

at  39^ 

'C 

1st  10  minutes 

K 

=0-0079 

2nd 

0-0046 

3rd 

0-0032 

4th 

0-0022 

5th 

0-0016 

7th 

0-0009 

&c. 

&c. 

The  cause  of  this  rapid  diminution  in  the  velocity  of  change  is  probably 
complex.  One  factor  may  be  an  auto-destruction  of  the  ferment,  which  is 
known  to  occur  in  watery  solution.  That  this  is  not  the  only,  or  even  the 
chief,  factor  involved  is  shown  by  the  fact  that,  when  the  action  of  trypsin 
on  caseinogen  has  apparently  come  to  an  end,  it  may  be  renewed  by  further 
dilution  of  the  mixture  or  by  removal  of  the  end-products  of  the  action  by 
dialysis.  It  is  evident  that,  in  this  retardation  of  the  later  stages  of  ferment 
action,  the  end-products  are  concerned  in  some  way  or  other,  and  the  retarda- 
tion can  be  augmented  by  adding  to  the  digesting  mixture  the  boiled  end- 
products  of  a  previous  digestion.  The  retarding  effect  of  the  end-products 
resembles  in  many  ways  that  observed  in  a  whole  series  of  reactions  which 
are  known  as  reversible. 

As  an  example  of  such  a  reaction  we  may  take  the  case  of  methyl  acetate  and  water. 
When  methyl  acetate  is  mixed  with  water,  it  undergoes  decomposition  with  the  forma- 
tion of  methyl  alcohol  and  acetic  acid.  On  the  other  hand,  if  acetic  acid  be  mixed 
with  alcohol,  an  interaction  takes  place  with  the  formation  of  methyl  acetate  and 
water.     These  changes  are  represented  by  the  equation  : 

MeCgHgOa  +   HOH  :==  MeOH   +   HCgHgOj. 

methylacetate       water     methylalcohol  acetic  acid 
Each  of  these  changes  has  a  certain  velocity  constant,  and,  since  they  are  in  opposite 
directions,  there  must  be  some  equilibrium  point  where  no  change  will  occur,  and 


CHEMICAL  CHANGES  IN  LIVING  MATTER.     FERMENTS     167 

there  will  be  a  definite  amount  of  all  four  substances  present  in  the  mixture,  namely, 
water,  alcohol,  ester,  and  acid.  This  equilibrium  point  can  be  shifted  by  altering 
the  amount  of  any  of  the  four  substances.  Thus  the  interaction  of  methyl  acetate  and 
water  can  be  diminished  to  any  desired  extent  by  adding  to  the  mixture  the  products 
of  the  interaction,  namely,  methyl  alcohol  and  acetic  acid. 

There  is  evidence  that  some  of  the  ferment  actions  are  reversible.  Thus 
maltase  acts  on  maltose  with  the  formation  of  two  molecules  of  glucose. 
If  the  maltase  be  added  to  a  concentrated  solution  of  glucose,  we  get  a 
reverse  efiect,  with  the  production  of  a  disaccharide  which  has  been  desig- 
nated as  isomaltose  or  revertose.  To  this  reverse  action  may  be  due  a 
certain  amount  of  the  retardation  observed  in  the  action  of  trypsin  on 
coagulable  protein.  A  more  important  factor  is  probably  the  combination 
of  the  ferment  itself  with  the  end-products  and  the  consequent  removal 
of  the  ferment  from  the  sphere  of  action.  Several  facts  speak  for  such  a 
mode  of  explanation.  Thus  the  action  of  lactase  on  milk  sugar  is  not  re- 
tarded by  both  its  end-products,  namely,  glucose  and  galactose,  but  only 
by  galactose.  In  the  same  way  the  action  of  invertase  on  cane  sugar  is 
retarded  by  the  end-product  fructose,  but  not  at  all  by  the  other  end-product, 
glucose. 

So  far,  therefore,  a  study  of  the  velocity  of  ferment  actions  would  lead 
us  to  suspect  that  the  ferment  combines  in  the  first  place  with  the  substrate, 
and  that  this  combination  is  a  necessary  step  in  the  alteration  of  the  sub- 
strate. In  the  second  place,  the  ferment  is  taken  up  to  a  certain  extent 
by  some  or  all  of  the  end-products,  and  this  combination  acts  in  opposition 
to  the  first  combination,  tending  to  remove  the  ferment  from  the  sphere 
of  action,  and  therefore  to  retard  the  whole  reaction.  Other  facts  can  be 
adduced  in  favour  of  these  conclusions.  Thus  it  has  been  shown  that 
invertase  ferment,  which  is  destroyed  when  heated  in  watery  solution  at  a 
temperature  of  60°  C,  can,  if  a  large  excess  of  its  substrate,  cane  sugar, 
be  present,  be  heated  25°  higher  without  undergoing  destruction.  The 
same  protective  effect  is  observed  in  the  case  of  trypsin.  Trypsin  in  watery 
or  weakly  alkaline  solutions  undergoes  rapid  decomposition.  At  37°  C.  it 
may  lose  50  per  cent,  of  its  proteolytic  power  within  half  an  hour.  If,  on 
the  other  hand,  trypsin  be  mixed  with  a  protein  such  as  egg  albumin  or 
caseinogen,  or  with  the  products  of  its  own  action,  namely,  albumoses  and 
peptones,  it  can  be  kept  many  hours  without  undergoing  any  considerable 
loss  of  power. 

It  has  been  found  that,  whereas  maltase  splits  up  all  the  a-glucosides,  it  has  no 
power  on  the  /3-glucosides  ;  that  is  to  say,  maltase  will  lit  into  a  molecule  of  a  certain 
configuration,  but  is  powerless  to  affect  a  molecule  which  ditTers  from  the  first  only 
in  its  stereochemical  structure.  On  the  other  hand,  emulsin.  which  breaks  up  /3-gluco- 
sides, has  no  influence  on  n-glucosides.  This  specific  affinity  of  the  ferments  for  optically 
active  groups  of  bodies  suggests  that  the  ferment  itself  may  be  optically  active.  We 
cannot  of  course  isolate  the  ferment  and  determine  its  optical  behaviour  ;  but  that 
it  is  optically  active  is  rendered  probable  both  by  these  results  and  certain  results 
obtained  by  Dakin  on  lipase,  tlic  fat -splitting  ferment.  Dakin  carried  out  his  experi- 
ments on  the  esters  of  mandelic  acid.  Mandelic  acid  is  optically  inactive,  but  this 
optically  inactive  modification  consists  of  a  mixture  of  equal  parts  of  dextro-rotatory 


168  PHYSIOLOGY 

and  lee vo -rotatory  mandelic  acid.  The  esters  prepared  from  the  optically  inactive 
acids  are  themselves  optically  inactive.  Dakin  found  that,  when  an  optically  inactive 
mandelic  ester  was  acted  upon  by  a  lipase  prepared  from  the  liver,  the  final  results 
of  the  action  were  also  inactive  ;  but  if  the  reaction  were  interrupted  at  the  half-way 
point,  the  mandelic  acid  which  had  been  liberated  was  dextro-rotatory,  while  the 
remainder  of  the  ester  was  lee vo -rotatory.  Thus  the  rate  of  hydrolysis  of  the  dextro- 
component  of  the  ester  is  greater  than  that  of  the  Isevo-component,  a  result  which  can 
be  best  explained  by  the  assumptions  (a)  that  the  enzyme  or  a  substance  closely  asso- 
ciated with  it  is  a  powerfully  optically  active  substance  ;  (b)  that  actual  combination 
takes  place  between  the  enzyme  and  the  ester  undergoing  hydrolysis.  Since  the 
additive  compounds  thus  formed  in  the  case  of  the  dextro-  and  lee vo -components  of 
the  ester  would  not  be  optical  opposites,  they  would  be  decomposed  with  unequal 
velocity,  and  thus  account  for  the  liberation  of  the  optically  active  mandelic  acid. 

We  may  conclude  that  in  the  action  of  ferments  on  the  food  substances, 
whether  carbohydrate  or  protein,  an  essential  factor  is  the  combination 
of  the  ferment  with  the  substrate.  Only  the  part  of  the  substrate,  which 
is  thus  combined  with  the  ferment,  can  be  regarded  as  the  active  mass  and 
as  undergoing  the  hydrolytic  change.  What  is  the  nature  of  this  combina- 
tion ?  Ferments,  which  are  all  of  a  colloid  or  semi-colloid  character,  cannot 
be  dealt  with  in  the  same  way  as  the  catalysts  of  definite  chemical  com- 
position, such  as  molybdic  acid  or  nitric  oxide.  In  many  cases  the  sub- 
strate, e.g.  starch  or  protein,  is  also  colloidal,  and  the  combination  therefore 
falls  into  the  class  of  combinations  between  colloids.  In  this  we  have  an 
interaction  between  two  substances  in  which  the  adsorption  by  the  surfaces 
of  the  molecules  of  one  or  both  substances  plays  an  important  part,  though 
this  adsorption  is  itself  determined  or  modified  by  the  chemical  configuration 
of  the  molecules.  The  combination  of  ferments  with  their  substrates  be- 
longs, therefore,  to  that  special  class  of  interactions,  not  entirely  chemical 
and  not  entirely  physical,  but  depending  for  their  existence  on  a  co-operation 
of  both  chemical  and  physical  factors,  which  we  have  discussed  earlier  under 
the  name  of  adsorption  compounds. 

FERMENTS  AS  SYNTHETIC  AGENTS 
If  maltase,  obtained  from  yeast,  or  from  the  so-called  takadiastase 
(prepared  from  Aspergillus  oryzce),  be  added  to  a  solution  of  maltose,  the 
latter  is  hydrolysed  to  glucose.  The  process  of  hydrolysis  stops  short  of 
complete  inversion  at  a  point  varying  with  the  concentration  of  the  sugar 
solution.  Thus  in  a  10  per  cent,  solution  of  maltose,  inversion  proceeds 
until  98  per  cent,  of  the  maltose  is  converted  into  dextrose,  whereas  in  a 
40  per  cent,  solution  the  change  stops  short  when  85  per  cent,  sugar  has 
undergone  inversion.  Croft  Hill  showed  that  if  the  maltase  were  added 
to  a  40  per  cent,  solution  of  dextrose,  a  change  took  place  in  the  reverse 
direction,  which  proceeded  until  85  per  cent,  of  the  glucose  was  left.  The 
sugar  formed,  which  is  a  disaccharide,  was  regarded  by  Croft  Hill  as  maltose. 
According  to  Emmerling,  however,  it  is  the  stereoisomeric  sugar,  iso-maltose, 
which  is  formed  ;  and  Croft  Hill  in  his  later  papers  spoke  of  the  sugar  as 
revertose. 

In  the  same  way  it  has  been  shown  by  Castle  and  Loewenhart  that  the 


CHEMICAL  CHANGES  IN  LIVING  MATTER.    FERMENTS    169 

hydrolysis  of  esters  by  lipase  is  a  reversible  reaction,  the  action  of  lipase 
being  simply  to  hasten  the  attainment  of  the  equilibrium  point  between 
the  four  substances — ester  (or  neutral  fat),  water,  fatty  acid,  and  alcohol. 
Similar  reversible  effects  have  been  described  for  other  ferments.  Thus 
the  addition  of  pepsin  to  a  strong  solution  of  albumoses  causes  the  appear- 
ance of  an  insoluble  precipitate,  which  is  called  plastem,  and  has  been  re- 
garded as  produced  by  the  resynthesis  of  the  original  protein  molecule. 

If  all  ferment  actions  are  in  this  way  reversible,  a  possibihty  is  opened 
of  regarding  the  S5nithetic  processes  occurring  in  the  hving  cell,  as  well 
as  the  processes  of  disintegration,  as  determined  by  the  action  of  enzymes. 
It  must  be  noted  that  these  effects  are  only  obtained  with  distinctness 
when  dealing  with  concentrated  solutions.  The  degree  of  synthesis  which 
would  be  produced  in  the  very  dilute  solutions  of  glucose,  &c.,  occurring 
in  the  animal  cell  would  therefore  be  infinitesimal.  But  if  a  mechanism 
were  provided  for  the  immediate  separation  of  the  synthetical  product 
from  the  sphere  of  reaction,  either  by  removing  it  to  a  different  part  of  the 
cell  or  by  building  it  up  into  some  more  complex  body  which  was  not  acted 
on  by  the  ferment,  the  process  of  synthesis  might  go  on  indefinitely,  and  the 
infinitesimal  quantities  be  summated  to  an  appreciable  amount. 

Some  experiments  by  Bertrand  on  fat  synthesis  have  been  interpreted 
as  showing  that  the  process  of  synthesis  by  ferments  is  not  the  mere  attain- 
ment of  an  equilibrium  point  in  a  reversible  reaction.  It  has  long  been 
known  that  watery  extracts  of  the  fresh  pancreas  split  neutral  fats  into 
the  higher  fatty  acids  and  glycerine.  This  observer  has  shown  that  if  the 
pancreas  be  dried  with  alcohol  and  ether  and  powdered,  addition  of  the  dry 
powder  to  a  mixture  of  the  higher  fatty  acids  and  glycerine  brings  about  a 
rapid  synthesis  of  neutral  fat.  The  process  of  synthesis  is  at  once  stopped 
by  the  addition  of  water.  In  this  case  either  there  are  two  ferments  present, 
one  a  synthetising,  the  other  a  hydrolysing,  ferment,  differing  in  their  con- 
ditions of  activity,  or  there  is  one  ferment  which  may  act  either  as  a  fat- 
sphtting  or  fat-forming  agent  according  to  the  conditions  under  which  it  is 
placed.  In  the  latter  case  the  effect  of  the  addition  of  water  would  be  simply 
to  alter  the  equilibrium  point  of  the  mixture.  It  has  been  shown  that 
in  all  reversible  reactions  the  equihbrium  position  is  the  same  from  which- 
ever side  it  be  approached.  The  action  of  the  ferment  is  to  hasten  the 
attainment  of  equihbrium,  the  position  of  the  latter  being  determined  by 
the  relative  concentration  of  the  reacting  molecules. 


6* 


SECTION  V 
ELECTRICAL  CHANGES  IN  LIVING  TISSUES 

The  material  composing  living  cells  and  tissues  is  permeated  throughout 

with  water  containing  electrolytes  in  solution.     All  salts,  as  we  have  seen, 

undergo  ionic  dissociation  in  watery  solution — a  dissociation  which,  in  the 

concentrations  occurring  in  the  animal  body,  must  be  nearly  complete. 

When  an  electric  current  passes  through  the  living  tissues  it  is  carried  by  the 

charged  ions  formed  by  the  dissociation  of  the  salts.     Thus,  n/10  solution 

+ 
of  sodium  chloride  contains  almost  entirely  Na  and  CI  ions.     In  addition  to 

these  charged  inorganic  ions,  the  cell  protoplasm  contains  in  solution  or 
suspension  various  colloidal  particles  which  in  many  cases  are  themselves 
charged.  By  the  presence  of  these  colloidal  particles  marked  differences 
may  be  caused  in  the  distribution  of  the  inorganic  ions  owing  to  the  power 
of  adsorption  possessed  by  the  colloids  for  many  inorganic  salts.  It  is 
evident  that  any  unequal  distribution  of  the  charged  ions  or  colloidal  particles 
in  a  tissue  or  on  the  two  sides  of  a  membrane  may  give  rise  to  corresponding 
unequal  distribution  of  electric  charges,  and  therefore  differences  of  potential 
between  different  parts  of  the  tissue,  which  under  suitable  conditions  may 
find  their  expression  in  an  electric  current.  It  is  therefore  not  surprising  that 
practically  every  functional  change  in  a  tissue  has  been  shown  to  be  associated 
with  the  production  of  differences  of  electrical  potential.  Thus  all  parts  of 
an  uninjured  muscle  are  isopotential,  and  any  two  points  may  be  led  off  to  a 
galvanometer  without  any  current  being  observed.  If,  however,  one  part 
of  the  muscle  be  strongly  excited,  as,  for  instance,  by  injury,  so  that  it  is 
brought  into  a  state  of  lasting  excitation,  it  will  be  found  that,  on  leading 
off  from  this  point  and  a  point  on  the  uninjured  surface  to  a  galvanometer, 
a  current  flows  through  the  latter  from  the  uninjured  to  the  injured  surface. 
Every  beat  of  the  heart,  every  twitch  of  a  muscle,  every  state  of  secretion  of 
a  gland,  is  associated  in  the  same  way  with  electrical  changes.  In  most 
cases  the  electrical  changes  associated  with  activity  have  the  same  general 
character,  the  excited  part  being  found  to  be  negative  in  reference  to  any 
other  part  of  the  tissue  which  is  at  rest.  The  uniform  character  of  the 
electric  response  in  different  kinds  of  tissues  suggests  that  an  accurate  know- 
ledge of  the  changes  in  the  distribution  of  charged  ions  responsible  for  the 
response  ought  to  throw  important  light  on  the  intimate  nature  of  excitation 
generally.     It  may  be  therefore  advisable  to  consider  more  closely  the 

170 


ELECTRICAL  CHANGES  IN  LIVING  TISSUES  171 

conditions  which  determine  differences  of  potential  in  a  complex  system  of 
electrolytes. 

As  a  simple  case  we  may  take  an  ordinary  concentration  cell.  Two 
vessels  (Fig.  29),  A  and  B,  are  united  by  a  glass  tube  C.  A  contains  a  10 
per  cent,  solution  of  zinc  sulphate  and  B  a  1  per  cent,  solution  of  the  same 
salt.  A  rod  of  pure  zinc  is  immersed  in  each  limb.  On  connecting  the  zinc 
by  a  zinc  wire  to  a  galvanometer  a  current  is  observed  to  flow  from  A  to  B 
through  the  galvanometer,  and  therefore  from  B  to  A  through  the  cell.     A 


^ 


1 

i 

i 

10% 

/»/ 1 

/  « 

B 


®Zn 


In® 


®Zn 
®2n 


®Zn 


©Z/7 

© 
Zn 


© 
Zn 


Fig.  29. 


Fig.  30. 


solution  of  zinc  sulphate  contains  partly  undissociated  ZnS04  and  partly 

dissociated  Zn  and  SO4  ions.  If  a  rod  of  zinc  be  immersed  in  a  watery  fluid 
the  zinc  tends  to  dissolve.  The  Zn  passing  into  the  fluid  is,  however, 
directly  ionised,  and  therefore  carries  a  positive  charge  into  the  fluid,  leaving 
the  zinc  negatively  charged  (Fig.  30).  This  process  of  solution  will  rapidly 
come  to  an  end,  since  the  positively  charged  ions  in  the  fluid  will  repel  back 
into  the  zinc  any  ions  which  may  be  escaping  from  the  zinc.  The  amount  of 
zinc  actually  dissolved  in  the  fluid  is  infinitesimal,  the  process  of  solution 
ceasing  when  the  pressure  (osmotic  pressure)  of  the  Zn  ions  in  the  fluid 
equals  what  may  be  called  the  '  electrolytic  solution  pressure  '  of  the  zinc. 
The  continued  solution  of  the  zinc  is  therefore  only  possible  when  means  are 
supplied  for  the  Zn  ions  in  the  fluid  to  get  rid  of  their  positive  charges. 

In  an  ordinary  Daniell  cell  the  Zn  ions  which  leave  the  zinc  are  dis- 
charged by  combining  with  the  SO4  ions  passing  to  the  zinc  from  the  copper 
sulphate  in  the  outer  cell.  It  is  a  well-known  fact  that  pure  zinc  docs  not 
dissolve  in  acid  until  some  other  metal,  such  as  copper,  is  brought  into  con- 
tact with  it,  so  as  to  set  up  an  electric  couple,  i.e.  to  provide  means  for  the 
discharge  of  the  Zn  ions  passii\g  into  the  solution.  When  the  zinc  is 
immersed  in  the  two  solutions  of  zinc  sulphate  in  the  concentration  battery, 
the  same  change  will  occur.     The  ZnSO.i  solution  in  the  two  limbs  of  the 


172  PHYSIOLOGY 

concentration  cell  already  contains  Zn  ions.  Since  their  pressure  in  the  10  per 
cent,  solution  is  greater  than  in  the  1  per  cent,  solution,  fewer  Zn  ions  will 
leave  the  zinc  in  A  than  in  B.  The  negative  charge  on  the  Zn  in  A  will 
therefore  be  less  than  that  on  the  rod  in  B,  and  positive  electricity  will  there- 
fore flow  from  A  to  B.  This  will  disturb  the  equihbrium  at  the  surface  both 
of  B  and  A,  so  that  Zn  ions  will  be  deposited  from  the  fluid  on  the  surface  of 
the  zinc  in  A  and  will  continue  to  pass  from  zinc  into  solution  in  B.  At  the 
same  time  there  is  a  movement  of  SO4  ions,  set  free  at  the  surface  of  A 
towards  B.  The  ultimate  result,  therefore,  is  that  the  zinc  in  B  dis- 
solves and  the  same  amount  of  zinc  is  deposited  on  A.  The  solution  of 
zinc  sulphate  on  A  becomes  progressively  weaker,  while  that  in  B  be- 
comes stronger,  until  finally  the  concentrations  in  the  two  limbs  are 
identical  and  the  current  ceases.  In  this  process  no  chemical  energy  is 
involved,  the  energy  set  free  by  the  conversion  of  zinc  into  zinc  sulphate 
in  B  being  exactly  balanced  by  the  energy  lost  by  the  deposition  of  zinc 
from  zinc  sulphate  in  A.  Yet  the  current  which  is  produced  has  a  certain 
amount  of  energy  which  can  be  utihsed  for  heating  a  wire  through 
which  it  is  made  to  pass.  Since  this  energy  must  be  taken  from  the 
cell,  the  cell  is  cooled  during  the  passage  of  the  current.  We  have 
here  a  close  analogy  with '  the  case  of  compressed  gases.  If  the  10 
per  cent,  and  1  per  cent,  solutions  were  mixed  together  in  a  calorimeter, 
no  change  of  temperature  would  be  produced,  since  no  work  is  done 
in  the  process.  In  the  same  way  no  cooHng  effect  is  observed  if  compressed 
gas  be  allowed  to  expand  into  a  vacuum.  If,  however,  the  compressed  gas 
be  allowed  to  expand  from  a  narrow  orifice  against  the  pressure  of  the  external 
air,  so  that  it  does  work  in  the  process,  it  is  cooled,  and  this  cooKng  eflect  is 
made  use  of  in  the  working  of  refrigerating  machines  or  for  the  hquef action 
of  gases.  We  may  therefore  regard  the  concentration  battery  as  a  machine 
for  making  the  substances  in  solution  do  work  as  they  expand  from  a  strong 
into  a  dilute  solution. 

The  differences  of  potential  obtained  from  an  ordinary  concentration 

cell  are  very  small    and  would  not 
^  suffice  to   account  for   such    a  high 

electromotive  force  as  is  set  up,  e.g. 
in  the  contraction  of  a  muscle.  We 
have  seen  earher,  however,  that  even 
in  isosmotic  solutions  differences  of 


u\/ 


B 


UV 


pressure  may  be  brought   about  by 
differences  in  diffusibihty  of  the  sub- 
stances in  solution,  especially  if  the 
two  solutions  be  separated  by  a  mem- 
brane.    Very  large  differences  may  be 
produced  if  this  membrane  be  practic- 
ally impermeable  to  one  or  other  of  the  dissolved  substances.      In  the  same 
way  a  semipermeable  membrane,  i.e.  a  membrane  with  different  permea- 
bihties  for  the  diflerent  ions  of  the  two  solutions,  may  suffice  to  bring  the 


31. 


ELECTRICAL  CHANGES  IN  LIVING  TISSUES  173 

differences  of  potential  of  a  concentration  cell  up  to  and  beyond  the 
extent  which  is  observed  in  living  tissues.  Supposing  we  have  (Fig.  31) 
two  solutions,  A  and  B,  each  containing  an  electrolyte,  UV,  in  different 
concentrations  separated  by  a  membrane  m.  If  u  represents  the  velocity  of 
transmission  of  U  through  m,  and  v  the  velocity  of  V,  then  the  electromotive 
force  of  the  cell  is  given  by  the  formula 

5i^l^  0-0577.  log.io  -  Volt. 

U  +   V  C'l 

If  V  is  taken  as  very  small,  the  membrane  maybe  regarded  as  semipermeable 
for  the  corresponding  ion  V.  Supposing  we  take  potassium  chloride  as  the 
solution,  we  should  have  to  make  the  concentration  in  B  eight  times  that  in 
A,  in  order  to  get  a  current  of  a  strength  equal  to  that  obtained  from  the 
olfactory  nerve  of  the  pike,  for  example.  Macdonald  has  made  such  an 
assumption  in  order  to  explain  the  normal  nerve  current.  He  suggests  that 
the  axis  cyhnder  contains  an  electrolyte  which  is  equivalent  to  a  2-6  per 
cent,  solution  of  potassium  chloride.  It  is  unnecessary,  however,  to  assume 
such  great  differences  of  concentration  if  we  regard  the  membrane  as  itself 
a  solution  of  electrolytes,  as  has  been  suggested  by  Cremer,  or  if  we  take 
different  substances  on  the  two  sides  of  the  membrane.  In  the  case  of  two 
electrolytes,  U^Vi,  UgVa  (L^  being  the  cation  in  each  case),  separated  by  a 
membrane  with  varying  permeabihty  for  the  different  ions,  "the  electro- 
motive force  of  the  cell  is  given  by  the  following  formula  : 

0-0677  log,.  !^^ 

where  m^,  v^,  Wgj  Vj,  are  the  velocities  of  the  corresponding  ions.  We  assume 
that  the  concentrations  of  the  two  solutions  are  identical.     Now  it  is  evident 

that  by  making  Wg  and  Vi  very  small,  the  expression  log-^,  — may  be 

made  to  attain  any  quantity,  and  in  the  same  way  by  making  u^  +  v, 
infinitesimally  small  the  electromotive  force  of  the  combination  wiW  also 
become  correspondingly  small.  The  thickness  of  the  membrane  does  not 
come  into  the  formula,  so  that  membranes  of  microscopic  or  even  ultra - 
microscopic  thickness,  which  we  have  seen  reason  to  assume  as  present  in 
and  around  cells  and  their  parts,  could  perform  all  the  fmictions  required 
of  the  hypothetical  membrane  in  the  above  example.  This  is  also  the  case 
when  Vj  is  the  same  as  V., — that  is  to  say,  there  is  a  common  anion  or  a 
connnon  cation  on  the  two  sides  of  the  membrane. 

It  must  be  remembered  that  the  passage  of  a  current  through  a  membrane 
impermeable  to  one  or  other  ion  in  the  surrounding  fluid  will  cause  an  accu- 
mulation of  the  ion  at  the  surface  of  the  membrane,  so  that  this  will  become 
polarised.  Such  an  accumulation  at  any  surface  will  naturally  alter  the 
properties  of  the  surface,  including  its  surface  tension.  The  construction  of 
the  capillary  electrometer  depends  on  this  fact.  When  mercury  is  in  contact 
with  dilute  acid  or  mercuric  sulphate  solution  it  takes  a  positive  charge  from 


174 


PHYSIOLOGY 


the  fluid,  and  the  state  of  stress  at  the  surface  of  contact  between  the  mercury 
and  the  negatively  charged  fluid  diminishes  the  surface  tension  of  the 
mercury.  If  the  mercury  be  in  the  form  of  a  drop  in  a  tube  drawn  out  to  a 
capillary,  the  mercury  will  run  down  the  capillary  and  the  drop  will  be 
deformed  until  the  surface  tension  tending  to  pull  the  mercury  into  a 
spherical  globule  is  just  equal  to  the  force  of  gravity  tending 
to  make  the  mercury  run  out  through  the  end  of  the 
capillary  (Fig.  32).  If  the  mercury  be  immersed  in  sul- 
phuric acid  it  will  descend  to  a  lower  level  in  the  capillary 
owing  to  the  diminution  of  its  surface  tension.  If  now  the 
acid  and  the  mercury  be  connected  with  a  source  of  current 
so  as  to  charge  the  mercury  negatively,  the  effect  will  be  to 
^^^  diminish  the  charge  previously  taken  up  by  the   mercury. 

^^^^k       The  state  of  tension  at  the  contact  with  the  acid  is  therefore 
^^I^H       diminished,  the  surface  tension  is  increased,  and  the  mercury 
i^^^^l  /      withdraws  itself  from  the  point  of  the  capillary.     If,  however, 
\^^^V/      the  mercury  be  connected  with  the  positive  pole,  its  charge 
^^^m/       will  be  increased  and    its  surface   tension   correspondingly 
\^^/  diminished,    so   that   the    meniscus   will   move   towards   the 

\ W /  point  of  the  capillary.     The  movement  of  the  meniscus  to  or 

n  I  away  from  the  point  may  thus  be  used,  as  in  the  capillary 

U  U  •  electrometer,  to  show  the  direction  and  amount  of  any 
Fig.  32.  moderate  electric  change  occurring  in  a  tissue,  two  points 
of  which  are  connected  with  the  mercury  and  the  acid  re- 
spectively. It  is  possible  that  this  electrical  alteration  of  surface  tension 
may  be  a  determining  factor  in  many  of  the  phenomena  of  movement 
observed  in  the  animal  body.  We  shall  have  occasion  to  discuss  this 
question  more  fully  when  endeavouring  to  account  for  the  ultimate  nature 
of  muscular  contraction. 


BOOK  II 

THE   MECHANISMS  OF   MOVEMENT  AND 

SENSATION 


CHAPTER  V 
THE   CONTRACTILE  TISSUES 

SECTION  I 

THE  STRUCTURE  OF  VOLUNTARY  MUSCLE 

The  most  striking  features  in  the  continual  series  of  adaptations  to  the 
environment,  which  make  up  the  hfe  of  an  individual,  are  the  movements 
carried  out  by  contractions  of  the  skeletal  muscles.  In  fact,  all  the  mechan- 
isms of  nutrition  can  be  regarded  as  directed  to  the  maintenance  of  the 
neuro-muscular  apparatus,  i.e.  of  the  mechanism  for  adapted  movement. 
With  the  growth  of  the  cerebral  hemispheres,  which  determines  the  rise 
in  the  scale  of  animal  life,  the  skeletal  muscles  become  more  and  more  the 
machinery  of  conscious  reaction.  Even  the  highest  of  the  adaptations 
possessed  by  man,  those  involving  the  use  of  speech,  are  impossible  ■\^'ithout 
some  kind  of  movement.  A  man's  relation  to  his  fellows,  and  his  value  in 
the  community,  are  determined  by  these  higher  nuiscular  adaptations. 
It  is  not,  therefore,  surprising  that  the  organs  of  the  body  which  present 
in  the  highest  degree  the  reactivity  characteristic  of  all  hving  things  should 
have  early  attracted  the  attention  of  physiologists  and  have  been  the  object 
of  numberless  researches  directed  to  determining  the  ultimate  nature  of  the 
processes  generally  described  as  vital. 

The  movements  of  the  muscles  are  carried  out  in  response  to  changes 
aroused  in  the  central  nervous  system  by  events  occurring  in  the  environ- 
ment and  acting  on  the  surface  of  the  body.  Every  movement  of  an  animal 
is  thus  in  its  most  primitive  form  a  reflex  action,  and  involves  changes  in  a 
peripheral  sense  organ,  in  an  afferent  nerve  fibre,  in  the  central  nervous 
system,  and  in  an  efferent  nerve  fibre,  before  the  actual  process  of  contrac- 
tion occurs  in  the  muscle  itself  and  gives  rise  to  the  resultant  movement 
(Fig.  33).  If  we  are  to  determine  the  nature  of  the  changes  involved  in  this 
reflex  action,  we  must  be  able  to  study  them  as  they  progress  along  the 
different  elements  which  make  up  the  reflex  arc.  This  analysis  is  facihtated 
by  the  fact  that  we  are  able  to  arouse  a  condition  of  activity  in  the  different 
parts  of  the  arc,  even  when  isolated  from  one  another.  Thus  we  can  excite 
any  given  reflex  movement  by  stimulation  of  the  periphery  of  the  body, 
or  of  the  afferent  nerve  passing  from  the  surface  to  the  central  nervous 

177 


178  PHYSIOLOGY 

system.  We  can  proceed  further  and  cut  the  efferent  nerve  away  from 
the  central  nervous  system  and  still  succeed  in  exciting  a  condition  of  activity 
in  the  efferent  nerve  or  in  its  attached  muscle.  All  parts  of  the  reflex  arc 
possess  the  property  of  excitability,  and  we  are  thus  able  to  arouse  the 
activity  of  each  part  in  turn,  to  study  its  conditions,  its  time  relations, 
and  the  physical  and  chemical  changes  concomitant  with  the  state  of 
acti^dty. 

It  will  be  convenient  for  our  analysis  to  begin  with  the  tissue  whose 

V  \ 

1      Central  Nervous 
'i^n.'^nry  11^    :>ensoryj^erve       y    '     I—     \Sysfem 


Fig.   33.     Diagram  of  a  reflex  arc. 

reaction  forms  an  end  link  in  the  reflex  chain,  namely,  the  muscle,  and  to 
proceed  from  that  to  the  consideration  of  the  processes  occurring  in  the 
conducting,  strand  between  central  nervous  system  and  muscle,  namely, 
the  nerve  fibre,  postponing  to  a  future  chapter  the  treatment  of  the  more 
complex  processes  associated  with  the  central  nervous  system. 

In  the  higher  animals  we  may  distinguish  several  varieties  of  muscle. 
All  movements  that  require  to  be  sharply  and  forcibly  carried  out  are 
effected  by  means  of  striated  muscular  tissue,  and  as  these  movements 
are  in  nearly  all  cases  under  the  control  of  the  will  the  muscles  are  generally 
spoken  of  as  voluntary.  Unstriated  or  involuntary  muscles  from  sheets 
or  closed  tubes  surrounding  the  hollow  viscera.  By  their  slow,  prolonged 
contractions  they  serve  to  maintain  and  regulate  the  flow  of  the  contents 
of  these  organs.  Such  fibres  are  found  surrounding  the  blood-vessels, 
the  ahmentary  canal,  the  bladder,  &c.  Intermediate  in  properties  as 
well  as  structure  between  these  two  classes  is  the  heart  muscle.  This, 
like  voluntary  muscle,  is  striated,  but  presents  considerable  variations  both 
in  structure  and  function  from  ordinary  skeletal  muscle.  Many  of  its 
properties  will  be  considered  in  treating  of  the  physiology  of  the  heart. 
The  properties  of  contractile  tissues  have  been  most  fully  investigated  in  the 
voluntary  muscles,  almost  exclusively  on  the  muscles  of  cold-blooded 
animals,  such  as  the  frog.  The  choice  of  skeletal  muscles  for  this  purpose 
is  justified  by  the  fact  that  a  function  is  most  easily  investigated  in  the 
organs  in  which  it  is  most  highly  developed.  The  choice  of  cold-blooded 
animals  is  guided  by  the  fact  that  it  is  possible  to  isolate  the  muscle  from 
the  rest  of  the  body  and  to  study  its  reactions  during  a  considerable  time 


THE  STRUCTURE  OF  VOLUNTARY  MUSCLE  179 

without  the  research  being  interfered  with  by  the  death  of  the  tissue.  We 
may  therefore  deal  at  length  with  the  properties  of  the  skeletal  muscles, 
pointing  out  incidentally  in  what  respects  the  heart  muscle  and  involuntary 
muscle  differ  from  the  skeletal  muscle. 

The  voluntary  or  striated  muscles  form  a  large  part  of  the  body,  and 
are  known  as  the  flesh  or  meat.  Each  muscle  is  embedded  in  a  layer  of 
connective  tissue,  and  is  made  up  of  an  aggregation  of  muscular  fibres, 
which  are  united  into  bundles  by  means  of  areolar  connective  tissue.  The 
individual  fibres  vary  much  in  length,  and  may  be  as  long  as  4  or  5  cm. 
At  each  end  of  the  muscle  the  fibres  are  firmly  united  to  tough  bundles 
of  white  fibres,  which  form  the  tendon  of  the  muscle,  and  are  attached  as 


Fig.  34.     Muscular  fibre  of  a  mammal,  examined  fresh  in  scrum, 
highly  magnified.     (Schafer.) 

a  rule  to  bones.  Running  in  the  connective  tissue  framework  of  the  muscle 
we  find  a  number  of  blood-vessels,  capillaries  and  nerves. 

On  examination  of  a  living  muscle,  each  fibre  is  seen  to  consist  of  a 
series  of  alternate  light  and  dark  striae,  arranged  at  right  angles  to  its  long 
axis,  and  enclosed  in  a  structureless  sheath — the  sarcolemma.  Lying  mider 
the  sarcolemma  are  a  number  of  oval  nuclei  embedded  in  a  small  amount 
of  granular  protoplasm.  Li  some  animals  these  nuclei  occupy  a  central 
position  in  the  fibre.  Each  band  may  be  considered  to  be  made  up  of  a 
number  of  prisms  (sarcomeres)  side  by  side,  with  interstitial  substance 
(sarcoplasm)  between  them.  The  muscle  prisms  of  adjacent  discs  are 
connected  to  form  long  columns  (primitive  fibrillae,  or  sarcostyles).  Each 
muscle  prism  is  more  transparent  at  the  two  ends  than  in  the  middle,  thus 
giving  rise  to  the  appeareance  of  hght  and  dark  stria?.  Li  the  middle  of 
the  hght  band  is  a  line  or  row  of  dots  (often  appearing  double),  called  Krause's 
membrane. 

The  development  of  this  regular  cross  and  longitudinal  striation  is 
closely  connected  with  the  evolution  and  speciahsation  of  the  muscular 
function,  i.e.  contraction.  Contractility  is  among  others  a  function  of  all 
undift'erentiated  protoplasm.  Undift'erentiated  cells,  such  as  the  ama?ba, 
can  eftect  only  slow  and  weak  contractions.  Directly  a  speciahsation  of 
function  is  necessary  and  some  cell  or  part  of  a  cell  has  to  contract  rapidly 
in  response  to  some  stimulus  from  within  or  without,  we  find  a  difierentiation 
both  of  form  and  of  internal  structure.  In  many  cases,  as  in  the  developing 
muscle  of  the  embryo  or  the  adult  muscles  of  many  invertebrates,  this 
difterentiation  aliects  only  part  of  the  cell,  so  that  while  one  part  presents 
the  ordinary  granular  appearance,  the  other  half  is  finely  and  longitudinally 


180 


PHYSIOLOGY 


striated,  the  striation  being  apparently  due  to  the  development  of  special 
contractile  fibrillee.  In  the  slowly  contracting  unstriated  muscle  of  the 
vertebrate  intestine,  the  longitudinal  striation  is  with  difficulty  made  out, 
but  as  the  muscle  rises  in  the  scale  of  efficiency,  the  longitudinal  striation 
becomes  more  apparent,  and  in  the  striated  muscle  of  vertebrates,  and  still 
more  in  the  wonderful  wing-muscles  of  insects,  which  can  perform  three 
hundred  complete  contractions  in  a  second,  the  longitudinal  is  associated 


Fig. 36. 


Fig.  35. 


Fig.  35.  Muscle  fibre  of  an  ascaris.  a,  the  differentiated  contractile  portion  of  the 
cell.     (After  Hbrtwig.) 

Fig.  36.  Muscle  fibres  from  the  small  intestine,  showing  the  fine  longitudinal  stria- 
tion.     (SCHAFER.) 

with  and  often  apparently  subordinated  to  a  transverse  striation,  due  to 
the  regular  segmentation  of  the  contractile  fibrillee  or  sarcostyles.  Every 
muscular  fibre,  which  presents  any  trace  of  histological  differentiation,  may 
be  said  to  consist  of  contractile  fibrillae  (sarcostyles),  each  composed  of  a 
series  of  contractile  elements  {sarcous  elements  or  sarcomeres),  and  embedded 
in  a  granular  material  known  as  sarcoplasm.  The  great  divergence  in  the 
aspect  of  muscular  fibres  from  different  parts  of  the  animal  kingdom  is 


THE  STRUCTURE  OF  VOLUNTARY  MUSCLE 


181 


largely  conditioned  by  the  varying  relations,  spatial  and  quantitative,  of 
the  sarcoplasm  to  the  sarcostyles.  Thus  in  the  higher  vertebrates,  two 
types   of   voluntary   muscular   fibre    are   distinguished,    according   to   the 


Fici.  37.  Transverse  sections  of  the  pectoral  muscles  of  a,  the  falcon,  h,  the  goose,  and  c, 
the  domestic  fowl.  It  will  be  noticed  that  the  relative  amount  of  granular  or  red  fibres 
present  varies  directly  as  the  bird's  power  of  sustained  flight.     (After  Knoll.) 

amount  of  sarcoplasm  they  contain  :   one  rich  in  sarcoplasm,  more  granular 

in  cross-section,  and  generally  containing  hsemoglobin  ;   and  the  other  poor 

in  sarcoplasm,  clear  in  cross-section,  and  containing  no  haemoglobin.     From 

the  fact  that  the  granular  fibres  are  B 

found  chiefly  in  those  muscles  which 

have  to  carry  out  long-continued  and 

powerful  contractions,  it  seems 

reasonable  to  regard  the  interstitial 

sarcoplasm  as  the  local  food-supply 

of  the  active    sarcostyles,  although 

some    authors    have    endowed    the 

sarcoplasm  ^^^th  a  contractile  power 

of   its    own,  differing    only    by  its 

extremely  prolonged  character  from 

the  quick  twitch  of  the    sarcostyles. 

The    connection    between   structure 

and  activity  of  the  muscle-fibres  is 

well  shown  by  Fig.  37. 


In  some  animals,  such  as  the  rabbit, 
we  find  muscles  consisting  almost  entire!}^ 
of  one  or  other  of  these  varieties  ;  but  iu 
most  animals  (amongst  which  we  may 
reckon  frog  and  man)  the  two  varieties 
occur  together  in  one  muscle,  so  that  what 
we  have  to  say  about  the  properties  of 
voluntary  muscle,  which  rests  nearly 
entirely  on  experiments  with  frog's-'^''"' 
muscle,  really  has  reference  to  a  mixed 
muscle,  i.e.  muscle  containing  both  red 
and  white  fibres. 


8 

i 


5  ,.  ■ 


38.  Fibrils  of  the  wing-muscles  of  a  wasp, 
prepared  by  Rollet's  method.  Highly 
magnified.     (E.  A.  Schafer.) 

A,  a  contracted  fibril,  b,  a  stretched 
fibril,  with  its  sarcous  elements  separated 
at  the  line  of  Hcn.sen.  c,  an  uncon- 
tracted  fibril,  showing  the  porous  struc- 
ture of  the  sarcous  elements. 


Since  the  sarcous  element  repre- 
sents   the    contractile    unit    of    the 
muscle,  a  knowledge  of   its    intimate   structure   should  be   of   great  im- 
portance for  the   theory   of   nuiscular  contraction.     Unfortunately,   how- 


182  PHYSIOLOGY 

ever,  we  are  here  at  the  hniits  of  the  demonstrably  visible.  It  becomes 
difficult  to  determine  how  far  the  appearances  observed  under  the  microscope 
are  due  to  actual  structural  differences  or  are  produced  by  the  unequal 
diffraction  of  hght  by  the  various  elements  of  the  muscle  fibre.  All 
observers  are  agreed  that  the  essential  contractile  element  is  the  row  of 
sarcous  elements  forming  the  muscle  fibril  or  sarcostyle.  Schafer,  working 
on  the  highly  differentiated  wing-muscle  of  the  wasp,  concludes  that  each 
sarcostyle  is  divided  by  Krause's  membranes  (the  hues  in  the  middle  of 
each  hght  stripe)  into  sarcomeres.  Each  sarcomere  contains  a  darker  sub- 
stance near  the  centre  divided  into  two  parts  by  Hensen's  disc.  At  each 
end  of  the  sarcomere  the  contents  are  clear  and  hyaline.  In  the  act  of 
contraction,  the  clear  material  flows,  according  to  Schafer,  into  tubular 
pores  in  the  central  dark  material. 

Most  histologists  agree  in  assigning  to  the  middle  part  of  the  sarcous 

element  (the  sarcomere)  a  denser  structure  than  to  the  two  ends.     According 

^  3  to    Macdougall,     however,     the     hghter 

appearance  at  each  end  of  the  sarcomere 

is   an   optical  illusion.      He   regards   the 

sarcous     element     as    a   cyHndrical    bag 

with  homogeneous  contents,  crossed  only 

by     one    or    three     dehcate    transverse 

Fig.  39.    Diagram  of  a  sarcomere  in   membranes.      Krause's  membrane  would 

a  moderately  extended  condition,     })q   rigid,    while     the     lateral     wall     of  the 
A,  and  in  a  contracted  condition,  B ;  ,  ,      .  ,         -i  i  i      • 

K,  K,  membranes  of  Krause;  h,    sarcous    element    IS    extensible,    and    is 
Hne  or  plane    of   Hensen ;     SE,   folded    longitudinally,    SO    that    it    can 

poriferous  sarcous  element.  ,     ,  ,  ,  ,       ,       .  , 

(Schafer.)  bulge  out  and  produce  a  shortemng  and 

thickening  of  the  whole  sarcous  element 

if  by  any  means  the  pressure  be  raised  in  its  interior.      In  favour  of  a 

differentiation  within  the  sarcomere  itself  is  the  fact  that  under  certain 

conditions  it  is  possible  to  produce  a  precipitate,  hmited  only  to  central  part, 

■i.e.  to  the  sarcous  element  to  which  Schafer  assigns  a  tubular  structure. 

When  a  muscle  fibre,  killed  by  osmic  acid  or  alcohol,  is  examined  under  the  micro- 
scope by  polarised  light,  it  is  seen  to  be  made  up  of  alternate  bands  of  singly  and  doubly 
refracting  material.  The  doubly  refracting  (anisotropous)  substance  corresponds  to 
the  dark  band,  and  the  singly  refracting  (isotropous)  to  the  light  band.  If  the  living 
fibre  be  examined  in  the  same  way,  it  is  found  that  nearly  the  whole  of  it  is  doubly 
refracting,  the  singly  refracting  substance  appearing  only  as  a  meshwork  with  long 
parallel  meshes  corresponding  to  the  muscle  prisms.  In  short,  in  a  living  fibre  the 
muscle  prisms  are  anisotropous,  the  sarcoplasm  isotropous. 

When  a  muscle  fibre  contracts,  there  is  an  apparent  reversal  of  the  situations  of  the 
light  and  dark  stripes,  owing  to  the  fact  that  the  interstitial  sarcoplasm  is  squeezed 
out  from  between  the  bulging  sarcomeres,  and  accumulates  on  each  side  of  the  mem- 
branes of  Krause.  The  accumulation  of  sarcoplasm  in  this  situation  makes  the  pre- 
viously light  striae  appear  dark,  and  the  dark  striae  by  contrast  lighter  than  they  were 
before.  That  there  is  no  true  reversal  of  the  striae  is  shown  by  examining  the  muscle 
by  polarised  light,  the  two  substances,  isotropous  and  anisotropous,  retaining  their 
relative  positions. 

Every  skeletal  muscle  is  connected  with  the  central  nervous  system 
by  nerve  fibres,  some  conveying  impressions  from  the  muscle  to  the  centre. 


THE  STRUCTURE  OF  VOLUNTARY  MUSCLE 


183 


the  others  acting  as  the  path  of  the  motor  impulses  from  the  centre  to  the 
muscle.  These  latter — the  motor  nerves — end  in  the  muscular  fibre  itself, 
by^  means  of  a  special  end-organ — the  motor  end- plate.  The  neurilemma 
of  the  nerve  fibre  becomes  continuous  with  the  sarcolemma,  the  medullary 
sheath  ends  suddenly,  while  the  axis  cyhnder  ramifies  in  a  mass  of  un- 
differentiated protoplasm,  containing  nuclei, 
and  lying  in  contact  with  the  contractile 
substance  of  the  muscle  immediately  under 
the  sarcolemma  (Fig.  -10).  This  mass  of 
protoplasm  is  known  as  the  '  sole  plate.'  It 
is  not  marked  in  all  animals.  Thus  in  the 
frog  the  axis  cylinder  ends  in  a  series  of 
branches  at  right  angles  to  one  another,  dis- 
tributed over  a  considerable  length  of  the 
muscle  fibre.  The  sole  plate  in  this  case 
seems  to  be  limited  to  scattered  nuclei  lying 
in  close  contact  with  the  terminal  branches 
of  the  nerve  fibre.  So  far  as  we  can  tell  at 
present,  the  ultimate  ramifications  of  the 
axis-cyhnder  end  freely  and  do  not  enter 
into  organic  connection  with  the  contractile 
substance  itself. 


Most  of  our  knowledge  on  the  subject  of  muscle 
has  been  derived  from  the  study  of  the  gastroc- 
nemius and  sartorius  muscles  of  the  frog.  The 
position  of  these  muscles  is  shown  in  the  accompany- 
ing diagram  (Fig.  41).  The  gastrocnemius,  which, 
with  the  attached  sciatic  nerve,  is  most  frequently 
employed  as  a  nerve-muscle  preparation,  forms  a 
thick  belly  immediately  under  the  skin  at  the  back 
of  the  leg,  and  arises  by  two  tendons  from  the  lower 
end  of  the  femur  and  the  outer  side  of  the  knee- 
joint.  The  two  tendons  converge  towards  the 
centre  of  the    muscle,    uniting    about    its   middle, 

and  from  them  a  number  of  short  muscular  fibres  arise,  passing  backwards  and 
dor.sally  to  be  inserted  into  a  fiat  aponeurosis  covering  the  lower  half  of  the  muscle, 
which  ends  in  the  tendo  Achillis.  On  account  of  this  irregular  arrangement  of  the 
muscular  fibres,  the  gastrocnemius  can  only  be  employed  when  the  contraction  of 
the  muscle  as  a  whole  is  the  object  of  investigation.  The  eft'ective  cross-area  of  the 
fibres  is  much  greater  than  the  actual  cross-section  of  the  muscle,  so  that,  while  the 
actual  shortening  of  the  gastrocnemius  is  but  small,  its  strength  of  contraction  is 
considerable. 

The  sartorius  muscle  consists  of  a  thin  band  of  muscle  fibres  running  parallel 
from  one  end  of  the  muscle  to  the  other.  It  lies  on  the  ventral  surface  of  the  thigh, 
arising  from  the  symphysis  pubis  by  a  thin  fiat  tendon,  and  is  inserted  by  a  narrow 
tendon  into  the  inner  side  of  the  head  of  the  tibia.  On  account  of  the  regularity  with 
which  its  fibres  are  disposed,  this  muscle  is  of  especial  value  in  experiments  on  the  local 
conditions  of  a  muscle  fibre  accompanying  its  activity.  When  a  greater  mass  of  ap- 
proximately parallel  fibres  is  necessary,  recourse  may  be  had  to  a  ]irei)aration  consisting 
of  the  gracilis  and  semi-membranosus  muscles  together.  This  latter  muscle  lies  dorsally 
to  the  gracilis  muscle  which  is  shown  in  the  illustration. 


if 

Fig.  40.  Motor  end-organ  of  a 
lizard,  gold  preparation.  (Kuhxe.) 
72,  nerve  fibre  dividing  as  it  ap- 
proaches the  end-organ:  r,  ramifi- 
cation of  axis  cylinder  upon  b,  gran- 
ular bed  or  sole  of  the  end-organ; 
m.  clear  substance  surrounding  the 
ramifications  of  the  axis  cylinder. 


184 


PHYSIOLOGY 


Other  muscles  in  the  frog  used  for  particular  purposes  are  the  mylohyoid  and  the 
dorsocutaneous  muscles.  The  mylohyoid  muscle  of  the  frog,  which  lies  on  the  ventral 
surface  of  the   tongue,  has  the  advantage  that  its  fibres  lie  in  close  contact  with  a 


Cruralis 
Add.  luagn.   — 


Tib.  aut.  loui 


Tendo  Achillis 


Fig.  41.     Muscles  of  hinder  extremity  of  frog.     (After  Ecker.) 


lymph-space  occupying  the  centre  of  the  tongue.  If  any  drug  be  injected  into  this 
lymph-space  it  acts  with  extreme  rapidity  on  the  muscle  fibres,  so  that  the  tongue- 
preparation  of  the  frog  is  a  useful  one  for  the  study  of  the  action  of  different  substances 
on  muscle  fibres. 


SECTION  II 

EXCITATION  OF  MUSCLE 

A  MUSCLE  may  be  caused  to  contract  in  various  ways.  Normally  it  con- 
tracts only  in  response  to  impulses  starting  in  the  central  nervous  system 
and  transmitted  down  the  nerves.  But  contraction  may  be  artificially 
excited  in  various  ways  in  a  muscle  removed  from  the  body.  If  we  make 
a  muscle-nerve  preparation  {i.e.  a  muscle  \\ath  as  long  a  piece  of  its  nerve 
as  possible  attached  to  it),  such  as  the  gastrocnemius  of  the  frog  with  the 
sciatic  nerve,  we  find  we  can  cause  contraction  by  various  forms  of  stimuli — 
mechanical,  thermal,  or  electrical — -applied  to  the  muscle  or  the  nerve 
(direct  and  indirect  stimulation).  Thus  the  muscle  responds  with  a  twitch 
if  we  pass  an  induction  shock  through  it  or  its  nerve,  or  pinch  either  with  a 
pair  of  forceps.  Or  we  may  use  chemical  stimuli,  and  cause  contraction 
by  the  application  of  strong  glycerin  or  salt  solution  to  the  nerve. 

These  experiments  do  not  prove  conclusively  that  muscle  itself  is  irritable. 
It  might  be  urged  that,  when  we  pinched  or  burnt  the  muscle  we  stimu- 
lated, not  the  muscle  substance  itself,  but  the  terminal  ramifications  of 
the  nerve  in  the  muscle,  and  that  these  in  their  turn  incited  the  muscle  to 
contract.  But  the  independent  excitability  of  muscle  is  shown  clearly  by 
the  following  experiment  by  Claude  Bernard. 

A  frog,  whose  brain  has  been  previously  destroyed,  is  pinned  on  a  board, 
and  the  sciatic  nerves  on  each  side  exposed.  A  ligature  is  then  passed 
round  the  right  thigh  underneath  the  nerve,  and  tied  tightly  so  as  effectually 
to  close  all  the  blood-vessels  supplying  the  limbs,  without  interfering 
with  the  blood-supply  to  the  nerve.  Two  drops  of  a  1  per.  cent,  solution 
of  curare  are  then  injected  into  the  dorsal  lymph-sac.  After  the  lapse  of  a 
quarter  of  an  hour  it  is  found  that  the  strongest  stimuli  may  be  applied 
to  the  left  sciatic  nerve  without  causing  any  contraction  of  the  muscles  it 
supplies.  On  the  right  side,  stinuilation  of  the  nerve  is  as  efficacious  as 
before.  Both  gastrocneniii  I'espond  readily  to  direct  stimulation,  showing 
that  the  muscles  are  not  affected  by  the  drug.  Since  both  sciatic  nerves 
have  been  exposed  to  the  influence  of  the  curare,  it  is  evident  that  the 
difference  on  the  two  sides  cannot  be  due  to  any  deleterious  effect  on  them 
by  the  curare.  We  have  also  excluded  the  nuiscles  themselves  :  so  we  nnist 
conclude  that  the  curare  paralyzes  the  nuiscles  by  affecting  the  terminations 
of  the  nerve  within  the  nuiscle.  and  probably  the  end-plates  themselves. 

185 


186 


PHYSIOLOGY 


This  experiment  teaches  us  that  muscle  can  be  excited  to  contract 
by  direct  stimulation,  even  when  the  terminal  ramifications  of  the  nerve 
within  it  are  paralyzed,  so  that  stimulation  of  them  would  be  without 
effect. 

The  same  fact  may  be  demonstrated  in  a  different  way  by  means  of 
chemical  stimuH.  It  is  found  that  whereas  strong  glycerin  excites  nerve 
fibres,  it  is  without  effect  on  muscle  fibres,  while  on  the  other  hand  weak 
ammonia  is  a  strong  excitant  for  muscle,  but  is  without  effect  on  nerve. 
If  the  frog's  sartorius  be  dissected  out  and  the  lower  end  dipped  in  glycerin, 
no  twitch  is  produced.  On  snipping  off  the  lower  third  of  the  muscle  and  then 
immersing  the  cut  end  in  glycerin,  a  twitch  at  once  occurs.  The  lower 
end  contains  no  nerve  fibres  (Fig.  42),  and  it  is 
only  when  a  section  containing  nerve-fibres  is  exposed 
to  the  action  of  glycerin  that  contraction  takes 
place.  On  the  other  hand,  mere  exposure  of  muscle 
to  the  vapour  of  dilute  ammonia  causes  con- 
traction (and  subsequent  death),  although  the 
nerve  to  the  muscle  can  be  immersed  in  the  solution 
without  any  excitation  being  produced. 

Of  all  the  different  stimuli  capable  of  exciting 
muscular  contraction,  the  electrical  is  that  most 
frequently  employed.  It  is  easy,  using  this  form, 
to  graduate  accurately  the  intensity  and  duration 
of  the  stimulus.  At  the  same  time  the  stimulus 
Fig.  42.    The  ramification  j^^^y  be  apphed  many  times  to  any  point  on  the 

oi  the  nerve  fibres  within  *^  ^^  .        "^         .  i  •        i         i 

the  sartorius  muscle  of  muscle  or  nerve  Without  kilung  the  part  stimulated, 
the  frog  showing  the  free-  whereas  with  other  forms  of  stimulus  it  is  difficult  to 

dom  oi  the  lower  portion  .  .  .... 

of  the  muscle  from  nerve  obtain    excitatory    effects    Without    injuring    to    a 
fibres.    (KuHNE.)  greater  or  less  extent  the  part  stimulated. 

METHODS  EMPLOYED  FOR  THE  STIMULATION  OF  MUSCLE  AND  NERVE. 
The  two  commonest  forms  of  electrical  stimuli  employed  are  (1)  the  make  and  break 
of  a  constant  current,  (2)  the  induction  currents  of  high  intensity  and  short  duration 
obtained  from  an  induction  coil. 

(1 )  Constant  Current.  As  a  source  of  constant  current  a  Daniell's  cell  is  generally 
employed.  This  consists  of  an  outer  pot  containing  a  saturated  solution  of  copper 
sulphate,  in  which  is  immersed  a  copper  cylinder.  To  the  cylinder  at  the  top  a  binding 
screw  is  attached,  by  which  the  connection  of  the  copper  with  a  wire  terminal  is  effected. 
Within  the  copper  cylinder  is  a  second  pot  of  porous  clay,  filled  with  dilute  sulphuric 
acid,  in  which  is  immersed  a  rod  of  amalgamated  zinc.  In  this  cell  the  zinc  is  the 
positive  and  the  copper  the  negative  element.  Hence  the  current  flows  (in  the  cell) 
from  zinc  to  copper,  and  if  the  binding  screws  of  the  two  elements  are  connected  by 
a  wire,  the  current  flows  in  the  wire  (outer  circuit)  from  copper  to  zinc,  thus  completing 
the  circuit.  Since  in  the  outer  circuit  the  current  flows  from  copper  to  zinc,  the  terminal 
attached  to  the  copper  is  called  the  positive  'pole,  and  that  to  the  zinc  the  negative 
pole.  When  the  current  is  required  to  be  very  constant,  the  zinc  may  be  immersed 
in  a  saturated  solution  of  zinc  sulphate  instead  of  dilute  sulphuric  acid.  A  Daniell's 
cell,  though  very  constant,  gives  only  a  small  current,  owing  to  its  small  electromotive 
force  and  high  internal  resistance. 

When  a  stronger  current  is  required  it  is  best  to  use  a  storage  battery.     In  this, 


EXCITATION  OF  MUSCLE  187 

when  charged,  the  two  elements  are  lead  and  lead  oxide,  PbOa-  It  has  the  advantage 
that  it  may  be  used  over  and  over  again,  being  recharged  through  a  resistance  from  the 
electrical  mains  when  it  has  run  down. 

Another  useful  type  of  cell  is  the  Leclanche  cell.  This  consists  o*  a  glass  jar  con- 
taining a  solution  of  sal-ammoniac.  Into  this  dips  an  amalgamated  rod  of  zinc,  which 
is  the  positive  plate.  A  piece  of  gas  carbon  forms  the  negative  plate.  This  is  surrounded 
by  peroxide  of  manganese  (MnOo)  which  is  kept  in  contact  with  the  surface  of  the 
carbon  by  being  placed  in  a  porous  pot.  In  some  forms  of  Leclanche  the  manganese 
and  carbon  are  ground  up  together  and  pressed  into  a  cylinder  which  surrounds  the 
zinc  rod.  When  the  cell  is  on  open  circuit — that  is,  when  the  terminals  are  not  con- 
nected and  no  current  is  passing — very  little  action  takes  place  ;  but  when  the  circuit 
is  closed  and  the  current  passes,  the  zmc  dissolves  in  the  sal-ammoniac,  forming  a  double 
chloride  of  zinc  and  ammonia,  while  ammonia  gas  and  hydrogen  are  liberated  at  the 
carbon  pole.  The  nascent  hydrogen  reduces  the  jjeroxide  of  manganese  and  so  polarisa- 
tion is  prevented.  On  account  of  its  great  solubility  in  water  the  ammonia  has  no 
polarising  action.  The  Leclanche  is  a  convenient  form  of  cell,  as  when  once  set  up  it 
requires  a  minimum  of  attention.  If  it  is  worked  through  a  considerable  resistance, 
it  will  keep  in  order  for  some  time,  particularly  if  the  work  is  intermittent  ;  but  if  it  is 
used  with  a  small  resistance  in  cu'cuit  it  polarises  very  rapidly.  The  E.M.F.  of  one 
Leclanche  cell  is  1-4  volt  in  the  external  circuit.  The  positive  current  is  conventionally 
said  to  run  from  the  zinc  to  the  carbon  in  the  cell,  and  from  the  carbon  to  the  zinc 
in  the  circuit  outside.  The  wire  attached  to  the  carbon  is  the  positive  pole,  that  to  the 
zinc  the  negative  pole.  Dry  cells  are  usually  Leclanche  cells,  in  which  the  solution  of 
sal-ammoniac  is  prevented  from  spilling  by  absorption  with  sawdust  or  plaster  of 
Paris.  The  E.M.F.  is  the  same  as  the  Leclanche,  but  they  polarise  much  more 
readily. 

If  the  poles  of  a  Darnell's  cell  be  connected  by  \vires  with  a  nerve  or  muscle  of  a 
nerve-muscle  preparation  (as  in  Fig.  43),  the  ciu-rent  will  flow  from  copper  to  the  nerve 
at  A,  and  along  the  nerve  from  a  to  k. 
At  K  the  current  will  leave  the  nerve  to 
flow  to  the  zinc  of  the  battery,  so  com- 
])leting  the  circuit.  The  point  at  which 
the  current  enters  the  nerve  {i.e.  the 
point  of  the  nerve  connected  with  the 
positive  pole  of  the  battery)  is  called  the 
anode,  and  the  point  at  which  the  current 
leaves  the  nerve  is  called  the  cathode.  The 
wires  by  which  the  current  is  conducted 

to  and  from  the  nerve  are  called  the  electrodes.  As  electrodes  we  generally  employ 
two  platinum  wires  mounted  together  on  a  piece  of  Aiilcanite. 

For  the  purpose  of  making  or  breaking  the  current  at  will,  various  forms  of  keys 
are  employed.  The  ordinary  make  and  break  key  consists  of  a  hinged  wire  dipping 
into  a  mercury  cup.  When  the  wire  is  depressed  so  that  it  dips  into  the  mercury, 
the  circuit  is  complete.  On  raising  the  wire  by  means  of  the  handle,  the  circuit  is 
broken. 

Du  Bois  Reymond's  key  consists  of  two  pieces  of  brass,  each  of  which  has  two 
l)iiKling  screws  for  the  attachment  of  wires.  These  are  connected  by  a  third  piece,  or 
bridge,  which  is  jointed  to  one  of  the  two  side  bits,  so  that  it  may  be  raised  or  lowered 
at  pleasure  {v.  Fig.  44).  It  may  be  used  either  as  a  simple  make-and-brcak  key.  or. 
as  is  more  usual,  as  a  short-circuiting  key.  In  the  first  case  one  brass  bank  is  attached 
to  one  terminal,  the  other  to  the  other  terminal.  If  the  bridge  be  now  lowered,  the 
connection  is  made  and  the  current  passes.  If  the  bridge  be  raised,  the  current  is 
broken.  Fig.  44  A  and  B  show  the  way  in  which  the  key  is  arranged  for  short-circuiting. 
It  will  be  seen  tliat  four  wires  are  attached  to  the  key  ;  two  going  (o  the  l)at(ery,  and 
two  we  may  suppose  going  to  a  nerve.  When  the  bridge  is  down,  as  in  Fig  44  a,  the 
current  from  the  cell  on  coming  to  the  key  has  a  choice  of  two  routes.  It  may  either 
go  through  the  brass  bridge,  or  through  the  other  wii-es  and  nerve.     The  resistance  of 


J  Ntrc/e. 


188 


PHYSIOLOGY 


the  nerve  however  is  about  100,000  ohms,  whereas  that  of  the  bridge  is  not  the  thousandth 
part  of  an  ohm.  When  a  current  divides,  the  amount  of  current  that  goes  along  any 
branch  is  inversely  proportional  to  the  resistance.  Here  the  resistance  in  the  nerve- 
circuit  is  practically  infinite  compared  with  that  in  the  brass  bridge,  and  so  all  the 


Fig.  44.     Du  Bois  key,  closed.     Du  Bois  key,  open. 

current  goes  through  the  bridge  and  none  through  the  nerve.     We  say  then  that  the 
current  is  short-circuited. 

It  is  often  necessary  to  reverse  the  direction  of  a  current  through  a  nerve-muscle 
preparation  or  a  galvanometer  in  the  course  of  an  experiment.  For  this  purpose 
Pohl's  reverser  may  be  used.  It  consists  of  a  slab  of  ebonite  or  paraffin  or  other  in- 
sulating material,  in  which  are  six  small  holes  filled  with  mercury.  A  binding  screw  is 
in  connection  with  the  mercury  in  each  of  these  holes.  Two  cross-wires  (not  in  contact 
with  one  another)  join  two  sets  of  pools  together,  as  shown  in  Fig.  45.  A  cradle  con- 
sisting of  two  wires  joined  by  an  insulating  handle  carries  two  arcs  of  wire  by  which 
the'pools  at  a  and  h  may  bs  put  into  connection  with  either  x  and  y,  or  the  corresponding 

pools  on  the  opposite  side.  It  will  be  seen 
that  with  the  cradle  tipped  to  one  side,  as  in 
Fig.  45  A,  the  current  from  the  battery  enters 
the  reverser  at  a  ;  this  proceeds  up  the  wire 
of  the  cradle,  down  towards  the  right,  then 
along  the  cross-wire  to  the  pool  at  x.  x  is 
therefore  the  anode,  and  y  the  cathode.  In 
Fig.  45  B  the  cradle  has  been  swung  over  to 
the  other  side.  Here  the  cross-wires  are  not 
used  at  all  by  the  current,  which  passes  from  a 
up  the  sides  and  down  the  curved  wire  to  y. 
In  this  case  y  is  now  the  anode  and  x  the 
cathode,  and  the  direction  of  the  current 
through  the  circuit  connected  with  x  and  y  is 
reversed.  By  taking  out  the  cross-wires, 
Pohl's  reverser  may  be  used  as  a  simple 
switch,  by  which  the  current  may  be  led  into 
two  different  circuits  in  turn. 

With  this  form  of  reverser  difficulty  is  often 
experienced  owing  to  dirt  accumulating  on  the 
mercury  and  forming  an  insulating  layer  be- 
tween it  and  the  binding  screw  or  copper 
wire.  Several  improved  forms  of  reverser  are 
now  made  where  the  mercury  poles  are  replaced  by  brass  banks,  and  these  are  gene- 
rally to  be  preferred  in  practice. 

(2)  Induced  Currents.  In  using  these  the  muscle  or  nerve  is  stimulated  by  the 
current  of  momentary  duration  produced  in  the  secondary  circuit  of  an  induction-coil 
by  the  make  or  break  of  a  constant  current  in  the  primary. 

The  construction  of  the  induction-coil  or  inductorium  is  founded  on  the  fact  that  if 
a  coil  of  wire  in  connection  with  a  galvanometer  be  placed  close  to  (but  insulated  from) 


Diagram  of  Pohl's  reverser. 


EXCITATION  OF  MUSCLE 


189 


Fig.  46.  Diagram  of  inductoiium.  r^.  primary  ; 
Rg,  secomlary  coil,  tn,  electro- magnet  of  Wagner's 
hammer,     w,  Helmholtz'.s  side  wire. 


another  coil  through  which  a  current  may  be  led  from  a  battery,  it  is  found  that  on 
make  and  break  of  the  current  of  the  second  coil  a  momentary  current  is  induced  in  the 
first.  The  induced  current  on  make  is  in  the  reverse  direction,  that  on  break  in  the 
same  direction  as  the  primary  current.  The  electromotive  force  of  the  induced  current 
is  proportional  to  the  number  of  turns  of  wire  in  the  coils.  The  induction-coil  consists 
of  two  coils,  each  containing  many 
turns  of  wire.  The  smaller  coil  (r^. 
Fig.  46),  consisting  of  a  few  turns  of 
comparatively  thick  wire,  is  the 
primary  coil,  and  is  put  into  connec- 
tion with  a  battery.  It  has  within 
it  a  core  of  soft  iron  wires,  which 
has  the  effect  of  attracting  the 
lines  of  force,  concentrating  them, 
and  so  increasing  its  power  of  in- 
ducing secondary  currents.  The 
secondary  coil,  R2,  of  a  large 
number  of  turns  of  very  thin  wire, 
is  arranged  so  as  to  slide  over  the 
primary  coil.  It  is  provided  with 
two  terminals,  which  may  be  con- 
nected with  the  nerve  or  other 
tissue  that  we  wish  to  stimulate. 
Since  the  electromotive  force  of 
the  induced  current  is  proportional 

to  the  number  of  turns  of  wire,  it  is  evident  that  the  electromotive  force  of  the 
current  delivered  by  the  induction  coil  may  be  many  thousand  times  that  of  the 
battery  current  flowing  through  the  primary  coil.  The  induced  currents  increase 
rapidly  in  strength  as  the  coils  are  approached  to  one  another  ;  the  strength  of 
these  therefore  may  be  regulated  by  shoving  the  secondary  up  to  or  away  from  the 
primary  coil. 

A  short-cu'cuiting  key  is  always  placed  between  the  secondary  coil  and  the  nerve 
to  be  stimulated.  If  only  single  induction  shocks  are  to  be  used,  a  make-and-break 
key  is  put  in  the  primary  battei'y  circuit,  and  the  two  wires  from  the  battery  and  key 
are  attached  to  the  two  top  screws  of  the  primary  coil  {c  and  d.  Fig.  46).  It  is  then 
found  that  the  shock  given  by  the  induced  current  on  break  of  the  primary  current  is 
much  stronger  than  that  on  make. 

In  endeavouring  to  explain  this  difference  in  the  intensity  of  the  make-and-break 
induction  shocks,  it  must  be  remembered  that  the  intensity  of  the  momentary  current 
induced  in  the  secondary  coil  at  make  or  break  of  the  primary  current  is  proportional 
(I )  to  the  number  of  turns  of  wire  in  each  coil ;  (2)  inversely  to  the  mean  distance  between 
the  coils  {i.e.  the  nearer  the  coils,  the  stronger  the  induced  current)  ;  (3)  to  the  rate  of 
change  in  strength  of  the  primary  current.  Now,  when  a  current  is  made  through  the 
primary  coil,  induction  takes  place,  not  only  between  primarj'  and  secondary  coils, 
but  also  between  the  individual  turns  of  the  primary  coil  itself.  This  current  of  self- 
induction,  being  opposed  in  direction  to  the  battery  current,  hinders  and  delaj's  the 
attainment  by  the  latter  of  its  full  strength,  and  so  slows  the  rate  of  change  of  current 
in  the  primary  coil.  Hence  the  intensity  of  the  momentary  current  induced  in  the 
secondary  coil  is  less  than  it  would  have  been  without  the  retarding  effect  of  self-induc- 
tion. At  break  of  the  current,  an  extra  current  is  also  produced  in  the  primary  coil 
in  the  same  direction  as  the  battery  current,  and  therefore  tending  to  reduce  the  rate 
of  change  of  the  current  from  full  strength  to  nothing.  In  this  case,  however,  the 
primary  circuit  being  broken,  the  current  of  self-induction  cannot  pass  without  jumping 
the  great  resistance  offered  by  the  air,  so  that  its  retarding  effect  on  the  rate  of  dis- 
appearance of  the  primary  current  may  be  practically  disregarded.  In  Fig  47  the  line. 
a,  b,  c,  d,  will  represent  the  changes  occurring  in  the  jirimary  current  at  make  and 
break,  a  b  corresponding  to  the  make  and  c  d  to  the  break.     The  lower  Hup  represents 


190 


PHYSIOLOGY 


the  momentary  currents  induced  in  the  secondary  circuit,  m  being  the  current  of  low 
intensity  and  long  duration  produced  by  the  make,  and  b  the  shock  of  high  intensity 
and  short  duration  caused  by  the  sharjj  break  of  the  primary  current. 

When  we  desire  to  use  faradic  stimulation — that  is,  secondary  induced  shocks 
rapidly  repeated  50  to  100  times  a  second — we  make  use  of  the  apparatus  attached 

to  the  coil,  known  as  Wagner's 
hammer  (Figs.  48a  and  48b). 
In  this  case  the  wires  from  the 
battery  are  connected  to  the 
two  lower  screws  (o  and  h.  Fig. 
46).  Fig.  48a  shows  the  direc- 
tion of  the  current  when  Wag- 
ner's hammer  is  used.  The  cur- 
rent enters  at  a,  runs  up  the 
pillar  and  along  the  spring  to  the 
screw  X.  Here  it  passes  up 
through  the  screw,  and  through 
the  primary  coil  Kj^.  From  the 
primary  coil  it  passes  up  the 
small  coil  m,  and  from  this  to 
the  terminal  b  and  back  to  the 
battery.  But  in  this  course 
the  coil  m  is  converted  into  an 
electro-magnet.  The  hammer  h 
attached  to  the  spring  is  attracted  down,  and  so  the  spring  is  drawn  away  from  the 
screw  X,  and  the  current  is  therefore  broken.  The  break  of  the  current  destroys  the 
magnetic  power  of  the  coil,  the  spring  jumps  up  again  and  once  more  makes  circuit 
with  the  screw  x,  only  to  be  drawn  down  again  directly  this  occurs.  In  this  way  the 
spring  is  kept  vibrating,  and  the  primary  circuit  is  continually  made  and  broken,  with 
the  production  at  each  make-and-break  of  an  induced  current  in  the  secondary  coil. 

It  is  evident  that,  when  the  primary  current  is  made  and  broken  fifty  times  in  the 
second,  there  will  be  a  hundred  momentary  currents  produced  during  the  same  period 
in  the  secondary  coil.     Every  alternate  one  of  these  produced  by  the  break  of  current 


<C^ 


Fig.  47. 


Fig.  48a.  Diagram  showing  course  of 
current  in  inductorium  when  Wagner's 
hammer  is  used. 


Fig.  48b.  Diagram  showing  course  of 
current  when  the  Helmholtz  side  wire 
is  used. 


in  the  primary  will  be  much  stronger  than  the  intervening  currents  produced  by  the 
make.  In  order  to  equalise  make  and  break  induction-shocks,  so  that  a  regular  series 
of  momentary  currents  of  nearly  equal  intensity  may  be  produced,  the  arrangement 
known  as  Helmholtz's  is  used.  In  this  arrangement  the  side  wire  w,  shown  in  Fig. 
46,  and  diagrammatically  in  Fig.  48b,  is  used  to  connect  the  binding  screw  o  with  the 
binding  screw  c  at  the  top  of  the  coil.  The  screw  x  is  raised,  so  as  not  to  touch  the 
spring,  and  the  lower  screw  y  is  moved  up  till  it  comes  nearly  in  contact  with  the  under 


EXCITATION  OF  MUSCLE 


191 


surface  of  the  spring.  If  we  consider  the  direction  of  the  current  now,  we  see  that 
it  enters  as  before  at  the  terminal,  travels  up  the  Helmholtz  wire  tv  to  the  screw  c, 
thence  through  the  primary  coil  Ri,  then  through  the  coil  m  of  the  Wagner's  hammer, 
and  so  back  to  the  battery.  The  coil  m,  thus  becoming  an  electro-magnet,  draws 
down  the  hammer  h.  In  this  act  the  under  surface  of  the  spring  comes  in  contact  with 
the  screw  y.  The  current  then  has  a  choice  of  two  ways.  It  may  either  go  through 
the  coil  as  before,  or  take  a  short  cut  from  the  terminal  a,  up  the  pillar,  along  the 
spring,  through  the  screw  y,  and  down  to  the  terminal  h  back  to  the  battery.  As 
the  resistance  of  this  latter  route  is  very  small  compared  with  the  resistance  of  the 
primary  coil,  &c.,  the  greater  part  of  the  current  takes  this  way.  The  infinitesimal 
current  which  now  passes  through  the  coil  of  Wagner's  arrangement  is  insufficient  to 
magnetise  this,  and  the  hammer  springs  up  again  ;  thus  the  process  is  restarted,  and  the 
spring  vibrates  rhythmically.  With  this  arrangement  the  primary  current  is  never 
broken,  but  only  short-cii'cuited,  and  so  diminished  very  largely.  Hence  the  retarding 
influence  of  self-induction  is  as  potent  with  break  as  with  make  of  the  current,  and  the 
effects  on  the  secondary  coil  in  the  two  cases  are  approximately  equal.  In  Fig.  47  ce 
represents  the  change  in  the  primary  current  when  the  current  is  short-circuited  instead 
of  being  broken,  and  b  represents  the  effect  produced  in  the  secondary  coil.  It  will  be 
seen  that  the  currents  m  and  b  are  practically  identical  in  intensity  and  duration. 

When  the  induction-coil  is  used  for  stimulating,  it  is  usual  to  graduate  the  strength 
of  the  shock  administered  to  the  excitable  tissue  by  moving  the  secondary  coil  nearer 
to  or  further  away  from  the  primary  coil.  It  must  be  remembered  that  the  strength 
of  the  induced  current  does  not  vary  in  numerical  proportion  with  the  distance  of  the 
two  coils  from  one  another.  If  one  coil  is  some  distance,  say,  20  cms.  from  the  primary 
coil,  the  induced  current  produced  by  make  or  break  of  the  primary  current  is  very 
small,  and  on  moving  the  secondary  from  20  up  to  10  cms.  the  increase  in  strength  of 
the  current  will  not  be  very  rapid.  The  increase  will  however  become  more  and  more 
rapid  as  the  two  coils  are  brought  closer  together.  Using  the  same  strength  of  current 
in  the  primary  coil  and  the  same  resistance  in  the  secondary  coil,  we  can  say  that  the 
make  or  break  current  will  be  uniform  so  long  as  the  distance  of  the  coils  remains 
constant.  We  are  not  able,  however,  to  say  by  how  much  the  current  will  increase 
as  the  secondary  coil  is  moved,  say,  from  11  to  10  cms.  distant  from  the  primary  coil. 
If  it  is  required  to  know  the  exact  increment  in  the  exciting  current  which  is  used,  it 
is  necessary  to  graduate  the  induction-coil  by  sending  the  induction  shocks,  obtained 
at  different  distances  of  secondary  from  primary  cod,  through  a  ballistic  galvanometer. 

Another  method  which  may  be  adopted  for  the  excitation  of  muscle  or  nerve  is  the 
discharge  of  a  condenser.  The  advantage  of  this  method  is  that  we  can  determine 
not  only  the  amount  of  electricity  discharged  through 
the  preparation,  but  the  actual  energy  employed.  If 
two  plates  of  metal  separated  from  one  another  by  a 
thin  insulating  layer  of  dielectric  such  as  air,  glass,  mica, 
or  paraffined  paper,  be  connected  with  the  two  poles  of  a 
battery,  each  plate  acquires  the  potential  of  the  pole  of 
the  battery  with  which  it  is  comiected,  and  receives 
therefrom  a  charge  of  electricity  (positive  or  negative). 
If  the  connections  be  broken  the  two  plates  retain 
their  charge.  If  now  they  be  connected  by  a  wire  they 
discharge  through  the  wire,  and  if  a  nerve  be  inserted  in 
the  course  of  the  wire,  it  may  be  excited  by  the  discharge. 

The  amount  of  electricity,  that  may  be  stored  up  in 
this  way,  will  depend  on  the  extent  of  the  plates  and 
their  proximity  to  one  another,  as  well  as  on  the  e.m.f.    Fig.    49.      Diagram   to  show 
of  the  charging  battery.     In  order  to  get  great  extent       the  mode  of  construction  of 
of  surface,  a  condenser  is  built  up,  as   in  the  diagram       "  '"'^"*^  cn&er. 
(Fig.  49),  of  a  very  large  number  of  plates  of  tinfoil. 

separated  by  discs  of  mica  or  paraffined   iiaper.     Alternate  discs  are  comiected  to- 
gether :  thus,  1,  3,  5  are  coimected  to  one  pole,  while  2.  4,  0  are  connected  to  the  other. 


192  PHYSIOLOGY 

The  rheocord  is  used  to  modify  the  amount  or  strength  of  current  flowing  through 
a  preparation.  One  form  of  it  is  represented  in  Fig.  50.  A  constant  source  of  current 
at  B  causes  a  flow  of  electricity  from  a  to  6  through  a  straight  wire.  As  the  resistance 
of  this  wire  is  the  same  throughout  its  length,  the  fall  of  potential  from  a  to  6  must 
be  constant.  The  nerve,  or  whatever  preparation  is  used,  is  connected  with  the 
straight  wu'e  at  two  points,  at  a  and  at'c,  by  means  of  a  sliding  contact  or  rider.  Sup- 
posing that  there  is  an  electromotive  difference  of  one  volt  between  a  and  b,  it  is  evident 
that  if  c  is  pushed  close  to  b,  the  e.m.f.  acting  on  the  nerve  will  be  also  one  volt.  The 
E.M.F.,  however,  may  be  made  as  small  as  we  like  by  sliding  c  nearer  to  a.     Thus  if 

ab  is  one  metre,  and  there  is  a  difference 
B  of  one  volt  between  the  two  ends,  then 

if  c  be  one  centimetre  from  a,  the  E.M.r. 

acting  on  the   nerve   will  be    Yho  '^olt. 

Thus  we  alter  the  current  passing  through 

the  nerve   by   altering   the  e.m.f.  which 

drives  the  current. 

If  a  weak  current  from  a  Daniell's 
cell  (or  any  other  form  of  battery) 
be  passed  through  a  muscle  or  any 
part  of  its  nerve,  at  the  make  of  the 
current  the  muscle  gives  a  single 
sharp  contraction — a  muscle-twitch.  In  this  contraction  the  whole  of 
the  muscle  fibres  may  be  involved.  During  the  passage  of  the  current 
no  effect  is  apparently  produced  and  the  muscle  seems  to  be  quiescent, 
though  on  careful  observation  we  may  see  that  there  is  a  state  of  con- 
tinued contraction  hmited  to  the  immediate  neighbourhood  of  the  cathode, 
which  lasts  as  long  as  the  current  is  passing  through  the  muscle,  and 
is  not  propagated  to  the  rest  of  the  muscle.  If  the  current  be  now 
broken,  the  muscle  may  remain  quiescent.  If  however  the  current  is  above 
a  certain  strength,  the  muscle  responds  to  the  break  of  the  current  with 
another  single  rapid  contraction.  With  a  current  of  moderate  strength  we 
may  get  a  contraction  both  at  make  and  break  of  the  current,  but  the  make- 
contraction  may  be  stronger  than  the  break-contraction.  Thus  stimulation 
is  caused  by  the  make  and  break  of  a  constant  current,  the  make-stimulus 
being  more  effective  than  the  break-stimulus.  If  the  duration  of  the  passage 
of  the  current  is  sufficiently  short,  no  contraction  is  produced  at  the  break 
of  the  current,  however  strong  this  may  be.  The  same  phenomenon  of  a 
single  twitch  may  be  evoked  by  the  passage  of  an  induction  shock.  This 
is  the  current  of  momentary  duration  produced  in  the  second  circuit  of 
an  induction-coil  by  the  make  or  break  of  a  constant  current  in  the  primary. 
Using  this  mode  of  stimulus,  it  is  found  that  the  contraction  on  break  of 
the  primary  current  is  much  stronger  than  that  on  make.  It  must  not 
be  imagined,  however,  that  there  is  any  contradiction  between  this  and  the 
fact  that  the  make  of  a  constant  current  is  a  stronger  stimulus  than  the  break. 
When  we  put  a  muscle  in  the  secondary  circuit  and  make  a  current  in  the 
primary,  there  is  a  current  of  momentary  duration  induced  in  the  secondary, 
so  that  there  is  a  current  made  and  broken  through  the  muscle ;  and  the 
same  thing  takes  place  again  when  the  primary  circuit  is  broken.  It  has 
been  shown  that,  when  we  use  currents  of  such  short  duration,  the  break 


EXCITATION  OF  MUSCLE  193 

stimulus  is  ineffective  ;  so  in  both  cases,  whether  we  make  or  break  the 
current  in  the  primary  circuit,  we  are  deahng  with  a  make  stimulus  in  the 
muscle.  The  difference  in  the  efficacy  of  make  and  break  induction  shocks 
is  purely  physical,  and  depends  on  the  fact  that  the  current  induced  in  the 
secondary  coil  on  make  is  of  slower  rise  and  smaller  potential  than  that 
produced  at  break. 

In  using  either  of  these  modes  of  stimulation  we  find  that  there  is  a  certain  intensity 
which  the  stimulating  current  must  possess  in  order  that  any  effect  shall  be  produced. 
Any  strength  of  stimulus  below  this  is  known  as  a  subminimal  stimulus.  A  m,inimal 
stimulus  (sometimes  known  as  liminal  or  thresltold  stimulus)  is  the  weakest  stimulus 
that  will  produce  any  result,  i.e.  in  muscle,  a  contraction.  A  maximal  stimulus  is 
one  that  produces  the  strongest  contraction  a  muscle  is  capable  of  under  the  effects 
of  a  single  stimulus.  A  suhmaximxil  stimulus  is  any  strength  of  stimulus  between  these 
two  extremes. 


SECTION  III 

THE  MECHANICAL  CHANGES  THAT   A  MUSCLE 
UNDERGOES  WHEN  IT  CONTRACTS 

If  a  skeletal  muscle,  such  as  the  gastrocnemius,  be  stimulated  either  directly 
or  by  the  intermediation  of  its  nerve  by  any  of  the  means  mentioned  in  the 
foregoing  chapter,  it  responds  by  a  single  short  sharp  contraction,  followed 
immediately  by  a  relaxation.  The  volume  of  the  muscle  does  not  alter  in  the 
shghtest  degree,  but  each  muscle-fibre  and  the  whole  muscle  become  shorter 
and  thicker.  At  the  same  time,  if  a  weight  be  tied  on  to  the  tendon  of  the 
muscle,  the  muscle  during  contraction  may  raise  the  weight  and  thus  perform 
mechanical  work.  In  order  to  determine  the  time  relations  of  the  simple 
muscle  contraction  or  the  muscle-twitch,  and  to  study  its  conditions,  it  is 
necessary  to  employ  the  graphic  method,  so  as  to  obtain  a  record  of  the 
changes  in  shape  of  the  muscle  during  contraction.  We  may  use  the  graphic 
method  either  for  recording  the  changes  in  shape  or  for  registering  changes  in 
tension  of  a  muscle  which  is  prevented  from  contracting. 

In  order  to  record  the  contraction  of  the  frog's  gastrocnemius,  the  muscle  is  excised 
together  with  a  portion  of  the  femur  to  which  it  is  attached,  and  the  whole  length 
of  the  sciatic  nerve  from  its  origin  in  the  spinal  canal  to  its  insertion  into  the  muscle. 
The  femur,  to  which  the  gastrocnemius  is  attached,  is  clamped  firmly,  and  the 
tendo  AchUlis  attached  by  a  thread  to  a  light  lever,  free  to  move  round  an  axis  at  one 
end.  The  point  of  this  lever  is  armed  with  a  bristle  (anything  that  is  stiff  and  pointed 
will  do),  which  just  touches  the  blackened  surface  of  a  piece  of  glazed  paper.  This 
paper  is  stretched  round  a  cylinder  (drum)  which  can  be  made  to  rotate  at  any  constant 
speed  required.  If  the  drum  is  moving,  the  point  of  the  bristle  draws  a  horizontal 
white  line  on  the  smoked  paper. 

If  a  single  induction  shock  be  sent  through  the  nerve  of  the  preparation  the  lever 
is  jerked  up,  falling  again  almost  directly,  and  a  curve  is  drawn  like  that  shown  in 
Fig.  52.     A  similar  curve  is  obtained  if  the  muscle  be  stimulated  directly. 

In  all  such  graphic  records  we  should  have  also — 

(1 )  ^  time  record.  This  is  furnished  by  means  of  a  small  electro-magnet,  armed  with 
a  pointed  lever  writing  on  the  smoked  surface.  This  electro-magnet  (time  marker  or 
signal)  is  made  to  vibrate  100  times  a  second  (more  or  less  as  may  be  required)  by 
putting  it  in  a  circuit  which  is  made  and  broken  100  times  a  second  by  means  of  a 
tuning-fork  vibrating  at  that  rate.  The  tuning-fork  is  maintained  in  vibration  in  the 
same  way  as  the  Wagner's  hammer  of  an  induction-coil. 

(2)  A  record  of  the  exact  point  at  which  the  nerve  or  muscle  is  stimulated.  This  may 
be  obtained  in  two  ways  : 

(a)  When  using  the  psndulum  or  trigger  myograph,  in  both  of  which  the  recording 
surface  is  a  smoked  flat  surface  on  a  glass  plate,  this  latter  is  so  arranged  that  it  knocks 

194 


THE  MECHANICAL  CHANGES  OF  MUSCLE 


195 


over  a  key  as  it  shoots  across,  and  so  breaks  the  primary  cu-cuit  and  excites  the  nerve 
or  muscle  of  the  preparation.  As  we  know  the  exact  point  that  the  plate  reaches 
when  it  knocks  over  the  key,  we  can  mark  on  the  contraction  curve  the  exact  moment 
at  which  stimuhition  took  place. 

(b)  If  we  wish  to  make  and  break  the  primary  circuit  at  will  by  means  of  a  key,  a 
small  electro-magnetic  signal,  interposed  in  the  circuit,  is  arranged  to  \vrite  on  the 
revolving  drum,  and  so  mark  the  j)oint  of  stimulation. 


Fig.  51.     Arrangement  of  apparatus  for  recording  simple  muscle-twitch. 

In  the  figure  (Fig.  52)  the  upper  line  is  the  curve  drawn  by  the  lever  of  the  muscle 
as  it  contracts  ;  the  small  upright  line  shows  the  point  at  which  the  muscle  was  stimu- 
lated ;  and  the  second  line  is  the  tracing  of  the  chronograph,  every  vibration  representing 
^1 J  of  a  second. 

In  the  pendulum  myograph  (Fig.  53)  a  smoked  glass  plate  is  carried  on  a  heavy 
iron  pendulum.  At  each  side  the  pendulum  is  armed  with  a  catch,  which  tits  on  to 
other  catches  at  the  side  of  the  triangular  box,  from  the  apex  of  which  the  pendulum 


Flo.  52.      Curve  of  single  jniisele-twitch  taken  on  a  rapidly  moving  surface 
(pendulum  myograph).     (Yeo.) 


is  suspanded.  At  its  lower  part  the  pendulum  carries  a  projecting  piece  which  can 
knock  over  the  '  kick-over '  key  K,  thus  breaking  a  circuit  in  which  is  included  the 
primary  coil  of  an  induction-coil.  The  lever  attached  to  the  muscle  is  arranged  so  as 
to  write  lightly  on  the  glass  plate.  Everything  being  ready,  and  the  key  k  closed,  the 
pendulum  is  raised  to  a,  the  catch  a  is  then  released,  and  the  pendulum  falls  at  an 
ever-accelerating  rate  and  then  rises  again,  gradually  slowing  off  until  it  is  caught 
again  at  b.  As  it  passes  by  the  key  it  breaks  the  circuit.  A  break  induction  shock 
is  sent  into  the  muscle  or  nerve,  which  contracts,  and  a  curve  is  obtained  similar  to  that 
shown  in  Fig.  52.  Since  the  rate  of  the  pendulum  is  constantly  varying  throughout  its 
course,  it  is  necessary  to  have  a  tuning-fork,  or  time-marker  actuated  electrically  by  a 
tuning-fork,  writing  just  below  the  muscle-lever. 

In  the  spring  myograjih,  otherwise  known  as  the  trigger  or  sliooter  myograph 
(Fig.  54),  a  smoked  glass  plate  is  also  iised.  "  The  frame  supiK)rting  the  glass  plate 
slides  on  two  horizontal  steel  wires.  To  make  the  instrument  ready  for  use.  the  frame 
is  moved  to  one  side,  which  compresses  a  short  spring.  When  the  catch  holding  it  in 
this  position  is  released  by  the  trigger,  the  spring,  which  only  acts  for  a  short  space, 


196 


PHYSIOLOGY 


gives  the  frame  and  the  glass  plate  a  rapid  horizontal  motion  ;   and  the  momentum 
carries  the  glass  plate  through  the  rest  of  the  distance,  till  stopped  by  the  buffers.     The 


Fig.  53.     Simple  form  of  pendulum  myograph. 

velocity  durmg  this  time  is  nearly  constant,  as  the  friction  of  the  guides  is  small.  Two 
keys  are  knocked  over  by  pins  on  the  frame  and  break  electric  circuits.  The  relative 
positions  at  which  the  circuits  are  broken  can  be  altered  by  a  convenient  adjustment. 


Fig.  54.     Diagram  of  spring  myograph,  or  '  shooter.' 

A  tuning-fork  vibrating  about  100  per  second  fixed  to  the  base'of  the  instrument  marks 
the  time  ;  its  prongs  are  sprung  apart  by  a  block  between  their  ends,  and  the  same 
action  which  releases  the  glass  plate  also  frees  the  fork  by  removing  the  block  and  allows 
it  to  vibrate  ;  a  writing  style  then  draws  a  sinuous  line  on  the  smoked  surface  of  the 
moving  glass  plate.  A  muscle  lever  with  a  scale-pan  attached  also  forms  part  of  the 
instrument." 

The  record  obtained  in  either  of  these  ways  may,  in  consequence  of  instrumental 


THE  MECHANICAL  CHANGES  OF  MUSCLE 


197 


inertia,  be  a  very  inaccurate  reproduction  of  the  true  events  occurring  in  the  muscle 
itself.  When  the  muscle  begins  to  contract  it  imparts  a  very  rapid  movement  to  the 
lever,  which  therefore  tends  to  overshoot  the  mark  and  deform  the  curve.  This  source 
of  error  may  be  almost  avoided  by  making  the  lever  as  light  as  possible,  and  hanging  the 
extending  weight  in  close  proximity  tothe  axle  of  the  lever,  as  shown  in  Fig.  55.  Since 
the  energy  of  a  moving  mass  is  proportional  to  the  square  of  the  velocity  (=  }rmv^,) 
and  the  tension  due  to  the  weight  as  well  as  the  velocity  on  contraction  is  directly 
proportional  to  the  distance  of  the  weight  from  the  axis,  it  follows  that  it  is  better  to 


r 


Cl— ' 


Fig.  .55.  Blix  apparatus  for  recording  isometric  and  isotonic  curves  synchronically.  (^Iiss 
BucHANAJf.)  p,  the  steel  cyUndrical  supi^ort  with  jointed  steel  arm  to  bear  the  isotonic 
lever  I,  which  consists  of  a  strip  of  bamboo  with  an  aluminium  tip.  t,  the  isometric 
lever,  also  of  bamboo,  except  for  a  short  metal  part  t',  in  which  are  holes  for  fixing  the 
muscle.  The  two  wires  from  an  induction  coil  are  brought,  one  to  x  ,  which  is  in  con- 
nection with  the  support  and  hence  with  the  metal  bar  t',  the  other  to  y.  which  is  insulated 
from  the  support  but  connected  by  a  copper  wire  with  a  thin  piece  of  copper  surrounding 
the  isotonic  lever  at  the  point  where  the  muscle  is  attached  to  it.  CI,  clamp  for  fixing 
the  lower  end  of  the  muscle  when  an  isometric  curve  is  to  be  taken.  The  axis  of  the 
isotonic  lever  is  at  x,  close  to  which  is  hung  the  weight  of  50  grm. 


load  the  muscle  with  40  grams  1  millimetre  from  the  axis  than  with  1  gram  40  milli- 
metres from  the  axis,  though  the  tension  put  on  the  muscle  will  be  the  same  in  both 
cases. 

In    the    first    case    the    energy    of    the    moving    mass    will    be    proportional    to 

40  X  (1)'  1  X  (-10)'  ^^  ,  .  .  ,  .  ,.•  u  J  . 
^ =  20,  and  in  the  second  to  r^ =  800'  and  it  is  this  energy  which  deter- 
mines the  overshooting  of  the  lever  and  the  deformation  of  the  curve.  Since  throughout 
the  contraction  in  the  latter  arrangement  the  lever  follows  the  muscle  in  its  movement, 
the  tension  on  the  muscle  remains  the  same  throughout,  and  the  method  is  therefore 
known  as  the  isotonic  method. 

It  is  of  importance  to  be  able  to  record  the  development  of  the  energy  (i.e.  the  tension) 
of  the  active  muscle  apart  from  any  changes  in  its  length.  For  tliis  purpose  the  muscle 
is  allowed  to  contract  against  a  strong  spring,  the  movements  of  which  are  magnified 
by  means  of  a  very  long  lever.  Thus  the  shortening  of  the  muscle  is  almost  entirely 
prevented,  but  the  increase  in  its  tension  causes  a  minute  but  proportionate  movement 
of  the  spring,  which  is  recorded  by  means  of  the  lever.  Since  in  this  case  the  length  or 
measurement  of  tlie  muscle  remains  approximately  constant,  while  the  tension  is 
continually  varying  throughout  the  contraction,  it  is  known  as  the  isometric  method. 
The  great  magnification  necessary  in  this  method  introduces  serious  sources  of  error  ; 
but  it  seems  that    if  all  due  precautions  be  taken  to  avoid  these  errors,  the  isometric 


198 


PHYSIOLOGY 


curve  differs  very  little  in  form  from  the  isotonic,  displaying  only  a  somewhat 
quicker  development  of  energy  at  the  beginning  of  contraction.  It  is  better 
to  eliminate  the  lever  altogether  and  magnify  the  minute  movements  of  the  spring 
by  attaching  to  it  a  small  hinged  mirror  by  which  a  ray  of  light  is  reflected  through  a 
slit  on  to  a  travelling  photographic  plate.  Since  the  ray  of  light  has  no  inertia,  magnifi- 
cation of  the  movements  may  be  carried  to  any  extent  without  increasing  the  instru- 
mental deformation  of  the  curve  (Fig.  56). 

A  simple  muscular  contraction  or  twitch,  such  as  that  in  Fig.  52,  produced 
by  a  momentary  stimulus,  consists  of  three  main  phases  : 

(1)  A  phase  during  which  no  apparent  change  takes  place  in  the  muscle. 


Fig.  56. 


Myograph  for  optical  registration  of  muscular 
contraction.     (K.  LrrcAS.) 


or  at  any  rate  none  which  gives  rise  to  any  movement  of  the  lever.     This 
is  called  the  latent  period. 

(2)  A  phase  of  shortening,  or  contraction. 

(3)  A  phase  of  relaxation,  or  return  to  the  original  length. 

The  small  curves  seen  after  the  main  curve  are  due  to  elastic  vibrations 
of  the  lever,  and  do  not  indicate  any  changes  occurring  in  the  muscle  itself. 
From  the  time-marking  below  the  tracing  we  see  that  the  latent  period 
occupies  about  ^xjjj  second,  the  phase  of  shortening  y^-q>  and  the  relaxation 
y^y^  second. 

Thus  a  single  muscle-twitch  is  completed  in  about  yL  second.  It  must 
be  remembered,  however,  that  this  number  is  only  approximate,  and  varies 
with  the  temperature  of  the  muscle  and  its  condition,  being  much  longer  in 
a  fatigued  muscle.  Moreover,  it  is  almost  impossible  to  avoid  some  deforma- 
tion of  the  curve  due  to  defects  of  the  recording  instruments  used.  Thus  the 
relative  period  during  which  no  mechanical  changes  are  taking  place  in 
the  muscle  must  always  be  shorter  than  is  apparent  from  a  curve  obtained 


THE  MECHANICAL  CHANGES  OF  MUSCLE 


199 


by  the  foregoing  method.  The  elasticity  and  extensibility  of  the  muscle  must 
prolong  the  apparent  latent  period,  since  the  first  effect  of  contraction  of  any 
part  of  the  muscle  will  be  to  stretch  the  adjacent  part,  and  only  later  to 


Fig.  57.     Burdon  Sanderson's  method  for  photographic  record  of  muscle-twitch. 
The  exciting  shock  is  sent  into  the  muscle  by  the  wires  d  and  d' . 

move  the  tendon  to  which  the  lever  is  attached.  Thus  if  we  have  a  weight 
supported  by  a  rigid  wire,  and  suddenly  pull  the  upper  end  of  the  wire  so  as  to 
raise  the  weight,  the  latter  will  rise  instantaneously.  If,  however,  the 
weight  be  suspended  by  a  piece  of  elastic,  it  will  not  follow  the  pull  exactly, 
but  will  lag  behind,  the  first  part  of  the  pull  being  occupied  with  stretching 
the  india-rubber,  and  only 
when  this  is  stretched  to  a 
certain  degree  will  the  weight 
begin  to  rise.  The  same  re- 
tardation of  the  pull  would  be 
observed  if,  instead  of  india- 
rubber,  we  used  a  piece  of 
Uving  muscle. 

It  is  possible  to  obviate 
this  instrumental  inertia  by 
employing  solely  photographic 
methods  for  the  record  and 
magnification  of  the  muscle- 
twitch.  Thus  in  the  experi- 
ments of  Sanderson  and  Burch 
the  thickening  of  the  muscle 
at  the  point  stimulated  was 
recorded  graphically  by  photo- 
graphing the  movement  on  a  Fu;.  ')S.  Photograjjhic  record  of  muscle-twitch. 
«K4-  /I?;™  KTN  V  I,"  J  1  •  1  (B.  Sanderson.)  The  upper  curve  is  the  move- 
Sht  (Fig.  57),  behmd  which  Wnt  of  the  muscle,  the  middle  curve  the  signal 
was  a  moving  sensitive  plate.  showing  the  moment  of  excitation,  and  the  lower 
mi  •  T  11  •      i  -    1        curve  is  that  of  a  tuning-fork  vibrating  .300  times 

inus  avoiding  all  instrumental      a  second. 
inertia,   and   diminishing   the 

inertia  of  the  muscle  to  a  minimum,  the  mechanical  latent  period  was 
found  to  be  only  0-0025  second  (Fig.  58).  This  figure  we  can  take  as  the 
average  latent  period  for  the  skeletal  muscle  of  the  frog  at  the  ordinary  tem- 
perature of  the  laboratory  (about  16°  C).     We  shall  have  occasion  later  on 


TBOLH^i^^^^ 

^^^^^^^M^^^^^HI 

200 


PHYSIOLOGY 


to  consider  the  changes  which  occur  in  the  muscle  between  the  application 
of  the  stimulus  and  the  moment  at  which  the  first  mechanical  change 
makes  its  appearance. 

The  relaxation  of  muscle  is  helped  by  a  moderate  load,  and  in  a  normal 
condition  is  complete.     It  is  not  active — that  is  to  say,  is  not  due  to  a  con- 


FlG. 


59.     V.  Kries'  apparatus  for  taking  '  after-loading  '  and  '  arrested    con- 
traction curves.' 


traction  in  the  transverse  direction — but  is  a  passive  effect  of  extension  and 
elastic  rebound.  This  may  be  shown  by  allowing  a  muscle  to  contract  while 
floating  on  mercury.  The  subsequent  lengthening  on  relaxation  is  very 
incomplete. 

Even  with  the  most  careful  arrangements  for  securing  isotonicity  in  the 
record  of  the  contraction  there  is  probably  a  certain  amount  of  over-shoot 
of  the  lever  whenever,  as  at  high  temperatures,  the  contraction  is  sufficiently 
rapid.  The  effect  of  this  is  that  one  cannot  assume  the  existence  of  an  actual 
pull  on  the  lever  during  the 
whole  time  of  the  ascent  of  the 
latter.  We  can  therefore  speak 
of  a  period  during  which  there 
is  contractile  stress — that  is  to 
say,  when  the  muscle  is  actually 
pulhng  on  the  lever,  which  will 
occupy  only  a  part  of  the 
ascent  of  the  curve.  The  dura- 
tion of  this  period  of  contractile 
stress  may  be  shown  by  re- 
cording what  is  known  as  '  arrested '  contractions.  One  mechanism 
for  this  purpose  is  shown  in  the  figure  (Fig.   59).     The  stop  Su  is  used 


AAAAAAAAAAAAAAAAAAAAA 

FiQ.  60.     Curves  of  isotonic  and  arrested  contractions 
of  an  unloaded  muscle.     (Kaiser.) 


THE  MECHANICAL  CHANGES  OF  MUSCLE 


20L 


simply  for  after-loading  the  muscle  so  that  the  weight  shall  not  act 
upon  the  muscle  until  it  begins  to  contract.  The  stop  So  may  be  regu- 
lated so  that  it  suddenly  checks  the  movement  of  the  lever  at  any  desired 
height  above  the  base  line.  We  may  thus  get  a  series  of  contractions 
such  as  those  shown  in  Fig.  60.  It  will  be  seen  that  at  the  points  x  , 
x",  and  x"'  the  muscle  was  still  pulling  on  the  lever,  and  therefore  held  it 
up  against  the  stop.     At  the  point  \  the  arrested  twitch  returns  rapidly  to 


r 

D 
ID 


i 


■|^^ 1 1 1 1 1 1 

■  \ 


Tension 


Fig.  CI.  Diagram  to  show  the  relation  between  the  initial  length  of  a 
muscle  and  the  tension  developed  in  it  during  excitation  (as  measured 
by  the  isometric  method).  The  tension  developed  at  each  initial 
length  is  measured  by  the  horizontal  distance  between  the  two  thick 
lines,  the  left  line  representing  the  resting  muscle,  and  the  curved  thick 
line  on  the  right  the  contracted  muscle.     (From  Blix.) 

the  base  hne,  showing  that  the  movement  of  the  lever  in  the  unarrested  curve 
above  this  point  was  due  to  the  inertia  of  the  mo^^ng  parts  and  not  to  the 
actual  pull  of  the  muscle. 

THE  ENERGY  OF  CONTRACTION.  When  a  muscle  contracts  we  may 
conceive  of  it  as  converted  into  a  body  with  elastic  properties  other 
than  those  which  it  possesses  during  rest.  Directly  after  it  has  been 
excited  it  possesses  potential  energy  which  can  be  measured  as  tension  by 
the  isometric  method  and  which  will  degenerate  in  a  few  hundredths  of 
a  second  into  heat,  or  can  be  turned  into  work  by  allowing  the  muscle 
to  shorten  and  to  raise  a  weight,  as  in  the  isotonic  method  of 
recordino;  muscular  contractions.  Under  the  conditions  of  an  ordinarv 
physiological  experiment,  a  contracted  muscle  loaded  only  by  a  light 
lever  is  shorter  than  the  non-contracted,  but   can  be   stretched   to   the 


202  PHYSIOLOGY 

length  of  the  latter  by  a  certain  weight,  when  it  will  be  in  a  con- 
dition of  tension.  In  their  natural  position  in  the  body  muscles  may 
possess  any  length  between  extreme  shortening  and  extreme  elongation 
whether  they  are  in  a  resting  or  in  an  excited  condition.  Since  the  relaxed 
muscle  requires  only  a  minimal  force  to  extend  it  to  the  maximal  length 
possible  in  its  natural  relationships  in  the  body,  it  is  usual  to  speak  of  the 
different  lengths  of  an  excited  and  unexcited  muscle,  the  lengths  being  in 
this  case  those  which  are  impressed  on  the  muscle  by  a  minimal  load.  When 
we  measure  by  means  of  the  isometric  method  the  maximum  energy  set  free 
in  a  muscle  as  the  result  of  excitation,  we  find,  as  Bhx  first  pointed  out,  that 
this  energy  depends  on  the  length  of  the  muscle  fibres  during  the  period  of 
contractile  stress  set  up  by  the  excitation.  With  increase  in  the  length  of 
the  muscle  the  tension  developed  on  excitation  increases  until  the  length  of 
the  muscle  is  somewhat  greater  than  that  which  it  possesses  in  its  normal 
relationships  in  the  body.  To  lengthen  the  muscle  beyond  this  point  a 
certain  stretching  force  must  be  apphed  to  it  which  rapidly  increases.  The 
tension  developed  on  excitation  however  soon  begins  to  diminish.  These 
relationships  are  shown  by  the  diagram  (Fig.  61),  where  the  ordinates  repre- 
sent the  length  of  the  muscle  and  the  abscissae  the  tension  on  the  muscle. 
The  left-hand  thick  line  represents  the  muscle  in  a  state  of  rest,  the  right- 
hand  curved  line  the  muscle  in  a  state  of  excitation.  The  horizontal 
distance  between  the  two  fines  gives  the  increase  of  tension  (as  measured 
by  the  isometric  method)  produced  when  the  muscle  passes  from  the 
resting  into  the  excited  state  as  the  result  of  stimulation  by  a  single  induction 
shock. 

Since  the  tension  set  free  on  excitation  depends  on  the  length  of  the 
muscle  fibres  during  the  production  of  the  condition  of  tension,  the  tension 
developed  will  be  diminished  if  the  muscle  be  allowed  to  shorten  before  its 
maximum  tension  has  been  reached.  This  is  the  case  with  all  isotonic 
records  of  muscular  contraction,  so  that  it  becomes  difficult  to  give 
any  exact  expression  for  the  total  energy  changes  in  a  muscle  which  is 
allowed  to  shorten.  As  A.  V.  Hill  has  pointed  out,  a  muscle  is  a  machine 
primarily  for  developing  tension,  and  the  potential  energy  thus  set  up  may 
be  used  for  the  production  of  work  to  any  degree  the  conditions  of  loading 
allow. 

The  work  done  by  a  muscle  when  it  contracts  is  measured  by  multiplying 
the  weight  hfted  by  the  height  through  which  it  is  hfted,  w  x  h.  Since 
however,  the  result  will  vary  according  to  the  conditions  of  loading  of  the 
muscle,  a  much  more  useful  quantity  is  obtained  by  measuring  the  tension 
produced  in  a  muscle  which  is  stimulated  but  not  allowed  to  shorten.  The 
potential  energy  available  due  to  the  new  elastic  conditions  of  the  fibres  is 
found  to  be  approximately  J  Til,  where  T  is  the  maximum  tension  developed 
in  the  twitch  and  I  is  the  length  of  the  muscle  (A.  V.  Hill). 


THE  MECHANICAL  CHANGES  OF  MUSCLE 


203 


^ 


THE  EXTENSIBILITY  OF  MUSCLE 
Living  muscle  in  a  perfectly  normal  condition  is  tlistinguislied  by  its 

slight  but  perfect  elasticity  ;   that  is 
to  say,  it  is  considerably  stretched  by  a 
shght  force  (in  the  longitudinal  direc- 
tion), but  returns  to  its  original  length 
when    the    extending   weight  is   re- 
moved.    The  length  to  which  muscle 
Fig.   62.      Extensibility  of  india-rubber  (n)   is    stretched    is    not   proportional    to 
compared  with  that  of  a  frog's  gastroc-  ^]^q  weight  used,  but  any  given  in- 
nemius  muscle  (o).  '^  .  .         '^  .  . 

crement  of  weight  gives  rise  to  less 

elongation  the  more  the  muscle  is  already  stretched.  The  accompanying 
curves  show  diagrammatically  the  elongation  of  muscle  as  compared  with  a 
piece  of  india-rubber  when  the  weight  on  it  is  uniformly  increased. 

Dead  muscle  is  less  extensible  and  its  elasticity  is  less  perfect.  A  given 
weight  appUed  to  a  dead  muscle  will  not  stretch  it  so  much  as  when  the 
muscle  was  alive,  but  the  dead  muscle  does  not  return  to  its  original  length 
when  the  weight  is  removed. 

A  contracted  muscle,  on  the  other  hand,  is  more  extensible  than  a  muscle 
at  rest.     A  gramme  applied  to  a  contracted  gastrocnemius  will  cause  greater 
lengthening  than  if  it 
were    apphed    to   the    n 
same  muscle   at  rest.      ■  ^ 
The  relation  between 
the    excitabihty   of  a 
muscle  under  the  two 
conditions  of  contrac- 
tion and  rest  are  shown 
in  the  diagram  in  Fig. 
63. 

At  the  Point  y  the 
muscle  is  unable  to 
shorten  at  all  against 
a  weight.  It  is  evi- 
dent from  this  diagram 

that  the  height  of  contraction  of  a  muscle  diminishes  as  the  load  is  increased, 
very  rapidly  if  the  muscle  is  after-loaded,  less  rapidly  if  the  weight  applied  to 
the  muscle  be  allowed  to  extend  it  at  rest.  It  is  evident  however  that  in 
either  case  the  diminution  in  height  is  not  in  proportion  to  the  load  and 
that  the  work  done  by  the  muscle,  w  x  h,  as  the  weight  is  increased,  rises  at 
first  quickly,  then  more  slowly  to  a  maximum  to  sink  finally  to  zero.  By 
inspection  of  diagram  (Fig.  63)  it  will  be  seen  that 

O.ho  <  lO.hi  <  20.h2  <  30.h3  >  40.h,,  >  SO.hj, 
so  that  in  this  case  the  maximal  mechanical  work  is  obtained  when  the  muscle 
is  loaded  with  about  30  gms. 


Fig.  63.  Curve  showing  the  length  of  a  muscle  under  various 
loads  in  the  contracted  condition  bjj,  and  uncontracted 
condition  cy.  The  double  lines  a  b,  &c.,  represent  the  con- 
tracted muscle,  while  the  long  single  lines  a  c,  &c.,  show  the 
lentfth  of  the  inactive  muscle. 


204 


PHYSIOLOGY 


PROPAGATION  OF  CONTRACTION.  THE  CONTRACTION  WAVE 
The  whole  muscle  does  not  as  a  rule  contract  simultaneously.  When 
excited  from  its  nerve  the  contraction  begins  at  the  end-plates  and  spreads 
in  both  directions  through  the  muscle.  The  rate  of  propagation  of  the  con- 
traction wave  can  only  be  measured  by  employing  a  curarised  muscle,  so  as 
to  avoid  the  wide  spreading  of  the  excitatory  change  by  means  of  the  intra- 
muscular nerve-endings.  For  this  purpose  a  curarised  sartorius  muscle 
is  taken,  stimulated  at  one  end,  and  the  thickening  of  the  muscle  recorded 
by  means  of  two  levers  placed,  one  near  the  exciting  electrodes  and  the  second 
at  the  other  end  of  the  muscle,  as  shown  in  the  diagram  (Fig.  64).      The 


Fig.  64.     Diagram  of  arrangement  for  recording  the  contraction  wave  in  a 
curarised  sartorius. 

difference  between  the  latent  periods  of  the  two  curves  represents  the  time 
taken  by  the  contraction  wave  in  travelUng  from  a  to  h.  By  measurements 
carried  out  in  this  way  it  is  found  that  the  rate  of  propagation  of  the  con- 
traction in  frog's  muscle  is  3  to  4  metres  per  second ;  in  the  muscle  of 
warm-blooded  animals  it  may  amount  to  6  metres. 

The  actual  duration  of  the  shortening  at  any  given  point  is  necessarily 
smaller  than  that  of  the  whole  muscle,  and  amounts  in  frog's  muscle  to  only 
0-05-0 -09  sec,  about  half  the  duration  of  the  contraction  of  a  whole  muscle 
of  moderate  length.  The  length  of  the  wave  is  obtained  by  multiplying  the 
rate  of  transmission  by  the  duration  of  the  wave  at  any  one  point.  It  varies 
therefore  in  frog's  muscle  between  3000  x  -05  (=  150)  and  4000  X  -09 
( —  360)  milUmetres.  Thus  the  muscle  fibres  in  the  frog  are  much  too  short 
to  accommodate  the  whole  length  of  the  wave,  and  the  contraction  of  the 
whole  muscle  must  be  made  up  of  the  summated  effects  of  the  contraction 
wave  as  it  passes  from  point  to  point.  Hence  the  longer  the  muscle,  the 
more  must  the  contraction  be  lengthened  by  the  time  taken  up  in  propagation 
from  one  end  to  another. 


SECTION  IV 


THE  CONDITIONS   AFFECTING  THE  MECHANICAL 
RESPONSE  OF   A  MUSCLE 

STRENGTH  OF  STIMULUS.  If  a  series  of  single  break-shocks  be  applied 
to  a  muscle  or  nerve  at  intervals  of  not  less  than  five  seconds,  it  will  be  found 
that  beyond  a  certain  distance  of  the  secondary  from  the  primary  coil  no 
effect  at  all  is  produced.  The  shocks  are  said  to  be  subminimal. 
On  pushing  the  secondary  coil  nearer  the  primary  a  point  will 
be  reached  at  which  a  small  contraction  will  be  observed. 
On  then  pushing  in  the  coil  a  millimetre  at  a  time  the  contrac- 
tion will  become  greater  for  the  next  couple  of  centimetres 
{e.g.  as  the  coil  is  moved  from  12  to  10  cm.  distance).  Further 
increase  of  current  by  approximation  of  the  coils  is  without 
effect,  although  the  current  actually  used  may  be  increased  a 
hundred  times  in  moving  the  coil  from  10  to  0.  It  was 
formerly  thought  that  this  limited  gradation  of  the  muscular 
response  according  to  strength  of  stimulus  was  due  to  a  similar 
gradation  in  the  response  of  each  indi\adual  muscle  fibre  of 
which  the  muscle  is  composed.  It  seems  more  probable,  however, 
that,  when  a  minimal  or  subminimal  response  is  obtained,  not 
all  the  fibres  making  up  the  muscle  are  contracting.  A  mini- 
mal contraction  is  in  fact  a  contraction  in  which  some  fibres 
of  the  whole  muscle  are  stimulated.  A  maximal  contraction 
is  one  in  which  all  the  fibres  are  stimulated.  So  far  as  con- 
cerns each  individual  muscle  fibre  every  contraction  is  a  maxi- 
mal contraction.  The  fibre  either  contracts  to  its  utmost  or  it 
does  not  contract  at  all.  The  rule  of  '  all  or  none  '  which  was 
first  enunciated  for  heart-muscle  is  probably  true  for  every  con-  y^^^.  ,;;, 
tractile  element.  The  difference  between  skeletal  and  heart 
muscle  lies  in  the  fact  that  in  the  former  the  excitatory  process  does  not 
spread  from  one  fibre  to  its  neighbours.  If,  for  instance,  we  take  a  curarised 
sartorius  and  split  its  lower  end,  as  in  Fig.  05,  the  stimulus  applied  to  a  causes 
a  contraction  only  of  the  left-hand  side  of  the  muscle,  while  a  stimulus  applied 
to  B  is  in  the  same  way  limited  to  the  right-hand  side.  If  a  piece  of  ventricu- 
lar or  auricular  muscle  of  the  frog  or  tortoise  were  treated  in  the  same  way, 
a  stimulus  appUed  at  a  would  cause  a  contraction  which  would  travel  across 
the  bridge  at  the  upper  end  and  extend  to  b. 

205 


206 


PHYSIOLOGY 


It  was  shown  by  Gotch  that,  if  each  of  the  three  roots  which  make  up  the  sciatic 
nerve  and  send  fibres  to  the  gastrocnemius  be  stimulated  in  turn,  it  is  often  impossible 
to  evoke  a  maximal  contraction  of  the  gastrocnemius,  however  strongly  each  root 
be  stimulated.  Keith  Lucas  has  shown  that  if  stimuli  in  gradually  increasing  strength 
be  applied  to  the  motor  nerve  (containing  only  seven  to  nine  fibres,)  which  supplies 
the  dorso-cutaneus  muscle  of  the  frog,  the  contraction  of  the  muscle  increases,  not 
gradually,  but  by  a  series  of  steps.  This  can  be  explained  only  by  assuming  that  the 
smallest  effective  stimulus  excites  perhaps  four  out  of  the  seven  nerve  fibres,  those 
immediately  in  contact  with  the  electrodes.  With  increasing  strength  of  current 
the  stimulus  becomes  effective  for  the  three  fibres  lying  next  to  these,  and  finally  still 
further  increase  of  current  may  excite  all  the  fibres  making  up  the  nerve  (Fig.  66). 


Fig 


66.  Curve  showing  relation  of  height  of  contraction  of  dorso-cutaneus  muscle 
to  strength  of  stimulus.  Ordinates  =  height  of  contraction ;  abscissa  = 
strength  of  stimulus.     (K.  Ltjcas.) 


THE   REPETITION  OF  STIMULUS 

SUMMATION.  The  response  of  a  muscle  fibre  to  a  single  shock,  whether 
measured  by  the  isotonic  or  the  isometric  method,  i.e.  as  shortening  or  as 
tension,  is  independent  of  the  strength  of  stimulus  and  varies  only  with  the 
length  of  the  fibre  during  the  rise  of  the  excitatory  condition.  If,  however, 
a  second  shock  is  sent  in  during  this  period  a  further  evolution  of  energy  is 
possible,  and  the  effect  is  still  further  increased  by  putting  a  series  of  stimuU 
into  the  muscle  or  its  attached  nerve  before  the  development  of  the  contractile 
stress  due  to  the  first  stimulus  has  reached  its  maximum.  If  two  shocks  at 
intervals  of  one  hundredth  of  a  second  be  sent  into  a  muscle,  the  response, 
whether  shortening  or  rise  of  tension,  will  be  greater  than  that  produced  by 
one  shock.  If  a  series  of  shocks  be  sent  in,  the  excitatory  condition  is  main- 
tained, so  that  instead  of  a  simple  muscle  twitch  rising  to  a  maximum  and 
then  falhng,  the  muscle  lever  rises  to  a  given  point,  which  in  the  muscle  con- 
tracting isometrically  may  be  double  that  due  to  a  single  stimulus,  and  then 
remains  at  this  height  during  the  continuation  of  the  repeated  excitations. 
If  the  muscle  be  allowed  to  contract  isotonically,  the  continued  contraction 
produced  by  a  series  of  stimuli  may  with  a  heavy  load  be  three  or  four  times 
as  considerable  as  that  produced  by  a  single  stimulus.  This  condition  of 
apparently  continued  stimulation  brought  about  by  continued  apphcation  of 
stimuli  is  said  to  be  summated. 

REFRACTORY  PERIOD.  If  the  interval  between  two  stimuh  sent  into 
a  muscle  be  successively  shortened  in  a  series  of  observations  we  finally 
arrive  at  a  point  at  which  summation  is  no  longer  apparent,  i.e.  the  effect  of 


THE  MECHANICAL  RESPONSE  OF  MUSCLE 


207 


Fig.  67.  Muscle  curves  showing  summation  of 
stimuli,  r  and  r' ,  the  points  at  which  the 
stimuli  were  sent  into  the  nerve.  From  the 
first  stimulus  alone  the  curve  abc  would  bo 
obtained.  From  r'  the  curve  rfe/  is  obtained. 
These  two  curves  are  summated  to  form  the 
curve  aghik  when  both  stimuli  are  sent  in  at 
the  interval  r  r'. 


the  two  stimuli  is  no  greater  than  the  effect  of  a  single  stimulus.  This 
means  that  the  second  stimulus  has  become  ineffective,  and  this  ineffective- 
ness we  must  ascribe  to  the  condition  set  up  in  the  muscle  as  the  result 
of  the  first  stimulus.  For  a  very  short  period  of  time  after  stimulation  a 
muscle  is  inexcitable  to  a  second  stimulus.  The  period  during  which  it  is 
inexcitable  is  known  as  the  refractory  period  and  amounts  in  skeletal  muscle 
to  about  -0015  second.  The  same  phenomenon  is  better  marked  in  certain 
other  excitable  tissues,  such  as  the  heart  muscle,  but  it  seems  to  be  a  common 
property  of  excitable  tissues  generally. 

When  a  loaded  muscle  is  made  to  record  its  contractions  isotonically  we  may  get 
summation  of  effects,  though  the  interval  between  the  stimuli  is  greater  than  that 
which  corresponds  to  the  duration  of 
the  rise  of  contractile  stress.  Thus  if 
the  interval  is  just  so  long  that  the 
second  becomes  effective  just  as  the 
contraction  due  to  the  first  has  com- 
menced to  die  away,  the  second  con- 
traction seems  to  start  from  the  point 
to  which  the  muscle  has  been  raised 
by  the  first  (Fig.  67).  By  repeating 
these  stimuli  in  a  heavily  loaded 
muscle,  the  contraction  may  be  made 
three  or  four  times  as  extensive  as  a 
single  twitch.  With  slow  stimuli  the 
summation  is,  however,  rather  mechan- 
ical than  physiological.  The  period  of  contractile  stress,  which  lasts  only  about 
•03  second,  is  so  short  that  it  has  no  time  to  raise  the  weight  to  the  maximum  height 
before  it  has  passed  away.  This  is  shown  by  the  fact  that  if  the  muscle  be  after- 
loaded,  so  that  the  lever  is  raised  to  the  top  of  the  curve  of  a  single  twitch,  application 
of  the  stimulus  will  make  it  shorten  still  more,  and  by  repeated  after-leading  in  this 
fashion,  it  is  possible  to  make  the  muscle  raise  a  weight  in  response  to  a  single  stimulus 

to  the  same   height  that 
it  would  if  excited  by  a 
series     of    stimuli.     This 
mechanical  factor  in  sum- 
mation is  showni   in  Fig. 
68.      It    will    be    noted, 
however,  that  the  tetanus 
is   not  a  steady   one   and 
is  probably  due  to  stimuli 
Fig.  68.     Contractions  of  a  frog's  muscle.    Two  single  twitches  repeated   at   intervals    of 
are  followed  by  a  tetanus,  which  is  almost  twice  as  high  as  a  about  -^-  of  a  second      If 
single  contraction.     After  two  more  single  twitches,  the  drum   ',  ^"      t-       i'  • 

was  made  to  rotate  more  slowly,  and  single  shocks  employed,  ^"^  ^'"^^^  °^  stimulation 
at  the  same  time  as  the  '  after-loading '  was  continually  were  increased  to  50  or 
increased.  It  can  bo  scon  that  the  curve  obtained  in  this  way  100  per  second  a  tetanus 
is  as  high  as  the  original  tetanus.     (V.  Frey.)  would  be  produced  and  the 

curve  would  be  probably 
twice  as  high  as  that  represented  in  the  figure.  We  thus  see  that  for  the  overcoming 
of  a  resistance  a  single  twitch  is  not  economical.  It  is  doubtful  whether  any  contractions 
of  muscles  which  occur  in  the  body  are  other  than  tetani  of  varying  duration. 

TEMPERATURE.  Speaking  generally,  the  eft'ect  of  warming  a  muscle 
is  to  quicken  all  its  processes.  The  latent  period  becomes  shorter  and  the 
muscle  curve  steeper  and  shorter. 


208 


PHYSIOLOGY 


It  is  very  often  observed  that  the  height  of  contraction  of  the  warmed  muscle  is 
greater  than  that  obtained  at  ordinary  temperatures.  It  seems  that  this  apparent 
increase  in  height  is  really  instrumental  in  origin,  the  quicker-moving  muscle  jerking 
the  lever  beyond  the  real  extent  of  the  contraction.  If  proper  means  are  taken  to 
eliminate  this  overshooting  of  the  lever,  it  is  found  that  the  height  of  contraction  is 
unaltered  between  5°  and  2C°  C,  the  only  change  being  in  the  time-relations  of  the 
curves.     This  is  especially  well  shown  in  the  so-cal'ed  '  arrest '  curves  (Fig.  69). 


Fig.  69.  Isotonic  and  '  arrest '  curves  of  muscle-twitch  :  (1)  unloaded  at  14°  C.  ; 
(2)  at  25°  C.  ;  (3)  at  0°  C.  ;  (4)  loaded  at  14°  C.  Note  that  the  arrest  curves 
attain  the  same  height  throughout.     (Kaisee.) 


If  a  muscle  be  heated  gradually  (without  stimulation)  up  to  about  45°  C, 
it  begins  to  contract  slowly  at  about  34°  C,  and  this  contraction  reaches  its 
maximum  at  45°  C,  at  which  point  the  muscle  has  entered  into  pronounced 
rigor  mortis. 

Cold  has  the  reverse  effect.  The  intra-molecular  processes  which  he  at 
the  root  of  the  muscular  activity  are  slowed,  so  that  the  latent  period  and  the 
contraction  period  are  prolonged.  The  action  of  cold  on  the  excitability  of 
muscle  is  to  increase  it,  so  that  any  form  of  stimulus  is  more  effective  at  5°  C. 
than  at  25°  C.  Moreover,  when  maximal  stimuh  are  being  used,  and  the 
muscle  is  heavily  loaded,  the  first  effect  of  the  application  of  cold  may  be  to 
increase  the  height  as  well  as  the  duration  of  contraction,  for  the  same 
reason  that  a  gentle  push  is  more  efficacious  in  closing  a  door  than  would  be 
a  heavy  blow  with  a  hammer.  If,  however,  a  muscle  be  cooled  for  a  short 
time  to  zero  or  a  httle  below,  it  loses  its  irritabihty,  which  returns  if  the 
muscle  be  gradually  warmed  again.  Prolonged  exposure  to  severe  cold 
irrevocably  destroys  its  irritability.  Warming  the  muscle  will  now  simply 
.  bring  about  rigor  mortis. 

FATIGUE.  A  muscle  will  not  go  on  contracting  indefinitely.  If  it 
be  repeatedly  stimulated,  changes  soon  become  apparent  in  the  curve  of 
contraction.  The  latent  period  is  prolonged,  as  well  as  the  length  of  the 
contractions  ;  the  absolute  height  and  work  done  are  diminished.  At 
the  same  time  the  muscle  does  not  return  to  its  original  length  ;  the  shorten- 
ing which  remains  is  spoken  of  as  '  contraction  remainder.''  After  an  initial 
rise  during  the  first  few   contractions,  these  diminish  uniformly  in   height 


THE  MECHANICAL  RESPONSE  OF  MUSCLE  209 

till  they  are  no  longer  apparent,  so  that  the  muscle  is  now  said  to  have  lost 
its  irritabihty.  At  the  same  time  there  is  a  great  prolongation  of  the  curve, 
occasioned  almost  entirely  by  a  retardation  of  the  relaxation,  so  that  after 
forty  or  fifty  contractions  several  seconds  may  elapse  before  the  lever 
returns  to  the  base  hne  (Fig.  70). 

The  fact  that  the  relaxation  part  of  the  muscle  curve  is  affected  by  various  conditions, 
especially  fatigue,  apparently  independently  of  the  contraction  part,  led  Fick  to  put 
forward  a  theory  that  two  distinct  processes  were  concerned  in  the  response  of  a 


Fiu.  70.  Muscle  curves  showing  fatigue  in  consequence  of  repeated  stimulation. 
The  first  six  contractions  are  numbered,  and  show  the  initial  increase  of  the 
first  three  contractions.     (Brodie.) 

muscle  to  excitation,  one  process  causing  the  active  shortening  and  the  other  the 
relaxation.  (It  must  be  noted  that  this  is  not  the  same  as  saying  that  the  lengthening 
is  an  active  jirocess,  a  statement  negatived  by  the  behaviour  of  a  muscle  when  caused 
to  contract  on  mercury.)  He  suggested  that  the  disintegration  associated  with  activity 
might  be  conceived  as  occurring  in  two  stages  :  the  first  resulting  in  the  production 
of  sarcolactic  acid  and  the  active  shortening  of  the  muscle  ;  the  second  in  the  further 
conversion  of  the  acid  into  CO2,  with  a  consequent  relaxation.  A  retardation  of  this 
second  phase  would  cause  the  prolonged  curve  with  '  contraction  remainder  '  observed 
in  a  fatigued  muscle.  We  shall  return  to  this  point  when  discussing  the  chemical 
and  heat  changes  which  accompany  contraction. 

If  left  to  itself,  the  muscle  which  has  been  exhausted  by  repeated  stimula- 
tion will  recover.  The  recovery  is  hastened  by  passing  a  stream  of  blood, 
or  even  of  salt  solution,  through  the  blood-vessels  of  the  muscle.  Recovery 
in  a  muscle  outside  the  body  is  never  complete. 

The  phenomena  of  fatigue  probably  depend  on  two  factors  : 

(1)  The  consiunption  of  the  contractile  material  or  the  substances  avail- 
able for  the  supply  of  potential  energy  to  this  material. 

(2)  The  accumulation  of  waste  products  of  contraction.  Among  these 
waste  products  the  lactic  acid  is  probably  of  great  importance.  Fatigue 
may  be  artificially  induced  in  a  muscle  by  '  feeding  "  it  with  a  dilute  solution 
of  lactic  acid,  and  again  removed  by  washing  out  the  muscle  with  normal 
saline  solution  containing  a  small  percentage  of  alkali. 


210 


PHYSIOLOGY 


THE  ACTION  OF  SALTS 

The  action  of  sodium  salts  on  muscle  is  of  considerable  interest.     We 

are  accustomed  to  use  a  0-6  per  cent,  solution  of  NaCl  as  a  '  normal  fluid ' 

to  keep  muscle  preparations  moist.     If,  however,  the  solution  be  made 

with  distilled  water,  it  has  a  distinctly  excitatory  efiect  upon  the  muscle, 


Fig.  71.     a.  Tracing  of  the  contraction  of  a  frog's  sartorius,  poisoned  with  veratrin, 
in  response  to  a  momentary  stimulus.     The  time-marking  indicates  seconds. 

B.  Tetanic  contraction  of  normal  sartorius  in  response  to  rapidly  interrupted 
stimuli.  (The  duration  of  the  stimulus  is  indicated  by  the  words  '  on  '  and 
'  off.')  It  will  be  noticed  that  the  two  curves  are  practically  identical.  (Miss 
Btjchakan.) 

SO  that  single  induction  shocks  may  cause  tetaniform  contractions.  The 
same  excitatory  effect  is  still  better  marked  with  solutions  of  NagCOg.  If 
a  thin  muscle,  such  as  a  frog's  sartorius,  be  immersed  in  a  solution  con- 
taining 0-5  per  cent.  NaCl,  0-2  per  cent.  Na2HP04,  and  0-04  per  cent.  NagCOg 
(Biedermann's  fluid),  the  muscle  enters  into  a  series  of  frequent  contractions, 

so  that  it  may  wriggle  from  side  to  side,  or 
may  even  '  beat '  for  a  time  with  the  regu- 
larity of  heart-muscle,  though  at  a  much 
greater  rate. 

This    excitatory    action    of    sodium    salts 

is  neutrahsed    by  the  addition    of  traces  of 

calcium  salts.     Hence  the  normal  saHne  used 

in  the  laboratory  should  always  be 

made   with    tap   water,   containing 

calcium  salts. 

Potassium  salts,  although  form- 


Excitation. 

^_aj^\J.jLA.a.AJLa_a.jlJI_A_/l/_(UlA_aaaji  Seconds. 


Fig.    72.     Tracing   of  the  contraction   of   a  .  .  . 

muscle  poisoned  by  the  injection  of  a  strong  Hlg    SO    important   a    constituent   ot 

solution   of    veratrin,    showing  the    double  ^^^    ^^^    ^f    muscle,  act    as    muscle 
contraction   due   to   unequal   poisoning   ot  •  i  i  i 

different  fibres.    (Biedeemann.)  poisons,   quickly  and  permanently 

destroying  its  irritabihty.  If  a 
muscle  be  transfused  with  normal  fluids  containing  minute  traces  of  potas- 
sium salts,  it  at  once  shows  all  the  signs  of  fatigue,  signs  which  may  be 
removed  by  washing  out  the  potassium  salts  by  means  of  0-6  percent.  NaCl 
solution.  It  is  possible  that  the  setting  free  of  potassium  salts  may  be  one  of 
the  factors  involved  in  the  development  of  the  normal  fatigue  of  muscle. 


THE  MECHANICAL  RESPONSE  OF  MUSCLE  211 


THE  ACTION  OF  DRUGS 

Of  the  drugs  that  ba\^e  a  direct  action  on  muscle,  the  most  remarkable  is  veratrin, 
which  causes  an  excessive  prolongation  of  a  muscular  contraction  (produced  by  a 
single  stimulus).  Thus  the  'twitch'  of  a  muscle  poisoned  ^vdth  veratrin  may  last 
fifty  or  sixty  seconds,  instead  of  the  normal  one-tenth  of  a  second  (Fig.  71). 

Barium  salts  have  a  similar,  though  less  marked  effect. 

In  order  to  carry  out  the  poisoning  with  veratrin,  very  weak  solutions  (1  in  100,000 
or  1  in  1,000,000  of  normal  saline)  should  be  used  and  the  muscle  exposed  to  its  action 
for  some  time.  We  get  then  on  a  single  stimulus  a  respMDiise  lasting  many  seconds 
and  exactly  similar  in  height  and  form  to  a  tetanus  obtained  by  discontinuous  stimu- 
lation. If  stronger  solutions  be  used,  the  action  of  the  drug  is  apt  to  affect  the  fibres 
unequally,  so  that  we  may  have  a  sharp  normal  twitch  preceding  the  prolonged  con- 
traction (Fig.  72).  If  the  muscle  be  excited  several  times  immediately  after  the 
prolonged  contraction  has  passed  away,  it  responds  with  twitches  like  those  of  a  normal 
muscle,  but  if  allowed  to  rest  a  few  minutes,  stimulation  is  again  followed  by  the 
peculiar  long-drawn-out  contraction. 


SECTION  V 

CHEMICAL  CHANGES  IN  MUSCLE 

CHEMICAL  COMPOSITION  OF  VOLUNTARY  MUSCLE 

Voluntary  muscle  consists  of  elongated  cells,  the  muscle  fibres  being 
embedded  in  a  connective  tissue  framework,  and,  as  in  all  cellular  tissues, 
proteins  form  its  chief  chemical  constituents.  The  contents  of  the  fibres 
are  semi-fluid  and  can  be  expressed  from  the  finely  divided  muscle  as  a 
viscous  fluid  known  as  muscle  plasma. 

Muscle  plasma  is  obtained  in  the  following  way.  The  living  muscle  of  frogs  is 
frozen,  minced  with  ice-cold  knives  and  pounded  in  a  mortar  with  four  times  its  weight 
of  sand  containing  -6  of  common  salt.  The  mixture  is  then  thrown  on  to  a  filter  kept 
at  0°  C.  when  an  opalescent  fluid  filters  through.  The  filters  soon  become  clogged 
and  therefore  must  be  frequently  changed,  and  their  temperature  must  not  be  allowed 
to  rise  above  2°  to  3°  C. 

If  the  temperature  of  the  muscle  plasma  be  allowed  to  rise,  clotting 
takes  place,  the  clot  later  on  contracting  and  squeezing  out  a  serum,  as  is 
the  case  with  blood  plasma. 

The  muscle-plasma  is  neutral  or  shghtly  alkaline.  When  coagulation 
takes  place,  however,  it  becomes  distinctly  acid,  and  this  acidity  is  due  to 
the  formation  of  sarcolactic  acid  in  the  process.  Arguing  chiefly  from 
analogy  with  the  blood-plasma,  the  muscle-plasma  has  been  said  to  contain 
a  body,  myosinogen,  which  is  converted  when  clotting  takes  place  into 
myosin. 

The  exact  nature  of  the  proteins  in  muscle-plasma,  as  well  as  of  the  protein  con- 
stituent of  the  clot,  which  we  have  called  myosin,  is  still  a  subject  of  debate.  Kiihne, 
to  whom  we  owe  our  first  acquaintance  with  muscle-plasma,  described  the  clot  as 
consisting  of  myosin,  a  globulin,  soluble  in  5  per  cent,  solutions  of  neutral  salts,  such 
as  NaCl  or  MgS04,  precipitated  by  complete  saturation  with  MgS04,  and  coagulated 
on  heating  to  56°  C.  In  the  muscle-serum,  obtained  after  separation  of  the  clot,  he 
found  three  proteins,  one  coagulating  at  45°  C,  one  he  called  an  albumate  {i.e.  a  derived 
albumen  or  metaprotein),  and  the  third  coagulating  about  75*  C,  and  apparently 
identical  with  serum  albumen.  Halliburton  extended  these  researches  to  the  muscles 
of  warm-blooded  animals.  He  described  four  proteins  as  existing  in  muscle-plasma, 
of  which  two,  paramyosinogen  and  myosinogen,  gave  rise  to  the  clot  of  myosin. 

In  no  case,  however,  is  it  possible  entirely  to  dissolve  up  the  clot  when  once  formed, 
and  it  seems  that  the  so-called  solution  in  dilute  salt  solutions  was  merely  an  extraction 
of  still  soluble  protein  in  the  meshes  of  the  clot.  Von  Fiirth  has  shown  that  if  the 
muscles  of  a  mammal  are  washed  free  of  adherent  lymph  and  blood,  the  plasma  obtained 
by  extraction  with  normal  salt  solution  contains  only  two  proteins.  These  proteins 
are  extremely  unstable,  and  are  gradually  transformed  on  standing  into  insoluble 

212 


CHEMICAL  CHANGES  IN  MUSCLE  213 

protein,  giving  ri.se  to  a  precipitate  in  dilute  solutions,  or  forming  a  jelly-like  clot  in 
strong  solutions.     The  properties  of  these  proteins  may  be  summarised  as  follows  : 

(1 )  Myosin  (paramyosinogen  of  Halliburton).  A  globulin,  coagulating  at  about  47°- 
50°C.,  precipitated  byhalf  saturation  with  ammoniumsuljjhateorondialy&is.  Transformed 
slowly  in  solution,  rapidly  on  precipitation,  into  an  insoluble  protein,  mj^osin  fibrin.  ■ 

(2)  Myogen  (myosinogen  of  Halliburton).  A  protein  allied  to  the  albumens  in 
that  it  is  not  precipitated  by  dialysis.  Coagulates  on  heating  at  55°-6G°  C.  It  changes 
slowly  into  an  insoluble  protein,  myogen  fibrin,  but  passes  through  an  intermediate 
soluble  stage  called  soluble  mj'Ogen  fibrin.  This  latter  body  coagulates  on  heating  to 
40°  C,  being  instantly  converted  at  this  temperature  into  insoluble  myogen  fibrin. 
It  does  not  seem  that  any  ferment  action  is  associated  with  these  changes,  which  we 
may  represent  by  the  following  schema  : 

Muscle-plasma. 


myosin  or  paramyosinogen.  4  myogen  (myosinogen  of  Halliburton, 

albumate  of  Kiihne). 

I 
Soluble  mj'ogen  fibrin. 

I 
Mj'osin  fibrin.  Insoluble  myogen  fibrin. 

Muscle  clot. 

Soluble  myogen  fibrin,  which  in  mammalian  muscle-plasma  forms  only  on  standing, 
exists  apparently  preformed  in  frog's  muscle.  Hence  the  instantaneous  clotting  of 
frog's  muscle-plasma  on  warming  to  4C°  C. 

The  residue  left  after  the  expression  of  the  muscle-plasma  consists 
chiefly  of  connective  tissue,  sarcolemma,  and  nuclei,  and  as  such  contains 
gelatin  (or  rather  collagen),  mucin,  nuclein,  and  adherent  traces  of  the 
proteins  of  the  muscle-plasma  itself. 

The  muscle-seium  contains  the  greater  part  of  the  soluble  constituents 
of  muscle. 

OTHER  CONSTITUENTS  OF  MUSCLE.  A  number  of  other  sub- 
stances are  found  in  muscle  in  small  quantities,  those  which  are  soluble 
being  contained  to  a  great  part  in  the  muscle  serum.  It  will  suffice  here 
to  enumerate  the  chief  of  these. 

(a)  Colouring-matter.  All  red  muscles  contain  a  considerable  amount  of  hanno- 
globin.  A  special  muscle  pigment  allied  to  ha-moglobin  has  been  described  by 
MacMunn  as  myohaematin.     The  only  evidence  for  its  existence  is  spectroscopic. 

(b)  Nitrogenous  extractives.  Of  these,  the  most  important  is  creatine  (C4H9X3O.,) 
of  which  0-2  to  0-3  per  cent,  may  be  found  in  muscle.  Its  significance  will  be  the 
subject  of  consideration  later.  Other  nitrogenous  bodies  occurring  in  smaller  quantities 
are  hypoxanthine,  xanthine,  and  traces  of  urea  and  amino-acids. 

(f)  Non-nitrogenous  constituents. 

Fats,  in  variable  amount. 

Glycogen.  This  substance  is  invariably  found  in  healthy  muscle.  Fresh  skeletal 
muscle  contains  about  1  per  cent.  In  the  embryo  the  muscles  may  contain  many 
times  this  quantity  of  glycogen. 

Glucose  is  present  in  fresh  muscle  in  minimal  quantities,  about  -01  }>er  cent. 

When  muscle  is  allowed  to  stand,  especially  in  a  warm  place,  the  glycogen  under- 
goes partial  conversion  into  glucose,  so  that  the  latter  increases  at  the  expense  of  the 
former. 


214  PHYSIOLOGY 

Inosit  (CgHjaOg  SHjO)  or  '  muscle  sugar '  occurs  in  minute  traces  in  muscle. 
It  does  not  belong  to  the  group  of  carbohydrates  at  all,  being  a  hexahydrobenzene. 
It  is  nonfermentable  and  does  not  rotate  polarised  light  nor  does  it  reduce  Fehling's 
solution.     Its  significance  is  quite  miknown. 

[d)  Inorganic  constituents.  Muscle  contains  about  75  per  cent,  of  water.  Ash 
forms  1  to  1-5  per  cent,  and  consists  chiefly  of  potassimn  and  phosphoric  acid,  with 
traces  of  calcium,  magnesium,  chlorine  and  iron. 

RIGOR  MORTIS 

All  muscles  after  removal  from  the  body,  or  if  left  in  the  body  after 
general  death,  lose  after  a  time  their  irritabihty,  and  this  loss  is  succeeded 
by  the  phenomenon  known  as  rigor  mortis.  The  muscle,  which  was  pre- 
viously flaccid,  contracts,  though  the  shortening  is  not  very  powerful  and 
can  be  prevented  by  a  moderate  load  on  the  muscle.  Whereas  the  hving 
muscle  is  translucent,  supple,  and  extensible,  it  becomes  in  the  process  of 
rigor  opaque,  rigid  and  inextensible.  When  rigor  has  been  estabUshed, 
the  reaction  of  the  muscle  is  also  found  to  have  changed  from  a  shghtly 
alkahne  to  a  distinctly  acid  one,  the  acid  being  due  to  the  presence  of  sarco- 
lactic  acid.  From  this  condition  of  rigor  there  is  no  recovery.  There  can 
be  no  doubt  that  the  change  in  consistence  of  the  muscle  and  probably  also 
its  shortening  in  rigor  are  due  to  the  coagulation  of  the  muscle  proteins.  Both 
changes  can  be  imitated  by  heating  the  muscle,  as  is  indicated  by  Brodie's 
experiments.  This  observer  found  that,  if  a  hving  muscle  be  hghtly  loaded 
and  then  warmed  very  gradually,  a  series  of  stages  in  the  heat-contraction 
could  be  distinguished  corresponding  to  the  coagulation  temperatures  of 
the  different  proteins  described  by  von  Fiirth  in  muscle-plasma.  It  seems 
Hkely,  however,  that  the  main  contraction  at  all  events,  that  which  comes 
on  spontaneously  after  death  or  immediately  on  warming  the  muscle  to 
45°  C,  has  another  component.  In  the  coagulation  of  the  separated  muscle- 
proteins  there  is  no  evidence  of  any  appreciable  formation  of  sarcolactic  acid, 
whereas  the  formation  of  this  substance  seems  to  bear  an  important 
relation  to  the  occurrence  of  rigor.  Thus  after  severe  muscular  fatigue, 
as  in  hunted  animals,  where  there  has  already  been  a  considerable  formation 
of  the  waste  products  of  muscular  contraction,  rigidity  may  come  on  almost 
immediately  after  death.  If  a  thin  hving  muscle  be  plunged  into  boihng 
water,  it  undergoes  instant  coagulation,  but  no  chemical  change.  The  re- 
action of  the  scalded  muscle,  hke  that  of  fresh  muscle,  is  shghtly  alkahne 
to  htmus.  No  sarcolactic  acid  or  carbonic  acid  is  produced.  On  the  other 
hand,  in  surviving  muscle,  after  the  cessation  of  the  circulation,  there  is  a 
steady  formation  of  lactic  acid  which  accumulates  in  the  muscle.  The 
actual  coagulation  of  the  muscle-proteins  occurring  in  rigor  is  largely,  if  not 
entirely,  determined  by  the  increasing  acidity  of  the  muscle  thereby  pro- 
duced. In  fact,  it  is  the  production  of  the  acid  which  causes  the  onset 
of  rigor,  and  not  the  rigor  which  causes  a  sudden  formation  of  acid.  Hence 
if  the  accumulation  of  lactic  acid  be  prevented  by  perfusing  the  muscle 
with  salt  solutions,  the  onset  of  rigor  may  be  postponed  indefinitely,  and 
the  muscle  may  begin  to  putrefy  without  having  undergone  rigor. 


CHEMICAL  CHANGES  IN  MUSCLE  215 

THE  PRODUCTION  OF  LACTIC  ACID  IN  SURVIVING  MUSCLE 

The  lactic  acid  formed  in  muscle  {.sarcolactic  acid)  is  a  physical  isomer  of  the  lactic 
acid  formed  in  the  fermentation  or  soui'ing  of  milk.  They  both  have  the  formula 
CH3 . CH(OH) . COOH,  i.e.  they  are  ethylidene  lactic  acids.  The  lactic  acid  of  fermenta- 
tion is  optically  inactive  ;  sarcolactic  acid  rotates  polarised  light  to  the  right  ;  while 
a  third  isomer  which  is  Isevo-rotatory  is  produced  by  the  action  of  various  bacilli  and 
vibriones  on  cane  sugar.  The  sarcolactic  acid  can  be  extracted  from  the  muscle  b}^ 
means  of  alcohol. 

It  was  pointed  out  by  Hopkins  and  Fletcher  that  most  of  the  methods 
previously  used  for  the  extraction  of  lactic  acid  from  muscle  caused  the  formation 
of  lactic  acid  in  this  tissue.  To  obviate  this  difficulty,  they  adopted  the  precaution 
of  cooling  the  muscles  before  cutting  them  out  of  the  body  and  then  dropping  them 
into  alcohol  cooled  to  0°  C.  While  in  this  ice-cold  alcohol  they  were  finely  divided 
with  scissors  and  then  pounded  up  in  a  cooled  mortar.  In  this  way  the  tissue  was 
destroyed  at  a  temperature  which  did  not  allow  of  the  changes  responsible  in  sur- 
viving muscle  for  the  production  of  lactic  acid.  It  is  generally  separated  in  the  form 
of  the  zinc  sarcolactate,  by  boiling  its  partially  purified  solution  with  zinc  carbonate. 
Its  presence  may  be  tested  for  by  means  of  Uflfelmann's  reagent,  which  is  made  by 
the  addition  of  ferric  chloride  to  dilute  carbolic  acid.  The  purple  solution  thus  pro- 
duced is  at  once  changed  to  yellow  by  the  addition  of  even  traces  of  lactic  acid. 

A  much  more  definite  colour  reaction  for  lactic  acid  has  been  introduced  by  Hopkins. 
The  test  is  carried  out  in  the  following  way.  About  5  c.c.  of  strong  sulphuric  acid 
are  placed  in  a  test-tube  together  with  one  drop  of  saturated  solution  of  copper  sulphate, 
which  serves  to  catalyse  the  oxidation  that  follows.  To  this  mixture  a  few  drops  of 
the  solution  to  be  tested  are  added,  and  the  whole  well  shaken.  The  test-tube  is  now 
placed  in  a  beaker  of  boiling  water  for  one  or  two  minutes.  The  tube  is  then  cooled 
under  a  water-tap,  and  two  or  three  drops  of  a  very  dilute  alcoholic  solution  of  thiophene 
(ten  to  twenty  drops  in  100  c.c.)  are  added  from  a  pipette.  The  tube  is  replaced  in 
the  boiling  water  and  the  contents  immediately  observed.  If  lactic  acid  is  present  the 
fluid  rapidly  assumes  a  bright  cherry  red  colour,  which  is  only  permanent  if  the  tube  be 
cooled  the  moment  after  its  appearance. 

A  study  of  the  lactic  acid  content  of  muscle  by  Fletcher  and  Hopkins,  using 
the  precautions  described  above,  has  shown  that  fresh  muscle  contains  only 
minimal  amounts  of  lactic  acid,  the  quantity  being  smaller,  the  greater  the 
care  that  is  taken  to  avoid  injury  to  the  muscle  and  to  keep  its  temperature 
low  until  sufficient  time  has  elapsed  for  its  vital  chemical  processes  to  be 
destroyed  by  the  action  of  the  cold  alcohol.  If  the  muscle  be  left  in  the 
body  after  the  death  of  the  animal  or  be  excised,  a  steady  formation  of 
lactic  acid  takes  place,  which  is  more  rapid  in  the  first  few  hours  after 
death,  but  continues  until  the  muscle  passes  into  rigor.  With  the  complete 
onset  of  rigor,  frog's  muscles  are  found  to  contain  about  4  per  cent,  lactic 
acid.  After  this  time  the  amount  does  not  increase.  The  onset  of  rigor 
and  the  rate  of  production  of  lactic  acid  are  quickened  if  the  muscle  be 
kept  warm.  It  is  interesting  to  note  that  the  amount  of  lactic  acid  found 
in  rigid  muscle  is  almost  invariable  whatever  the  previous  history  of  the 
muscle.  Thus,  if  the  muscle  be  finely  minced  and  then  extracted  with 
cold  alcohol,  it  is  found  to  contain  about  -2  per  cent,  lactic  acid.  If.  how- 
ever, it  be  allowed  to  stand  after  mincing,  there  is  a  slow  production  of 
lactic  acid  up  to  the  maximum  -4  per  cent.  Again,  a  muscle  which  has  been 
tetanised  to  exhaustion  contains  about  -2  per  cent,  lactic  acid.  "When 
allowed  to  undergo  rigor,  the  amount  rises  to  about  4  per  cent. 


216  PHYSIOLOGY 

It  has  long  been  known  that  the  onset  of  rigor  is  associated  with  an  evolu- 
tion of  carbonic  acid  by  the  muscle.  Fletcher  has  shown  that  this  increased 
output  of  carbonic  acid  by  a  surviving  muscle  is  due  simply  to  the  driving 
off  of  carbonic  acid  from  the  carbonates  in  the  muscle  as  a  result  of  the 
production  of  lactic  acid.  There  is  no  evidence  of  a  new  formation  of  carbonic 
acid  in  the  dying  muscle  as  a  result,  for  instance,  of  oxidative  changes. 

THE  CHEMICAL  CHANGES  WHICH   ACCOMPANY  ACTIVITY 

The  principle  of  the  conservation  of  energy  teaches  us  that  the  energy 
of  the  contraction  of  muscle  must  be  derived  from  chemical  changes,  probably 
processes  of  decomposition  and  oxidation,  occurring  in  the  muscle  itself. 
In  seeking  out  the  nature  of  these  changes  three  methods  are  open  to  us  : 

(1)  We  can  examine  the  changes  in  the  muscle  itself,  avoiding  so  far 
as  possible  reintegrative  changes  by  working  on  excised  muscles. 

(2)  We  can  investigate  the  changes  in  the  medium  surrounding  the 
muscle.  Muscle  may  be  exposed  in  a  vacuum  or  in  a  confined  space  of 
air,  and  its  gaseous  interchanges  during  rest  and  activity  compared.  Or 
we  may  lead  a  current  of  defibrinated  blood  through  excised  muscles,  and 
determine  the  change  in  the  composition  of  the  blood  in  passing  through  the 
muscle  under  various  conditions. 

(3)  A  method  which,  although  apparently  complex,  has  rendered  the 
utmost  service  to  the  physiology  of  muscle  is  to  use  the  changes  in  the 
total  metabohsm  of  the  animal  during  rest  and  muscular  work  as  a  clue 
to  the  muscular  metabohsm  itself.  In  such  a  case  the  respiratory  exchanges 
of  the  animal  are  determined  (viz.  its  oxygen  intake  and  its  COg  output), 
and  the  urine  and  faeces  are  carefully  analysed,  in  order  to  judge  of  the 
action  of  muscular  work  on  the  carbon  and  nitrogen  metabohsm  of  the  body. 

By  the  third  of  these  methods  we  may  show  that  muscular  exercise 
increases  largely  the  intake  of  oxygen  and  the  output  of  carbon  dioxide 
by  the  body.  No  corresponding  changes  are  found  in  the  nitrogenous 
metabohsm,  so  that  ultimately  we  may  regard  the  energy  of  the  muscular 
contraction  as  derived  from  the  oxidation  of  the  food-stuffs  and  especially 
the  carbohydrates.  That  it  is  this  class  of  bodies  which  is  the  immediate, 
or  at  any  rate  the  most  accessible,  source  of  muscular  energy,  is  shown  by 
the  rise  in  the  respiratory  quotient  which  occurs  during  muscular  exercise. 
When  the  exercise  is  moderate  there  is  no  evidence  of  the  production  of  any 
other  substance  than  carbon  dioxide  as  a  result  of  the  muscular  metabohsm, 
but  with  violent  exercise  it  can  be  shown  that  lactic  acid  is  not  only  pro- 
duced in  the  muscle,  but  appears  in  the  blood  and  is  excreted  in  the  urine. 

It  has  been  shown  by  Ryflfel  that  normal  urine  contains  3—4  mg.  of  lactic  acid 
per  hour.  In  one  expsriment  the  urine  passed  after  running  one  third  of  a  mile  with 
the  production  of  severe  breathlessness  contained  454  mg.  of  lactic  acid.  In  another 
experiment  blood  obtained  before  running  contained  12-5  mg.  per  100  c.c,  and  that 
obtained  immediately  after  running  one  third  of  a  mile  contained  70  mg.  lactic  acid 
per  100  c.c.  On  the  other  hand,  the  examination  of  the  urines  of  competitors  in  a 
twenty-four  hours  track  walking  race  showed  no  increase  in  the  output  of  lactic  acid 
above  the  normal  4  mg.  per  hour. 


CHEMICAL  CHANGES  IN  MUSCLE  217 

The  appearance  of  lactic  acid  thus  seems  to  be  attendant  on  a  relative 
deficiency  in  the  oxygen  supply  to  the  contracting  muscle.  The  same 
conclusion  may  be  drawn  from  experiments  made  many  years  ago  by  Araki, 
in  which  lactic  acid  was  observed  in  quantities  in  the  urine  in  cases  where 
the  oxidative  processes  of  the  body  were  interfered  with  by  CO  poisoning. 

Similar  results  are  obtained  when  we  investigate  the  chemical  changes 
accompanying  the  contraction  of  excised  muscles  of  the  frog.  If  frogs' 
muscle  be  hung  up  in  an  atmosphere  of  nitrogen  and  stimulated  repeatedly 
with  single  shocks,  it  will  give  a  series  of  contractions  gradually  diminishing 
in  size  {v.  p.  209).  After  a  time  the  muscle  is  completely  fatigued,  and 
no  further  response  can  be  ehcited  on  stimulation.  On  now  examining  it, 
it  is  found  to  be  acid  in  reaction  and  to  contain  about  -2  per  cent,  lactic 
acid.  There  is  no  evidence  that  under  these  conditions  any  carbonic  acid 
is  produced,  though  a  certain  amount  may  be  hberated  in  consequence  of  the 
acidification  of  the  muscle.  Almost  the  same  results  are  obtained  when 
the  muscle  is  stimulated  in  ordinary  atmospheric  air.  The  penetration 
of  oxygen  from  the  air  through  the  body  of  the  muscle  is  so  slow  that  all 
the  muscle  except  the  thin  layer  on  the  surface  may  be  regarded  as  cut  ofi 
from  the  action  of  oxygen.  By  hanging  the  muscle,  especially  a  thin  muscle 
such  as  the  sartorius,  in  an  atmosphere  of  pure  oxygen,  the  results  are  quite 
different.  In  the  first  place  the  muscle  does  not  fatigue  so  soon.  More- 
over, a  muscle  which  has  been  stimulated  to  exhaustion  in  an  atmosphere  of 
nitrogen,  if  restored  to  one  of  pure  oxygen,  will  rapidly  recover  its  power 
of  contraction.  In  pure  oxygen  no  lactic  acid  is  produced,  and  a  muscle 
stimulated  to  exhaustion  contains  very  httle  more  lactic  acid  than  does 
resting  muscle.  On  the  other  hand,  the  intake  of  oxygen  and  the  output 
of  carbonic  acid  by  the  muscle  is  increased  at  each  contraction.  We  thus 
find  that  a  muscle  during  contraction  may  produce  lactic  acid  or  carbonic 
acid  according  as  oxygen  is  absent  or  present.  In  both  cases  contraction 
takes  place  apparently  normally,  but  fatigue  supervenes  much  more  rapidly 
in  the  absence  of  oxygen.  The  question  arises  whether  we  should  regard 
the  formation  of  lactic  acid  and  carbonic  acid  as  alternative  processes,  or 
whether  lactic  acid  is  first  formed  and  is  then  removed  under  the  action  of 
oxygen,  undergoing  partial  or  complete  oxidation  to  carbonic  acid  in  the 
process.  The  evidence  is  distinctly  in  favour  of  the  second  h}^othesis. 
Thus  Hopkins  and  Fletcher  have  fomid  that  muscle  possesses  in  itself  a 
chemical  mechanism  for  the  removal  of  lactic  acid.  If  a  fatigued 
muscle  be  exposed  to  pure  oxygen,  30  per  cent,  of  the  lactic  acid  present  in 
the  muscle  may  disappear  within  two  hours  and  50  per  cent,  within  six  to 
ten  hours.  Thus,  even  apart  from  the  circulation  which  of  course  would 
remove  large  quantities  of  any  lactic  acid  which  might  be  produced 
in  the  muscles,  these  can  deal  with  this  metabolite  locally.  It  has 
been  found  that  a  muscle  may  be  fatigued  several  times  and  then  placed 
in  oxygen  to  recover,  so  that  lactic  acid  is  produced  and  removed  also  several 
times.  If  at  the  end  the  muscle  be  allowed  to  undergo  rigor,  it  is  found  to 
contain  -4  per  cent,  lactic  acid,  i.e.  exactly  the  same  amount  as  if  it  had 


218  PHYSIOLOGY 

given  no  contractions  at  all.  Fletcher  and  Hopkins  interpreted  this  result 
as  showing  that  under  the  influence  of  oxygen,  lactic  acid  is  put  back  into 
the  precursor  from  which  it  arose,  and  would  assume  that  part  of  the  lactic 
acid  is  completely  oxidised  to  carbonic  acid  and  water,  the  energy  so  evolved 
being  employed  in  the  building  up  of  the  precursor  from  the  rest  of  the  lactic 
acid.  On  the  other  hand  it  is  possible  that  the  lactic  acid  produced  in  the 
initial  stage  of  contraction  may  be  under  normal  circumstances  completely 
removed  by  oxidation,  and  that  the  energy  or  part  of  the  energy  so  made 
available  is  used  to  build  up  some  precursor  substance,  not  out  of  the  lactic 
acid,  but  out  of  the  glycogen  already  present  in  the  muscle  (Parnas).  It 
is  certain  that  prolonged  activity  of  muscle,  especially  in  the  presence  of 
oxygen,  may  be  associated  with  a  diminution  in  the  glycogen  store  of  the 
muscle.  We  cannot,  however,  discuss  this  question  further  without  refer- 
ence to  the  total  energy  changes  in  muscle  contracting  with  or  without 
oxygen,  and  the  clue  to  these  changes  is  given  by  a  study  of  the  heat  pro- 
duction in  muscle. 


SECTION  VI 

THE   PRODUCTION  OF  HEAT  IN  MUSCLE 

The  experience  of  everyday  life  teaches  us  that  muscular  exercise  is  asso- 
ciated with  increased  production  of  heat.  Thus  a  man  walks  fast  on  a 
frosty  day  to  keep  himself  warm.  In  large  animals  the  production  of  heat 
in  muscular  contraction  can  be  easily  shown  by  inserting  the  bulb  of  a 
thermometer  between  the  thigh  muscles,  and  stimulating  the  spinal  cord. 
The  rise  of  temperature  produced  in  this  way  may  amount  to  several  degrees. 
This  observation  is  confirmed  when  we  investigate  the  contraction  of  an 
isolated  muscle  outside  the  body.  If  a  frog's  muscle  is  tetanised,  its  tem- 
perature rises  from  0-l-l°  to  0-18°  C,  and  for  each  single  twatch  from  0-001° 
to  0-005°  C. 

It  is  evident  that  such  small  changes  in  temperature  as  0-001°  cannot  be  estimated 
by  ordinary  thermometric  methods.     By  converting  a  heat  change  into  an  electrical 
change,  however,  we  can  estimate  differences  of  temperature  with  much  greater  accuracy 
and   fineness  than  by  the   use  of   a  thermometer. 
Two   main  principles  are  employed  in    measuring  cool 

temiDerature   by  electrical  methods.      The  thermo-  /^ 

electrical  method  depends  on  the  fact  that,  when 


o 


the  junctions  of  a  circuit  made  of  two  metals  are      ntimon     ■  |  | 

at  different   temperatures,  a  current  of  electricity  ^^^r"^/ 

generally  flows  through  the  circuit.    This  current  can  ■'^ 

be  measured   by  means  of  a  galvanometer,    and  is  '^ 

proportional  to  the  difference  of  temperature  between  ^^^  ^^• 

the    two   junctions.     Thus   in  the  circuit  (Fig.  73) 

composed  of  two  metals,  antimony  and  bismuth,  if  the  upper  junction  be  cooled,  there 

will  be  a  cm-rent  flowing  from  antimony  to  bismuth  in  the  direction  of  the  arrow,  and 

this  current  will  within  limits  be  proportional  to  the  difference  of  temperature. 

To  measure  the  production  of  heat  dming  muscular  contraction,  a  small  flat  thermo- 
pile (containing  four  or  six  elements  composed  of  iron  and  German  silver,  or  copper 
and  '  constantan ')  is  fixed  with  one  of  its  ends  between  two  frog's  gastrocnemii. 
Another  exactly  similar  pile,  but  reversed,  is  placed  between  two  other  gastrocnemii, 
which  are  kept  resting  and  at  a  perfectly  constant  temperature.  So  long  as  the  two 
piles  are  at  the  same  temperature  no  current  flows  ;  but,  with  a  sensitive  galva- 
nometer, the  slightest  difference  of  temperature,  such  as  that  caused  by  the  contraction 
of  one  pair  of  muscles,  at  once  causes  a  deflection  of  the  galvanometer,  the  extent  and 
direction  of  which  enable  us  to  estimate  exactly  the  seat  and  amount  of  heat  produced. 

When  we  are  using  such  delicate  detectors  of  temperature  difference,  we  are  met 
by  the  difliculty  that  every  junction  in  the  circuit  tends  to  become  the  seat  of  an  electro- 
motive force  in  consequence  of  slight  changes  of  tcni])crature  due  to  currents  of  air.  &c. 
It  is  therefore  advisable  to  use  a  plan  adopted  by  Blix,  of  placing  all  the  apparatus, 
the  muscle  included,  within  the  galvanometer  case.  The  arrangements  of  such  an 
experiment  as  emiilovcd  bv  A.  V.  Hill  are  shoAvn  in  the  diagram  (Fig.  74). 

219 


220 


PHYSIOLOGY 


In  this  instrument  the  junction  of  copper  with  the  alloy  constantan  constitutes 
a  thermo-electric  couple.  The  magnet  and  mirror  chamber  is  entirely  separated  off 
from  the  rest  of  the  instrument  by  the  walls  of  the  tube  containing  the  magnet.  The 
grooves  are  usually  filled  with  plasticine,  and  into  them  fit  the  edges  of  an  outer  case 
of  brass  constituting  the  walls  of  the  muscle  chamber.  The  inside  of  this  case  is  lined 
with  wet  blotting-paper.  The  copper  coil  consists  of  many  more  turns  than  are  shown 
in  the  figure  :  its  ends,  aa  and  bb,  are  separated  by  the  celluloid  plate,  and  are  con- 
nected by  the  constantan  plug  ;  the  points  where  the  copper  meets  the  constantan 
constitute  the  thermo-electric  jmictions.     The  tube   containing  the  magnet   hangs 


Magnet  &  Mirror  Chambe. 


Constantan  Plug 


Muscle 


Quartz  Fibre 

Mirror 

Groove 

^  Broca  Magnet 
System 

Copper  Coll 


Electrode 


Celluloid  Plate 


Electrode 


Fig.  74. 

down  through  holes  bored  in  the  broad  copper  coil.  The  two  semimembranosus  muscles 
ride  astride  of  the  celluloid  plate,  one  in  contact  with  each  end  of  the  constantan  plug. 
The  small  piece  of  bone  at  their  upper  ends  which  has  been  left  connecting  the  two  muscles 
is  placed  exactly  on  the  top  of  the  celluloid  plate  at  x  and  held  in  position  by  a  clamp 
(not  shown  in  the  figiure).  The  cojiper  terminals  of  the  coil  are  coated  with  celluloid 
varnish  to  prevent  short  circuiting  of  the  thermo-electric  currents,  and  to  prevent 
poisoning  of  the  muscles.  Each  muscle  is  in  contact  with  a  pair  of  electrodes,  made 
of  fine  platinum  wire  ;  the  muscle  lies  over  the  upper  and  beneath  the  lower  of  these 
electrodes,  as  shown  in  the  figure.  The  tendons  at  the  lower  ends  of  the  muscles  are 
tied  to  silk  threads  which  pass  through  holes  in  the  base  of  the  instriunent.  These  are 
then  attached  to  recording  levers  which  write  on  a  drum  beneath  the  table.  When 
all  is  ready  three  heavy  soft-iron  cylinders  are  placed  over  the  instrument :  the  latter 
is  screwed  to  a  wooden  block  which  is  fixed  to  a  thick  iron  plate  attached  to  the  table. 
In  the  cylinders  holes  are  bored  to  admit  and  let  out  after  reflexion  the  light  from  a 
Nernst  lamp.  The  lamp,  which  is  about  three  metres  away,  shines  upon  the  mirror, 
and  a  line  in  it,  after  reflexion,  is  focussed  on  to  the  screen,  which  is  also  three  metres 
away.  The  line  is  brought  on  to  the  scale  by  the  small  field  exerted  by  a  control  magnet 
placed  outside  the  cylinders  at  a  suitable  position  on  the  table  :  its  position  may  be 
read  easily  to  half  a  millimetre,  and  the  movement  due  to  a  twitch  is  usually  of  the  order 
of  80  mm.  These  soft-iron  cylinders  cut  off  entirely  all  external  magnetism  sufficient 
to  cause  harmful  disturbance  during  an  experiment.  They  lower  very  largely  the 
strength  of  the  constant  external  field  in  which  the  magnet  lies,  and  leave  it  chiefly 


PRODUCTION  OF  HEAT  IN  MUSCLE 


221 


Fig.  74;A.     Arrangement  of  apparatus  for  measuring  small 
differences  of  temperature. 


supported  in  any  position  by  the  quartz  fibre.  Thus  all  the  movements  set  up  in 
the  magnet  by  the  thermo-electric  cm-rents  are  working  against  little  more  than  the 
torsion  of  a  quartz  fibre  only  6  fj,  thick.  This  explains  the  great  sensitivity  of  the 
instrument. 

A  second  method  depends  on  the  fact  that  rise  of  temperature  increases  the  resistance 
of  a  wire  to  the  passage  of  an  electric  current.  A  current  detector  consists  of  a  small 
grid  of  fine  platinum  wire  which  is  i)laced  against  the  muscle  between  two  muscles. 
This  grid  is  then  made  one 
limb  of  a  Wheatstone's  bridge 
(Fig.  74a).  a  small  current 
is  passed  through  the  circuit, 
and  the  resistances  are  so 
adjusted  that  no  current 
flows  through  the  galvano- 
meter. Any  alteration  in 
temperature  of  the  grid  will 
alter  the  balance  of  the  re- 
sistance and  will  cause  a 
current  to  flow  through  the 
galvanometer  in  a  direction 
which  will  vary  according 
as  the  resistance  in  the  grid 
is  increased  or  diminished.  It 
is  possible   to   calibrate   the 

arrangement  so  that  a  deflection  of  the  galvanometer  over  one  degree  will  correspond 
to  a  certain  fraction  of  a  degree  of  difference  in  temperature  of  the  grid.  This  method 
is  employed  in  Callender's  recording  thermometers,  and  has  been  made  by  Gamgee 
the  basis  of  an  arrangement  for  the  continuous  record  of  the  temperatvu-e  of  the 
human  body. 

Most  of  the  earlier  work  on  the  development  of  heat  in  muscle  had  as 
its  leading  motive  the  discovery  of  the  relation  between  the  heat  produced 
and  the  work  performed  by  a  muscle  mider  varpng  conditions  of  load. 
When  a  loaded  muscle  contracts,  however,  it  is  not  easy  to  analyse  its 
mechanical  conditions,  since  part  of  the  shortening  of  the  muscle  during 
contraction  can  be  regarded  merely  as  a  recovery  from  the  condition  of 
extension  induced  by  the  weight,  and  the  amphtude  of  the  excursion  may 
be  largely  conditioned  by  the  inertia  of  the  weight  moved.  Working  on 
these  lines,  Heidenhain  discovered  that  the  heat  production  in  muscle 
during  contraction  is  not  an  invariable  quantity,  but  varies  according  to 
the  condition  of  the  muscle  and  especially  according  to  the  tension  developed 
in  it  during  contraction.  It  was  therefore  at  its  maximum  under  isometric 
conditions  when  it  was  not  allowed  to  shorten  at  all  during  contraction. 
As  we  have  seen,  the  muscle  changes,  as  the  result  of  excitation,  from  a  body 
having  certain  elastic  properties  to  one  having  other  elastic  properties. 
The  whole  energy  of  the  contraction  is  converted  for  a  short  period  into  a 
state  of  tension  which  can  be  used  to  do  work  by  raising  a  weight.  If  it 
be  not  allowed  to  shorten,  the  state  of  tension  passes  off  and  the  whole 
energy  which  has  been  set  free  must  appear  as  heat.  The  potential  energy 
developed  in  a  muscle  twitch  is  approximately  equal  to  i.  TL  where  T  is  the 
tension  developed  and  /  the  length  of  the  muscle,  and  it  is  this  amount 
which  must  be  compared  with  the  heat  production  measured  in  the  muscle 


222  PHYSIOLOGY 

by  one  of  the  metliods  described.  A.  V.  Hill  has  shown  that  the  heat 
production  in  a  contracting  skeletal  muscle  occurs  in  two  phases,  a  rapid 
production  of  heat  which  apparently  is  synchronous  with  the  contraction 
itself,  and  a  slow  production  of  heat  which  continues  for  some  time  after 
the  muscle  has  relaxed.  The  second  phase  of  heat  production  depends  on 
the  presence  of  oxygen,  and  is  observed  at  its  best  when  the  muscle  is  kept 
in  pure  oxygen.  If  the  muscle  be  allowed  to  contract  in  nitrogen  only 
the  initial  heat  production  is  observed.  The  heat  production  of  the  second 
phase  is  stated  by  Hill  to  be  approximately  equal  to  that  in  the  first  phase. 
These  results  have  been  interpreted  as  showing  that  the  initial  change  in 
muscular  contraction  is  the  development  of  lactic  acid.  The  appearance 
of  this  lactic  acid  in  some  way  changes  the  muscle  and  sets  up  potential 
energy  at  the  surface  of  its  ultimate  fibrils,  which  will  result  in  a  shortening 
of  the  muscle  if  any  movement  of  its  ends  be  allowed.  A  comparison  of 
the  energy  of  the  tension  set  up  with  the  actual  heat  evolved  in  the  initial 
stage  when  a  muscle  is  not  allowed  to  contract  shows  that  the  two  quantities 
are  approximately  equal.  In  a  series  of  experiments  Hill  found  that  the 
ratio  -J-  Tl :  H  in  the  sartorius  muscle  under  low  initial  tensions  and  in 
comparatively  weak  contractions  approximated  to  the  value  1,  the  mean 
value  being  -91.  Under  high  initial  tensions  and  in  strong  contractions 
of  the  sartorius  muscle,  it  is  lower,  being  roughly  from  04  to  0-6.  He 
concludes  from  this  that  under  certain  conditions  the  initial  process  of  con- 
traction consists  largely,  if  not  entirely,  of  the  hberation  of  free  potential 
energy  manifested  as  tension  in  the  muscle.  This  potential  energy  may  be 
used  for  the  accomplishment  of  work  or  for  the  production  of  heat.  The 
efficiency  of  the  initial  stage  of  contraction  is  therefore  almost  100  per  cent. 

If,  however,  a  muscle  is  to  go  on  contracting  without  rapidly  showing 
signs  of  fatigue,  it  must  be  kept  in  oxygen,  so  that  the  processes  of  replace- 
ment or  of  removal  of  the  lactic  acid  may  take  place.  Under  these  circum- 
stances there  is  a  further  evolution  of  heat  after  the  contraction,  equal  to 
that  set  free  during  the  initial  stage.  So  that  the  total  efficiency  of  a  muscle 
kept  in  oxygen  would  not  be  more  than  50  per  cent. 

This  is  assuming  that  the  process  of  oxidation  of  the  lactic  acid  and  its  replace- 
ment in  whole  or  in  part  in  the  muscle  molecule  is  completely  carried  out  diu-ing  the 
time  of  the  observation.  It  is  improbable  that  such  is  the  case,  and  it  seems  possible 
that  the  evolution  of  heat  during  the  so-called  recovery  stage  of  the  muscle  has  been 
imder-estimated. 

If  a  series  of  observations  of  the  heat  production  and  tension  developed 
during  isometric  contractions  be  made  with  varying  initial  tension  on  the 
muscle,  it  is  found  that  while  the  ratio  of  tension  developed  to  heat  produced 
is  approximately  constant,  both  these  quantities  first  increase  and  then 
finally  diminish.  The  optinmm  of  the  heat  production  in  some  experiments 
seems  to  fall  later  than  the  optimum  of  the  tension  developed.  It  seems 
probable  that  in  this  case  the  essential  factor  is  not  so  much  the  tension 
exerted  on  the  muscle  previous  to  its  excitation,  but  the  length  of  the  muscle 
fibre  during  the  time  that  it  is  excited.     The  longer  the  muscle  fibre,  within 


PRODUCTION   OF  HEAT   IN  MUSCLE  223 

Umits,  when  it  is  excited,  the  greater  the  tension  and  the  greater  the  heat 
production  developed,  i.e.  we  may  assume  that  increased  length  of  muscle 
fibre  increases  the  chemical  changes,  ensuing  on  excitation,  which  are  respon- 
sible both  for  the  development  of  mechanical  energy  and  the  production  of 
heat.  The  significance  of  these  results  for  the  essential  nature  of  muscular 
contraction  we  shall  discuss  in  a  later  chapter. 


SECTION  VII 
ELECTRICAL  CHANGES  IN  MUSCLE 


Fig.  75.     Diagram  of  non- 
polarisable  electrode. 

a.covered  wire;  &,  amal- 
gamated zinc  rod;  c, 
glass  tube ;   d,  saturated 


If  a  current  from  a  battery  be  passed  between  two  plates  of  platiniun  immersed  in 
acidulated  water  or  salt  solution,  electrolysis  of  the  water  takes  place,  bubbles  of  oxygen 
appearing  on  the  positive  plate  (anode),  and  bubbles  of  hydrogen  on  the  negative 
plate  (cathode).  If  now  we  remove  the  battery,  and  connect  the  two  plates  (electrodes) 
by  wires  with  a  galvanometer,  a  cm-rent  passes  through  the  galvanometer  and  water 
in  the  reverse  direction  to  the  previous  battery  current. 
This  current  is  called  the  polarisation  current,  and  is  due 
to  the  electrolysis  of  the  water  that  has  taken  place. 
The  vessel  in  which  the  electrodes  are  immersed  has  in 
fact  become  a  galvanic  cell,  the  platinum  covered  with 
oxygen  bubbles  being  the  positive  element,  and  that  covered 
with  hydrogen  bubbles  the  negative  element.  Exactly  the 
same  process  of  electrolysis  or  polarisation  takes  place 
when  we  pass  currents  through  the  tissues  of  the  body  by 
means  of  metallic  electrodes. 

Hence  before  we  can  study  accm'ately  the  delicate 
electrical  changes  that  may  occur  normally  in  living 
tissues,  it  is  necessary  to  have  some  form  of  electrodes  in 
which  this  polarisation  will  not  occur.  The  '  non-polari- 
sable '  electrodes  which  are  most  generally  used  for  this 
ZnSO^  solution  ;erplugo'f  Pu^'POse  are  made  in  the  following  way.  A  glass  tube 
zinc  sulphate  clay ;/,  plug  (Fig.  75)  is  closed  at  one  end  with  a  plug  of  kaolin  made 
of  normal  saline  clay.  into  a  paste  with  a  saturated  solution  of  zinc  sulphate. 

The  rest  of  the  tube  is  filled  with  a  similar  solution. 
Dipping  into  the  zinc  sulphate  solution  is  a  rod  of  pure  zinc,  amalgamated.  Just 
before  use,  a  plug  of  china  clay  made  with  normal  saline  solution  is  put  on  the 
end  of  the  tube,  so  as  to  effect  a  connection  between  the  zinc  sulphate  clay  and  the 
nerve  or  muscle  which  it  is  desired  to  stimulate  or  lead  off.  In  these  electrodes 
there  is  no  contact  of  metals  with  fluids  that 
can  produce  dissimilar  ions  {e.g.  hydrogen  or 
oxygen)  at  the  surface  of  contact,  and  hence 
they  may  be  regarded  as  practically  non-polari- 
sable.  A  more  convenient  form  is  that  employed 
by  Burdon  Sanderson,  in  which  the  glass  tube  is 
bent  into  a  U  (Fig.  76).  The  mouth  of  the  tube  is 
closed  by  a  smaller  glass  tube  plugged  with  clay, 
and  bearing  a  plug  of  normal  saline  clay. 

In  such  electrodes  the  conduction  of  the  cur- 
rent through  the  nerve  or  muscle  to  the  metallic 
part  of  the  circuit  may  be  represented  as  shown  on  the  opposite  page  (see  Fig.  77). 

If  a  muscle  such  as  the  sartorius  be  removed  from  the  body,  and  two  non- 
polarisable  electrodes  connected  with  a  dehcate  galvanometer  be  apphed 
to  two  points  of  its  surface,  there  will  be  a  deflection  of  the  mirror  attached 
to  the  galvanometer,  showing  the  presence  of  a  current  in  the  muscle  from 

224 


Fig.  76. 


U-shaped    non-polarisable 
electrodes. 


ELECTRICAL  CHANGES  IN  MUSCLE 


225 


the  ends  to  the  middle,  and  in  the  external  circuit  from  the  middle  (or  equator) 
to  the  ends.  It  was  formerly  thought  that  this  current  was  always  present 
in  all  normal  muscles,  and  it  was  spoken  of  as  the  '  natural  muscle  current '  ; 
the  muscle  was  said  to  be  made  up  of  a  series  of  electromotive  molecules,  the 
equator  of  each  molecule  being  positive  to  the  two  poles  (du  Bois  Raymond). 
It  has  been  conclusively  shown,  however  (by  Hermann  and  others),  that  this 


Zn 


+ 
Zn 


Na  ^ 


Na 


Zn 


<— < 


50^  a 


a     50^ 


Zn 


FiG.  77. 


Fic.  1?.     Cm-rent  of  rest. 


current  of  resting  muscle  is  not  a  natural  current  at  all,  but  is  due  to  the 
effects  of  injury  in  making  the  preparation.  The  less  the  preparation  is 
injured,  the  smaller  is  the  current  to  be  obtained  from  it,  and  in  some  con- 
tractile tissues,  such  as  the  heart,  there  may  be  absolutely  no  current  during 
quiescence. 

Hermann  describes  the  fact  of  the  existence  of  currents  of  rest  thus  : 
"  In  partially  injured  muscles  every  point  of  the  injured  part  is  negative 
towards  the  points  of  the  uninjured  surface."  Fig.  78  shows  the  direction 
of  the  current  in  a  muscle  with  two  cut  ends 
When  the  whole  muscle  is  quite  dead,  this  cur- 
rent of  rest,  or  '  demarcation  current '  (Her- 
niaim),  disappears.  The  current  is  due  to  the 
electrical  differences  at  the  junction  of  living 
and  dying  (not  dead)  tissue.  If  the  sartorius 
of  the  frog  be  cut  out  and  immersed  for  twenty- 
four  hours  in  0-6  per  cent.  NaCl  solution  made  with  tap  water  {i.e.  con- 
taining hme),  all  the  injured  fibres  die,  and  the  uninjured  fibres  are  then 
found  to  be  iso-electric  and  therefore  currentless. 

The  existence  of  this  current  may  be  demonstrated  without  using  a  galva- 
nometer. If  the  nerve  of  a  sensitive  muscle-nerve  preparation  {a,  Fig.  80)  be 
allowed  to  fall  on  an  excised  muscle  h,  so  that  two 
points  of  the  nerve  are  in  contact  with  the  cut  end 
and  with  the  surface  of  the  second  muscle  6,  the 
muscle  a  will  contract  each  time  the  nerve  touches  h 
so  as  to  complete  the  circuit. 

Whatever  be  the  explanation  of  this  current  of 
resting  muscle,  there  is  no  doubt  that  a  very  definite 
electrical  change  occurs  in  a  muscle  when  it  contracts. 
To  show  this  change,  we  may  lead  off  two  points,  one 
on  the  cut  end  and  one  on  the  surface  of  the  muscle  of  a  nniscle-nerve  pre- 
paration, to  a  galvanometer.     We  shall  then  obtain  a  deflection  of  the  mirror 


Fic.  70. 
Rhcoscopic  frog. 


226 


PHYSIOLOGY 


of  the  magnet,  due  to  the  current  of  rest  or  demarcation  current.  If  now  the 
nerve  be  stimulated  with  an  interrupted  current  so  as  to  throw  the  muscle 
into  a  tetanus,  the  ray  of  hght  from  the  galvanometer  mirror  swings  back 
towards  the  zero  of  the  scale,  showing  that  the  current  which  was  present 
before  is  diminished.  When  the  excitation  of  the  nerv^e  is  discontinued,  the 
galvanometer  indicates  once  more  the  original  current  of  rest.  This 
diminution  of  the  current  of  rest  during  activity  of  a  muscle  is  spoken  of  as 
the  '  negative  variation.' 

In  carrjdng  out  this  experiment  it  is  usual  to  compensate  the  demarcation  current 
by  sending  in  a  small  fraction  of  the  current  from  a  constant  cell.  The  arrangement 
of  the  apparatus  is  represented  in  the  accompanying  diagram.     Two  non-polarisable 

D 


Fig.  80. 

electrodes  np  are  applied  to  the  surface  and  cross-section  of  a  muscle  m.  These  are 
connected  with  the  shunt  of  the  galvanometer,  one  of  the  wires,  however,  being  con- 
nected with  a  Pohl's  reverser  P,  and  this  in  its  turn  with  the  shunts.  The  two  end- 
terminals  of  the  reverser  are  coimected  with  a  rheochord,  through  the  wire  of  which 
ah  a  constant  current  is  passing  from  the  Daniell  cell  D.  By  means  of  the  rider  c  the 
fraction  of  current  passing  through  the  reverser  can  be  modified  to  any  extent.  The 
key  k  being  open,  the  muscle  is  connected  with  the  shunt  and  galvanometer,  and  the 
direction  and  extent  of  the  swing  noticed.  The  key  h  is  then  closed,  and  by  means 
of  the  reverser  the  current  is  sent  through  the  galvanometer  in  the  opposite  direction  to 
the  demarcation  current,  and  the  rider  c  shifted  until  the  two  cm'rents  exactly  b9,lance 
one  another,  and  the  needle  of  the  galvanometer  returns  to  zero  of  the  scale.  This 
adjustment  is  first  made,  using  only  y^j^  of  the  total  current,  and  then  by  means  of 


the  shunt, 


Jjj,  and  finally  the  whole  current  is  thrown  into  the  galvanometer. 


If  this  precaution  be  not  taken,  much  too  large  a  current  may  in  the  first  case  be  sent 

through  the  galvanometer,  to  the  detriment  of  the  instrument.     If  we  know  the  difference 

ac 
of  potential  between  the  two  ends  of  the  wire,  the  proportion  —r  will  give  us  the  E.M.F.  of 

the  demarcation  current.  The  galvanometer  needle  having  by  compensation  been 
brought  to  zero,  stimulation  of  the  nerve  at  e  by  interrupted  currents  causes  the  needle 
to  swing  at  once  in  the  opposite  direction  to  the  first  variation.  This  swing  is  the 
measure  of  the  negative  variation  or  current  of  action. 

In  order  to  study  the  electrical  changes  accompanying  a  single  muscle  twitch, 
it  is  necessary  to  employ  some  instrument  which  can  react  much  more  rapidly  than  the 


ELECTRICAL  CHANGES  IN  MUSCLE 


227 


ordinary  galvanometer.     For  this  purpose  we  may  employ  either  the  capillary  electro- 
meter or  the  string  galvanometer  of  Einthoven. 

The  capillary  electrometer  is  an  instrument  for  recording  and  measuring  difference 
of  potential.  That  is  to  say,  if  connected  with  two 
points,  it  measures  the  force  which  would  make  a 
current  flow  between  these  two  points  if  they  were 
comiected  by  a  wire.  Its  structure  is  very  simple.  It 
consists  of  a  glass  tube  di'awn  out  to  a  fine  capillary 
point.  This  tube  with  the  capillary  is  filled  with 
mercury.  The  point  dips  into  a  wide  tube  containing 
dilute  sulphuric  acid,  at  the  bottom  of  which  is  a 
little  mercury.  Two  platinum  wires  fused  into  the 
glass  and  dipping  into  the  mercury  serve  as  terminals. 
When  the  instrument  is  used,  the  meniscus  of  the 
merciu"y  in  the  capillary  at  its  junction  with  the  acid 
is  observed  under  the  microscope,  or  a  magnified 
image  of  it  is  thrown  on  a  screen  with  the  aid  of  the 
electric  light.  If  now  the  capillary  and  acid  be  con- 
nected with  two  points,  it  will  be  observed  that  any 
difference  in  the  potential  of  these  two  points  causes 
a  movement  of  the  meniscus.  If  the  point  comiected 
to  acid  be  negative  as  compared  with  the  point 
comiected  to  mercury  in  capillary,  the  meniscus 
moves  towards  the  point  of  the  cajiillary.  If  the 
acid  be  positive  as  compared  with  the  capillary,  the 
meniscus  moves  away  from  the  point.  The  extent 
of  the  excursion  is  proportional  to  the  difference  of 
potential.  Since  the  capillary  electrometer  appears 
to  have  no  latent  period,  and  is  free  from  instru- 
mental vibrations,  it  is  extremely  useful  in  recording 
the    quick  changes    in    potential  occurring  in  the 

diphasic   electrical   changes    that  accompany  every    Capillary  electrometer.     (Burcii.) 
contraction-wave  in  the  body.      The  excursions  lend 

themselves  well  to  photography,  so  that  we  may  obtain  a  graphic  record  of  every 
electrical  variation,  and  thus  determine  its  extent  and  its  time-relations. 

It  must  be  remembered  that  this  instrument  is  an  electrometer  (measurer  of  diifer- 
ence  of  potential),  and  not  a  galvanometer  (current  measurer).     When  the  electrometer 


Fig.  81. 


R 

Fig.  82.  Fig.  83. 

is  connected  with  two  points  at  different  potential,  current  passes  into  it  for  a  fraction 
of  a  second,  and  polarises  the  surface  of  the  mercury,  so  that  it  takes  up  a  new  position 


228 


PHYSIOLOGY 


Diagram  showing  diphasic  variation 
of  uninjured  muscle. 


in  the  capillary.  This  polarisation  causes  an  electromotive  force  which  exactly  balances 
the  E.M.F.,  setting  up  the  polarisation  so  no  current  passes  the  surface.  Hence  the 
use  of  non-polarisable  electrodes  is  not  so  essential  in  experiments  with  this  instrument 
as  when  we  make  use  of  the  galvanometer. 

In  the  D'Arsonval  galvanometer  (Fig.  82)  the  current  is  sent  through  a  coil  of  fine 
wire  hung  between  the  poles  of  a  permanent  magnet.  The  same  principle  is  made  use 
of  in  the  string  galvanometer  of  Einthoven  (Fig.  83).  In  this  a  very  delicate  thread 
of  silvered  quartz  or  of  platinum  is  stretched  between  the  poles  of  a  strong  magnet. 
The  poles  of  the  magnet  are  pierced  by  holes  so  that  the  thread  may  be  illumined  by 
an  electric  light  from  one  side,  and  from  the  other  may  be  observed  by  means  of  a 
microcope  ;  or  a  magnified  image  of  the  thread  may  be  thrown  upon  a  screen.  When- 
ever a  current  passes  through  the  thread  it  moves  laterally,  and  the  lateral 
movement  may  be  photographed  on  a  moving  photographic  screen.  Owing  to  the 
minute  dimensions  of  the  thread  the  instrument  is  one  of  extreme  delicacy.  It  will 
detect  very  minute  currents  and  will  respond  accurately  to  very  rapid  changes  in 
potential. 

If  a  perfectly  uninjured  regular  muscle  (Fig.  84),  such  as  the  sartorius, 

be  stimulated  with  a  single  in- 
duction shock  at  one  end,  x, 
and  two  points,  a  and  6,  be 
led  off  to  a  capillary  electro- 
meter, each  stimulus  appHed 
at  X  gives  rise  to  an  excursion 
of  the  meniscus  of  the  electro- 
meter, known  as  a  '  spike,'  and 

shown  in  Eig.  85.     Knowing  the  constants  of  the  instrument  used,  we 

can  analyse  this  spike,  and  we  find  that  it  represents  a  diphasic  change. 

Our  study  of  the   mechanical 

changes  in  muscle  has  shown 

that,  when  the  muscle  is  stim- 
ulated at  X,  a  contraction  wave 

commences  which  travels  down 

the  muscle  through  a  and  h. 

The  electrical   investigation  of 

the  muscle  shows  that  exci- 
tation of  X  arouses  an  electrical 

change  which  also  passes  down 

the  muscle  at  the  same  rate  as 

the  mechanical  change  which 

it  precedes.     If  we  are  leading 

off  from  X  and  a,  the  electrical 

change     ensues      immediately 

upon  stimulus,  i.e.  there  is  no 

latent   period  to  the  elpctrical 

chano^e.      On  leading  off  from  a    Fig.  8.5.     A  typical  electrometer  record  from  a  sar- 
T    ■/.  T  •  1    -      J.  -J        torius  muscle  excited  by  a  single  induction  shock. 

and  6  there  is  a   latent  period       Time-marking  =  200  D.V.     (Keith  Lucas.) 

between  the  stimulus   and  the 

first  change,  representing  the  time  taken  from  the  change  to  travel  from 

X  to  a.    When  the  change  reaches  a  this  becomes  the  seat  of  an  electro- 


ELECTRICAL  CHANGES  IN  MUSCLE 


229 


motive  force  of  such  a  direction  that  the  current  would  pass  in  the 
outer  circuit  from  b  to  a.  We  may  say,  therefore,  that  a  is  negative  to  b. 
A  fraction  of  a  second  later  the  excitatory  change  has  passed  on  to  b  and  has 
died  away  at  a.  Now  b  is  negative  to  a*  and  the  current  therefore  passes 
in  the  opposite  direction.  Between  a  and  b,  therefore,  there  is  a  diphasic 
current,  the  first  phase  representing  negativity  of  a  to  b,  and  the  second  phase 


""A" 

♦•04 

•03- 

M 

T  02- 

\^ 

^ 

..0, 

\\ 

\ 

T       -J 

1-  i 

\ 

-  01- 

\ 

[^ 

-  02- 

/ 

-■03- 

-  CM- 

j 

O 

1 

V. 

.,,,.-. 

.  . 

1     • 

'     ■     ■ 

Fiii.  86.     Diphasic  response  of  uninjured  sartorius  (obtained  by  analysis  of  curves  such  as 
Fig.  85).     A,  at  8°  C.  ;  B,  at  18°  C.     (Keith  Lucas.) 

representing  negativity  of  b  to  a.  A  diphasic  change  is  thus  also  a'  sign  of  a 
propagated  change.  Every  excitation  of  a  normal  muscle  gives  rise  to  a 
diphasic  variation  of  such  a  direction  that  the  point  stinmlated  first  becomes 

*  The  statement  that  the  excited  portion  of  the  muscle  becomes  '  negative/  tliough 
sanctioned  by  long  usage,  is  not  very  exact  and  may  give  rise  to  misconception.  When 
we  lead  oft  the  terminals  of  a  cojiper-zinc  couple  or  cell  to  a  galvanometer,  a  current 
flows  outside  the  cell  from  copper  to  zinc  and  inside  the  cell  from  zinc  to  copper.  In 
this  case  the  zinc  is  said  to  be  electropositive  to  the  copper,  and  in  the  same  way  we 
must  assume  that  the  excited  portion  of  a  muscle  is  electropositive  to  the  unexcited 
portions.  When,  therefore,  we  speak  of  any  part  of  a  tissue  being  negative,  we  are 
using  a  conventional  expression  to  indicate  the  direction  of  the  current  in  the  outer 
circuit,  and  not  the  electrical  condition  of  the  tissue  itself.  In  order  to  avoid  the  con- 
fusion which  might  result  from  an  attempt  to  replace  the  loose  expression  '  negative  ' 
by  the  more  correct  expression  '  electroijositive,'  Waller  has  suggested  the  employ- 
ment of  the  term  'zincative'  to  indicate  the  electrical  condition  accompanying 
excitation.  This  term  would  also  serve  to  emphasise  the  fact  that  tlie  excited  portion, 
like  the  zinc  in  a  zinc-copper  cell,  is  the  chief  seat  of  chemical  change. 


230  PHYSIOLOGY 

negative  to  all  other  points  of  the  muscle,  and  this  '  negativity ',  to  use  a  loose 
but  convenient  expression,  passes  as  a  wave  down  the  muscle,  preceding  the 
wave  of  contraction  and  travelhng  at  the  same  rate. 

If  one  leading-ofi  point  be  injured,  e.g.  at  h,  the  change  accompanying 
excitation  is  absent  at  that  point.  A  single  stimulus  apphed  at  x  will  in 
this  case  give  only  a  monophasic  variation  in  which  a  is  relatively  negative 
to  h. 

When  we  study  the  time  relation  of  the  electrical  variation  ensuing  on  a 
single  stimulus,  we  find  that  the  electrical  change  under  the  electrodes 
begins  at  the  moment  that  the  stimulus  is  apphed.  It  takes  about  -0025 
sec.  to  attain  its  culminating-point.  At  this  point  the  mechanical  change 
or  contraction  of  the  muscle  begins.  These  time-relations  vary  with  the 
temperature  of  the  muscle.  We  have  already  seen  that  the  efiect  of  lowering 
the  temperature  is  to  increase  the  latent  period  of  the  contraction.  In  the 
same  way  it  slows  the  rise  of  the  electrical  change  and  the  rate  of  propagation 
of  the  wave  of  electrical  change.  This  is  shown  in  Fig.  86,  in  which  are 
given  the  diphasic  response  of  the  sartorius  first  at  8°  C.  and  secondly  at 
18°  C.  We  are  therefore  justified  in  regarding  the  electrical  change  as  an 
index  to  the  chemical  changes  evoked  in  the  muscle  as  the  direct  result  of  the 
stimulus.  The  flow  of  material,  which  is  responsible  for  the  change  in  form 
of  each  contracting  unit,  is  secondary  to  these  changes.  As  the  result  of 
stimulation,  a  chemical  change  is  aroused  at  the  point  of  excitation  and 
travels  thence  along  the  muscle  fibres  at  a  rate  of  about  three  metres  per 
second,  i.e.  the  same  rate  as  that  of  the  following  wave  of  mechanical  change 
and,  hke  this,  varying  with  the  temperature.  Under  certain  conditions 
an  excitatory  condition  may  be  propagated  without  the  presence  of  a  visible 
contraction.  Thus,  if  the  middle  third  of  the  sartorius  be  soaked  for  a  time 
in  water,  it  passes  into  a  condition  known  as  '  water  rigor,'  in  which  it  is 
incapable  of  contracting,  although  capable  of  transmitting  an  excitation  from 
one  end  of  the  muscle  to  the  other. 

The  connection  of  a  diphasic  current  of  action  with  an  excited  condition 
of  the  tissues  passing  as  a  wave  from  one  end  to  the  other  is  shown  still  more 
clearly  on  a  slowly  contracting  tissue,  such  as  the  ventricle  of  the  frog  or 
tortoise.  Fig.  87,  a,  is  a  photographic  record  of  the  variation  obtained  from 
the  tortoise  ventricle,  which  is  led  off  to  a  capillary  electrometer,  one  (acid) 
terminal  being  connected  with  the  base  of  the  ventricle,  the  other  (mercury) 
with  the  apex.  Each  part  of  the  ventricle  remains  contracted  for  a  period  of 
\\  to  2  seconds,  and  then  the  contraction  passes  of!,  first  at  the  base  and  later 
at  the  apex.  The  electrical  events  are  an  exact  replica  of  the  mechanical. 
Directly  after  the  stimulus  has  been  applied,  the  base  becomes  negative  and 
the  column  of  mercury  moves  up.  A  moment  later  the  excitatory  condition 
extends  to  the  apex.  There  is  thus  a  sudden  equahsation  of  potential 
between  the  two  terminals,  and  the  mercury  comes  back  quickly  to  the  base 
line.  Here  it  stays  for  1|  to  2  seconds.  During  this  time  the  whole  heart  is 
in  an  excited  condition.  Both  base  and  apex  are  equally  excited,  and  there 
can  be  no  difference  of  potential  between  them.     The  excitatory  condition 


ELECTRICAL  CHANGES  IN  MUSCLE  231 

then  passes  off,  first  at  the  base  and  then  at  the  apex.  There  is  thus  a  small 
period  of  time  in  which  the  apex  is  still  contracted  or  excited  while  the  base 
is  relaxed,  and  the  apex  is  therefore  negative  to  the  base.  This  terminal 
negativity  of  the  apex  is  shown  on  the  photograph  by  the  excursion  of  the 
column  of  mercury  away  from  the  point  of  the  capillary.  If  one  terminal, 
e.g.  the  apex,  be  injured,  we  obtain  quite  a  different  variation,  which  is  shown 
in  Fig.  87,  b.   It  is  evident  from  this  figure  that  the  electrical  sign  lasts  practi- 


FiG.  87.     Electrometer  records  of  the  electrical  variations  in  a  tortoise  ventricle, 

excited  to  beat  rhythmically  by  single  shocks. 

A,  Ventricle  uninjured,     b.  One  leading  oflf  spot  injured.     (B.  Sajidersox.) 

cally  as  long  as  the  mechanical  sign  of  the  excited  state,  and  that  we  are  not 
justified  in  regarding  the  first  spike  of  the  diphasic  variation  as  indicative 
of  an  excitatory  wave  attended  by  an  electrical  change  which  is  independent 
of  the  succeeding  mechanical  change. 

The  only  difference  between  the  electrical  changes  in  this  case  and  in  that 
of  voluntary  muscle  is  that  in  the  latter  all  processes  are  very  much  quicker, 
so  that  as  a  rule  the  point  a  (Fig.  81)  has  ceased  to  be  negative  before  the 
negativity  of  h  has  attained  its  full  height,  and  there  is  thus  no  prolonged 
equipotential  stage. 

Although  iu  the  case  of  the  slowly  contracting  ventricle  of  the  tortoise,  the  record 
obtained  of  the  electrical  changes  accompanying  its  contraction  by  means  of  the  capillary 
electrometer  shows  with  great  clearness  the  diphasic  nature  of  the  variation,  and  there- 
fore the  wave  character  of  the  electrical  change,  considerable  difficulty  is  experienced 
sometimes  in  recognising  that  the  '  spike  '  record  of  the  electrical  change  in  voluntary 
muscle  or  in  nerve  is  also  due  to  a  diphasic  variation.     In  this  case  the  electrical  change 


232  PHYSIOLOGY 

at  any  spot  lasts  only  about  ^1^  second,  and  there  is  not  a  prolonged  equipotential 
period,  as  in  the  case  of  the  heart.  The  natm-e  of  the  variation  is,  however,  obvious,  if 
we  compare  the  electrometer  record  of  an  intact  and  therefore  currentless  muscle  with 
that  of  a  muscle  in  which  one  of  the  leading-off  points  has  been  injm-ed,  so  as  to  give 
rise  to  a  demarcation  current.  The  two  curves  are  given  in  Fig.  88,  the  upper  shadowy 
tracing  being  that  obtained  from  the  injured  muscle.  It  will  be  seen  that  the  dis- 
tinguishing character  of 
an  electrometer  record  of 
a  diphasic  variation  in 
the  rapidly  contracting 
striated  muscle  consists 
in  the  fact  that  the  down- 
stroke  of  the  image  of 
the  meniscus  is  as  rapid 
as  the  upstroke,  whereas 
the  monophasic  variation 
of  the  injured  muscle 
presents  a  slow  fall  pro- 
duced by  the  gradual 
leakage  of  the  charge  imparted  to  the  instrument  back  tlu?ough  theelectrodes  and  muscle. 
When  such  a  record  is  analysed,  we  obtain  a  curve  similar  to  those  in  Fig.  89,  which  retire- 
sent  monophasic  variations  of  a  sartorius  injured  at  one  end,  under  different  conditions  of 
temperature.     A  similar  curve  to  the  diphasic  variation  can  be  obtained  by  putting 


Fig.  88.  Superimposed  photographs  of  the  J  electrical  varia- 
tion of  the  sartorius  in  response  to  a  single  stimulus. 
(Btjedon  Sanderson.) 


then  in  a  reverse  direction 
for  another  -^Iq- second.  It 
must  be  remembered  that 
a  diphasic  variation  does  not 
mean  that  one  part  of  a 
muscle  changes  from  normal 
in  one  direction,  and  then 
swings  back  past  the  normal 
in  another  direction,  but 
that  a  change  in  one  direc- 
tion at  one  electrode  dies 
away  and  is  succeeded  by  a 
similar  change  in  the  same 
direction,  which  also  dies 
away,  at  the  second  electrode : 
that  is  to  say,  a  diphasic 
variation  implies  the  pro- 
gression of  a  wave  of  electrical 
change  between  the  leading- 
off  points.  Using  a  string 
galvanometer,  which  reacts 
much  more  rapidly,  the 
diphasic  nature  of  the  varia- 
tion is  immediately  apparent 
from  the  photographic  record, 
even  with  voluntary  muscle.  Fig. 
or  nerve. 


STIM  /  j 


89.      Monophasic  variations   of  an  injured  sartorius. 
A,  at  18°  C.  ;  B,  at  8°  C.     (Keith  Lucas.) 


The  electrical  variation  obtained  by  leading  off  a  heart  beating  normally 
is  a  much  more  complex  affair,  and  even  now  physiologists  are  not  agreed  as 
to  its  interpretation.  Gotch  has  suggested  that  the  complex  character  of 
the  variations  obtained  both  from  the  spontaneously  beating  frog's  heart  as 


ELECTRICAL  CHANGES  IN  MUSCLE  233 

well  as  from  the  mammalian  heart  is  due  to  the  twisting  and  alteration  in 
direction  of  the  fibres  and  of  the  course  of  the  contraction  wave  which  have 
occurred  in  the  evolution  of  the  heart  from  a  simple  tube.  The  question  will 
be  discussed  more  fully  in  chapter  xiii. 

THE  DEMARCATION  CURRENT  OR  CURRENT  OF  INJURY 
According  to  Hermann,  muscle  or  nerve  may  become  negative  under 
two  conditions  :  (1)  During  activity  ;  (2)  when  dying  as  the  result  of  injury. 
It  is  doubtful,  however,  whether  these  two  conditions  are  really  distinct. 
Section  or  injury  of  a  muscle  causes  a  prolonged  stimulation  of  the  adjacent 
parts  of  the  muscle  fibres.  These  parts,  therefore,  being  excited,  must  be 
negative  to  the  unexcited  parts  which  are  further  away  from  the  seat  of  injury 
so  that  a  demarcation  current  is  really  an  excitatory  current.  We  thus 
come  to  the  conclusion,  only  paradoxical  in  terms,  that  the  so-called  currents 
of  rest  are  really  currents  of  action  and  are  due  to  excitation  around  the 
injured  spot.* 

SECONDARY  CONTRACTION.      RHEOSCOPIC  FROG 

The  negative  variation  of  one  muscle  may  be  used  to  make  another 
contract. 

If  the  nerve  of  the  preparation  a  (in  Fig.  90)  be  laid  so  as  to  touch  at  two 
points  the  cut  end  and  surface  of  the  muscle  h,  and  the 
nerve  of  h  then  stimulated  with  single  induction 
shocks,  every  contraction  of  h  will  be  attended  by  a 
contraction  of  a,  excited  by  the  negative  variation 
of  the  current  passing  through  its  nerve  from  the 
point  touching  the  cut  end  to  that  in  contact  with 

the  equator  of  h. 

.  .  Fio.  90. 

If   the    nerve   of  h  is  tetanised,    a  as   well   as  h         Rheoscopic  frog. 

enters  into  a  continued  contraction.     This  '  secondary 

tetanus  '  is  of  interest  as  showing  that,  although  the  contractions  of  h  are 

fused,  the  excitatory  process  and  negative  variations  are  still  quite  distinct. 

*  If  the  demarcation  current  is  really  only  due  to  excitation,  -we  should  expect 
to  find  it  weaker  than  the  action  current  obtained  by  exciting  the  whole  muscle  to 
contract.  And  this  is  the  case.  The  E.M.F.  of  the  demarcation  current  of  a  sar- 
torius  equals  about  0-05  of  a  Daniell  cell.  The  action  cm'rent  of  the  same  muscle  may 
attain  to  an  E.M.F.  =  0-08  of  a  Daniell  cell  (Gotch). 


8* 


SECTION  VIII 

THE   INTIMATE  NATURE  OF  MUSCULAR 
CONTRACTION 

Experiments  on  the  metabolism  of  the  body  as  a  whole  show  that  the 
energy  of  muscular  work  is  derived  from  the  oxidation  of  the  food-stuffs. 
In  man  the  performance  of  work  involves  an  increase  of  the  oxidative 
processes  of  the  body  with  a  corresponding  evolution  of  energy,  of  which 
four-fifths  will  appear  as  heat  while  one-fifth  may  be  transformed  into 
mechanical  work.  In  this  respect  the  physiological  mechanisms  for  the 
production  of  mechanical  energy  resemble  the  greater  number  of  the  machines 
employed  by  man  for  the  same  purpose.  In  nearly  all  these  the  prime 
source  of  energy  is  the  oxidation  of  carbon  ^nd  hydrogen  in  the  form  of 
coal  or  oil.  In  the  steam-engine  and  internal-combustion  engine  the  whole 
energy  set  free  by  the  process  of  oxidation  appears  first  as  heat,  and  then  a 
certain  portion  of  the  heat  is  converted  into  mechanical  work.  There 
is  a  hmit  to  the  efficiency  of  such  heat  engines,  depending  on  the  maximum, 
differences  of  temperature  available  between  the  two  sides  of  the  working 
part  of  the  machine.     The  efficiency  of  any  heat  engine  is  expressed  by 

T  -  Ti 

the  formula  E  =  — ^ — ,  where  T  is  the  highest  temperature  (in  absolute 

measurement)  obtained  by  the  working  substance  and  T^  is  the  lowest 
temperature  of  the  same  substance.  Ordinary  engines  rarely  attain  more 
than  half  this  ideal  efficiency,  but  it  is  evident  that  the  greater  the  difference 
of  temperature  available  the  greater  will  be  the  efiiciency  of  the  machine. 
Internal- combustion  engines,  such  as  the  gas  engine  or  the  oil-engine, 
therefore  give  a  greater  percentage  of  the  total  energy  of  the  fuel  out  as 
mechanical  energy  than  is  the  case  with  the  steam-engine. 

Engelmann  has  maintained  that  in  muscle  there  is  a  similar  transforma- 
tion of  heat  into  mechanical  energy.  He  has  found  that  non-living  sub- 
stances, which  contain  doubly  refractive  particles  and  possess  the  property 
of  imbibition  {e.g.  catgut)  when  soaked  with  water,  will  contract  on  heating 
and  relax  again  on  coohng.  He  has  constructed  a  model  in  which  a  thread 
of  catgut  in  water,  surrounded  by  a  platinum  coil,  can  be  made  to  simulate 
muscular  contractions  and  relaxations  by  passing  a  heating  current  through 
the  platinum  coil.  He  imagined  that  the  chemical  changes  in  the  muscle 
liberate  heat  and  that  the  effect  of  this  heat  upon  the  doubly  refractive 
particles  is  to  make  them  imbibe  the  surrounding  water  so  that  they  change 

234 


THE  INTIMATE  NATURE  OF  MUSCULAR  CONTRACTION    235 

from  an  oval  to  a  spherical  shape.  It  would  be  impossible,  however,  for 
any  large  changes  of  temperature  to  take  place  in  the  muscle  without  en- 
tirely destroying  its  chemical  character,  and  with  small  differences  of  tem- 
perature it  would  be  impossible  to  attain  the  efhciency  of  12  to  20  per  cent, 
which  characterises  muscle. 

Under  certain  conditions  we  may  obtain  by  a  machine  almost  the  entire 
energy  of  a  chemical  change.  The  condition  is  that  the  chemical  change 
shall  be  susceptible  of  taking  place  in  a  galvanic  battery.  We  may  use, 
for  instance,  a  series  of  Daniell  cells  to  drive  an  electric  motor  and  allow 
the  motor  to  perform  mechanical  work.  Under  these  circumstances  we 
could  theoretically  obtain  100  per  cent,  of  the  total  chemical  energy  avail- 
able, and  in  conditions  of  practice  the  efficiency  of  the  machine  may  attain 
to  70  or  80  per  cent.  A  similar  arrangement  might  be  present  in  the  ultimate 
contracting  elements  of  the  muscle  fibre.  The  mechanism  in  the  fibre  must 
be  one  which  will  provide  for  a  more  or  less  direct  transformation  of  chemical 
energy  into  mechanical  energy  without  a  previous  conversion  of  the  chemical 
into  heat  energy.  In  the  living  body,  where  everything  is  in  solution,  all 
the  energies  may  be  reduced  to  one  of  two  kinds,  osmotic  energy  and  surface 
energy.  The  contractile  machine  must  therefore  be  one  which  employs 
one  or  other,  or  both,  of  these  forms  of  energy.  We  might  with  Macdougall, 
regard  the  contractile  element  as  a  cylindrical  structure  differing  in  its 
contents  from  the  surrounding  sarcoplasm.  When  the  muscle  is  at  rest 
the  contents  of  the  muscle  prism  will  be  in  equihbrium  with  the  surrounding 
sarcoplasm.  We  might  imagine  the  excitatory  process  to  consist  in  a  sudden 
chemical  change  occurring  in  the  contents  of  the  muscle  prism.  The 
production  of  a  number  of  new  molecules  within  the  muscle  prism  {e.g.  of 
lactic  acid)  would  raise  tlie  osmotic  pressure  within  the  prism  and  occasion 
a  rapid  flow  of  water  from  the  sarcoplasm.  As  a  result  the  pressure  in  the 
muscle  prism  would  rise  and  cause  a  bulging  of  its  lateral  wall  and  a  shorten- 
ing of  the  whole  element.  The  subsequent  phase  of  relaxation  may  be  due 
either  to  a  secondary  change,  e.g.  oxidation,  leading  to  the  formation  of  a 
substance  to  which  the  walls  of  the  prism  are  freely  permeable,  or  to  the 
gradual  leak  of  the  primary  products  of  oxidation  or  disintegration  into  the 
sarcoplasm.  The  substance  or  substances  giving  rise  to  the  osmotic  differ- 
ences which  determine  contraction  may  be  either  products  such  as  lactic 
acid  and  carbon  dioxide,  which  are  formed  during  contraction,  or  may 
possibly  be  of  the  nature  of  neutral  salts  set  free  from  some  condition  of 
combination  with  the  proteins  of  the  sarcous  element.  Macdonald  has 
brought  forward  micro-chemical  evidence  of  the  appearance  of  potassium 
salts  in  the  sarcous  element  during  the  state  of  activity  of  the  muscle. 

On  the  other  hand,  Bernstein  has  suggested  that  the  changes  during 
muscular  contraction  arc  determined  by  alterations  in  surface  tension. 
If  a  little  mercury  be  spilt  on  a  plate  tlie  particles  form  globules.  They  are 
kept  from  spreading  themselves  out  in  a  thin  liltu  under  the  influence  of 
gravity  inconsequence  of  tlie  surface  tension  of  the  mercury.  Any  modification 
of  the  surface  will  alter  the  tension,  and  therefore  state  of  expansion,  of  the 


236  PHYSIOLOGY 

globule.     Thus,  if  the  globule  be  in  sulphuric  acid  it  undergoes  a  certain 

amount  of  polarisation,  and  becomes  positively  charged.     By  altering  the 

charge  of  such  a  globule  we  can  change  its  shape,  as  is  shown  diagram- 

matically  in  Fig.  91.     If  b  represents  the  shape  of  the  globule  lying  on  the 

plate  in  some  weak  sulphuric  acid,  a  will  represent  the  shape  of  the  globule 

when  it  is  connected  with  the  negative  pole  of  a  battery,  while  c  will  repre- 

_  sent  its  shape  when  it  is  connected 

^  with  the  positive  pole  of  a  battery, 

the  other  pole    in    each   case  being 

connected    with    the    acid.      If    we 

consider  muscle   as   made  up   of  a 

series  of  chains  of  oval  particles,  a 

chemical  change  in  the  surface  of  these  particles,  causing  an  increase  of 

surface  tension,  will  tend   to  make  them  assume  the  globular  shape,  and 

will  therefore  cause  a  shortening  and  thickening  of  the  whole  fibre. 

According  to  Schafer,  contraction  is  associated  with  a,  flow  of  the  outer  hyaline 
contents  of  the  sarcous  element  into  the  tubular  structiu'e  forming  the  middle  portion. 
Such  a  flow  may  be  determined  either  by  osmotic  differences  between  the  centre  and 
periphery  of  the  sarcous  element,  or  by  a  change  in  the  surface  tension  obtaining  between 
the  isotropic  fluid  at  the  ends  and  the  anisotropic  structures  in  the  centre  of  the  muscle 
prism. 

The  tendency  of  recent  investigation  is  all  in  favour  of  the  second  hypo- 
thesis, namely,  that  the  essential  factor  in  the  processes  of  excitation  and 
contraction  is  an  alteration  of  surface.  In  the  first  place  the  electrical 
changes  accompanying  the  excitatory  process  denote  a  polarisation  or 
accumulation  of  ions  on  the  surfaces  situated  in  the  excited  area.  The 
chemical  change  which  is  responsible  for  the  current  of  action,  or  the  negative 
charge  at  the  excited  spot,  takes  place  almost  instantaneously  and  disappears 
somewhat  more  slowly.  It  would  seem  that  the  excitatory  process  consists 
essentially  in  the  setting  free  of  certain  ions  on  the  surface  or  surfaces  in 
the  contractile  tissue,  and  that  the  passing  away  of  the  excitatory  state 
is  due  to  the  disappearance  of  these  ions,  either  by  diffusion  away  into  the 
surrounding  fluid  or  by  further  chemical  changes,  such  as  oxidation.  A 
study  of  the  development  of  tension  and  of  heat  production  in  a  muscle  on 
excitation  has  shown  that  in  both  cases  the  yield  of  energy  on  excitation 
is  increased  by  lengthening  and  diminished  by  shortening  the  muscle.  Now 
alteration  in  length  of  the  muscle  will  not  alter  its  volume,  but  will  alter 
the  extent  of  its  longitudinal  surfaces,  and  it  appears  therefore  that  the 
production  of  heat  as  well  as  of  mechanical  energy  is  not  a  volume,  but  a 
surface  effect.  Finally  the  work  of  A.  V.  Hill  on  the  heat  production  in 
muscle  seems  to  show  that  the  rise  of  tension  in  a  muscle  on  excitation  is 
due  to  the  hberation  of  chemical  bodies,  of  which  lactic  acid  is  certainly  one, 
in  the  neighbourhood  of  certain  longitudinal  surfaces  or  membranes,  and 
that  the  presence  of  these  bodies  changes  the  tension  at  such  surfaces  and 
thereby  the  longitudinal  tension  of  the  fibre.  The  extent  and  intensity  of 
the  production  of  these  bodies  must  depend  on  the  area  of  the  chemically 


THE  INTIMATE  NATURE  OF  MUSCULAE  CONTRACTION    237 

active  surfaces.  The  muscle  reacts  at  the  end  of  the  excitatory  stage^  not 
by  any  active  process  of  lengthening,  but  by  neutrahsation,  or  simply  physical 
diffusion  of  the  active  chemical  bodies  away  from  the  interfaces  or  mem- 
branes. Later  on,  lactic  acid  is  removed  or  replaced  by  its  previously 
unstable  precursor  under  the  influence  of  oxygen  with  the  production  of  some 
carbon  dioxide  and  a  certain  amount  of  heat.  We  have  seen  already  that 
the  efficiency  of  the  initial  chemical  change  in  which  lactic  acid  is  set  free 
may  approximate  100  per  cent. 

It  must  be  noted  that  although  the  oxidative  processes  are  responsible 
ultimately  for  all  the  energies  of  the  higher  animal,  no  oxidative  change 
is  involved  in  the  production  of  lactic  acid  from  e.g.  glucose,  nor  is  the 
presence  of  oxygen  necessary  for  the  contraction  of  muscle  to  take  place. 
On  the  other  hand,  if  we  wish  to  obtain  the  maximum  amount  of  work 
from  a  muscle,  we  must  supply  it  richly  with  oxygfen,  the  presence  of 
which  seems  essential  not  to  the  contractile  process  but  to  the  stage  of 
recovery.  In  this  stage  a  certain  amount  of  heat  is  evolved,  set  free  by 
the  oxidation  of  the  lactic  acid,  and  we  must  assume  that  part  of  the 
energy  so  available  is  utihsed  for  building  up  the  precursor  from  which 
the  lactic  acid  is  derived.  It  is  as  if  the  process  of  oxidation  furnished 
the  energy  for  winding  up  a  spring,  whereas  excitation  removed  a  catch  and 
allowed  the  spring  to  run  down,  setting  free  this  energy  for  the  performance 
of  work  or  for  conversion  into  heat.* 

For  many  years  it  was  imagined,  as  a  result  of  expeiiments  by  Hermann,  Pfliiger, 
and  othei's,  that  the  oxygen  sujiplied  to  a  muscle  was  built  up  with  its  other  constituents, 
especially  carbohydrates,  into  a  complex  'inogen'  molecule.  On  stimulation  this  mole- 
cule underwent  an  explosive  rearrangement,  the  carbohydrate  and  oxj'gen  parts  of 
the  molecule  combining  to  form  carbonic  acid,  another  product  of  the  decomposition 
being  lactic  acid.  The  careful  experiments  of  Fletcher  have  shown,  however,  that 
in  the  absence  of  oxygen  there  is  no  e\idence  of  the  formation  of  carbonic  acid  during 
contraction,  and  therefore  no  reason  to  assume  the  presence  of  oxygen  in  the  muscle 
in  an  intramolecular  form.  Everything  points  to  oxygen  being  taken  in  and  applied 
forthwith  to  the  pm-posesof  oxidation,  so  that  the  output  of  carbon  dioxide  and  water 
keeps  pace  with  the  intake  of  oxygen. 

It  is  at  present  quite  impossible  to  come  to  any  conclusion  as  to  the  nature  of  the 
precursor  from  which  the  lactic  acid  is  derived.  The  immediate  precursor  cannot  be 
glucose  or  glycogen  since  the  heat  evolved  in  the  initial  stage  of  contraction  is  two  or 

*  Peters  has  shown  that  if  a  muscle  be  stimulated  to  exhaustion  under  anaerobic 
conditions,  about  0-2  per  cent,  lactic  acid  is  formed  with  the  evolution  of  -9  calories 
per  gramme  of  muscle  substance.  The  production  of  1  gm.  of  lactic  acid  is  therefore 
accompanied  by  the  evolution  of  450  calories.  According  to  A.  V.  Hill  the  '  recovery 
heat  production  '  in  oxj'gen  is  of  about  the  same  order  as  the  initial  heat  production, 
so  that  in  the  oxidative  removal  of  1  gm.  of  lactic  acid  there  would  also  be  an  evolution 
of  about  450  calories.  The  oxidation  of  1  gm.  of  lactic  acid  produces  3700  calories, 
about  eight  times  as  much  as  the  quantity  observed.  Hill  considers  this  amount 
far  too  large  to  have  escaped  detection  in  his  experiments,  and  therefore  concludes 
that  the  lactic  acid  is  not  oxidised  but  replaced  in  its  previous  position  under  the 
influence  and  with  the  energy  of  the  oxidation  either  ;  [a)  of  a  small  part  of  the  lactic 
acid  itself,  or  {h)  some  other  body.  He  regards  the  latter  alternative  as  the  more 
probable,  and  concludes  therefore,  that  the  lactic  acid  is  part  of  the  machine  ard  not 
part  of  the  fuel  of  the  muscle. 


238  PHYSIOLOGY 

three  times  as  great  as  could  be  derived  from  the  mere  conversion  of  either  of  these 
substances  into  lactic  acid.  We  must,  therefore,  conclude  that  the  oxidation  of  lactic 
acid  which  goes  on  during  the  process  of  recovery  is  used  to  yield  the  energy  necessary 
for  building  up  the  active  molecules,  which  are  the  precm'sors  of  lactic  acid  and  which 
have  a  higher  potential  energy  than  glucose  itself,  so  that  when  it  rapidly  decomposes 
sufficient  energy  is  set  free  to  account  for  the  observed  heat  production.  Some  such 
utilisation  of  the  energy  of  oxidation  of  the  lactic  acid  is  indicated  by  the  results  of 
Parnas,  who  found  that  the  heat  evolved  dm'ing  this  recovery  process  corresponded  to 
only  about  one  half  the  heat  which  would  be  evolved  by  the  formation  of  the  carbon 
dioxide  output  of  the  muscle  during  the  same  time  as  a  result  of  the  oxidation  of  lactic 
acid. 


SECTION  IX 

VOLUNTARY   CONTRACTION 

The  whole  of  our  analysis  of  the  processes  accompanying  the  contraction 
of  a  skeletal  muscle  has  so  far  had  reference  merely  to  the  contractions 
evoked  by  artificial  stimuli,  mainly  electric.  These  contractions  have 
either  been  the  simple  twitch,  with  a  duration  of  about  one- tenth  of  a  second, 
evoked  by  a  momentary  stimulus,  or  the  tetanus,  a  continued  contraction 
composed  of  a  number  of  single  twitches,  summated  and  fused  together. 
Under  normal  circumstances  the  contraction  of  skeletal  muscles  is  brought 
about  either  reflexly,  or  in  response  to  some  stimulus  descending  from  the 
cerebral  cortex,  the  so-called  '  voluntary  contraction.'  These  contractions 
may  have  a  duration  of  almost  any  extent.  The  quickest  contractions 
carried  out  by  man  have  a  duration  of  about  0-1  sec.  Considerable  effort 
and  training  are  required  to  reduce  a  muscular  movement  to  this  degree, 
and  nearly  all  contractions,  even  the  rapid  ones,  last  considerably  over 
0-1  sec.  Since  we  have  no  certain  means  of  producing  contractions  of  any 
given  length,  except  by  means  of  repeated  stimuh,  it  is  natural  that  physiolo- 
gists have  regarded  voluntary  contractions  as  similar  to  the  artificial  tetanus, 
and  as,  like  this,  composed  of  fused  single  contractions,  and  have  endeavoured 
to  determine  the  number  of  contractions  per  second,  i.e.  the  natural  rhythm 
of  the  tetanus.  If,  however,  every  muscular  contraction  in  the  body  is  to 
be  regarded  as  of  the  nature  of  a  tetanus,  effected  by  rapidly  repeating 
stimuli  sent  down  the  motor  nerve  from  the  central  nervous  system,  we 
must  assume  a  similar  discontinuity  for  the  process  underlying  the  normal 
tone  of  muscles,  and  for  the  continued  contraction  of  unstriated  muscles, 
e.g.  of  the  arteries.  Is  this  discontinuity  of  muscles  really  essential  for  the 
production  of  a  prolonged  contraction  ?  So  far  as  our  present  knowledge 
of  the  intimate  nature  of  muscular  contraction  goes,  it  would  seem  quite 
possible  that  the  continuous  state  of  contraction  is  dependent  on  a  continuous 
evolution  of  energy  in  the  muscle.  We  have  seen  reason  to  regard  the 
chemical  processes  in  a  contracting  muscle  as  presenting  two  phases,  namely, 
(1)  the  production  of  a  substance  which  increases  the  osmotic  pressure 
within  the  sarcous  elements,  or  raises  the  surface  tension  of  the  ultimate 
contractile  elements  of  the  muscle,  thus  causing  a  shortening  and  thickening 
of  those  elements  ;  and  (2)  the  further  change  of  this  substance  into  one 
which  can  escape  by  diffusion,  or  into  a  substance  with  a  low  surface  tension, 
so  that  now  the  muscle  relaxes  and  can  be  stretched  by  any  extending 

239 


240  PHYSIOLOGY 

force.  If  these  two  phases  went  on  continuously,  but  the  Jfirst  phase  kept 
ahead  of  the  second  one,  a  continuous  state  of  contraction  would  be  produced 
in  the  muscle.  Since  the  contraction  of  the  muscle  only  occurs  in  response 
to  impulses  from  the  central  nervous  system,  we  should  have  to  imagine 
also  a  continuous  stream,  e.g.  of  negatively  charged  ions,  descending  the 
nerve  and  evoking  an  excitatory  change  in  the  muscle  fibres  as  they  impinge 
on  the  neuro -muscular  junction.  We  have  evidence  that  a  state  of  excita- 
tion of  a  nerve,  which  is  apparently  continuous,  may  excite  a  correspondingly 
continuous  state  of  excitation  in  the  muscle  attached.  During  the  passage 
of  a  constant  current  through  muscle  there  is  a  continuous  contraction  in 


Fig.  92.     Continued  contraction  followed  by  rhythmic  contractions  of  a  muscle 
in  response  to  a  constant  stimulas.     (Biedbemenn.) 
The  muscle  was  excited  by  the  passage  of  a  constant  current,  the  cathoda 
end  having  been  moistened  with  a  weak  solution  of  NaC03. 

the  neighbourhood  of  the  cathode.  If  the  irritabihty  of  the  muscle  at  this 
point  be  increased  by  the  apphcation  of  a  solution  of  sodium  carbonate, 
Biedermann  has  shown  that  this  excitation  is  propagated  to  the  rest  of  the 
muscle,  and  on  closure  of  the  current  we  obtain  a  prolonged  contraction 
followed  by  rhythmic  contractions  (Fig.  92).  Moreover  in  frogs,  the  ex- 
citabihty  of  which  has  been  heightened  by  keeping  them  at  2°  to  3°  C.  for 
some  days,  the  closure  of  a  descending  current  through  the  sciatic  nerve 
causes  a  prolonged  contraction  of  the  gastrocnemius  ;  and  in  the  same  way 
there  may  be  a  prolonged  contraction  produced  by  the  opening  of  an  ascend- 
ing current  through  the  nerve. 

The  question,  however,  can  only  be  decided  by  experiment.  If  a  volun- 
tary or  reflex  contraction  is  of  the  nature  of  a  tetanus,  we  should  be  able, 
by  a  study  of  the  mechanical  and  electrical  phenomena  combining  the 
contraction,  to  obtain  distinct  evidence  'of  this  causation.  It  was  shown 
by  Wollaston  that,  on  hstening  to  a  contracting  muscle,  a  low  sound  was 
heard  which,  according  to  him,  corresponded  to  a  vibration  frequency  of 
36  to  40  per  second.  The  same  observation  was  made  by  Helmholtz,  and 
can  be  repeated  by  any  one  who  will  place  the  end  of  a  stethoscope  on  a 
muscle,  e.g.  the  biceps,  and  listen  to  the  sound  produced  when  it  contracts, 
Helmholtz  pointed  out,  however,  that  the  tone  heard  corresponded  to  the 
resonance  tone  of  the  external  ear,  and  was  the  same  as  that  noted  when 
listening  to  any  irregular  sound  of  low  intensity.  Thus  the  roar  of  London 
that  we  hear  in  the  middle  of  Hyde  Park  has  the  same  pitch  as  the  muscle 
sound  of  the  contracting  biceps.  The  muscle  sound,  therefore,  teaches  us 
nothing  as  to  the  pitch  or  number  of  contractions  per  second  making  up  the 


VOLUNTARY  CONTRACTION  241 

voluntary  tetanus.  It  merely  points  to  an  irregularity  or  discontinuity  in 
this  contraction.  By  bringing  ^^brating  reeds  of  different  frequency  in 
contact  with,  the  contracting  muscles  of  the  frog,  Helmholtz  came  to  the 
conclusion  that  the  chief  element  in  the  muscle  sound  was  the  first  over-tone 
of  a  sound  with  a  vibration  frequency  of  18  to  20  per  second,  which,  according 
to  him,  was  to  be  taken  as  representing  the  number  of  single  contractions 
in  every  voluntary  muscular  contraction. 

Nearly  all  voluntary  contractions  present  a  certain  degree  of  irregularity, 
and  the  same  irregularities  are  observed  when  a  tetanic  spasm  in  the  muscle 
of  the  body  is  caused  by  strong  excitation  of  the  cerebral  cortex,  as  in  epilepsy. 
On  taking  a  record  of  such  contractions,  Schaefer  and  Horsley  showed  that 
in  nearly  all  cases  the  tracing  presents  superposed  undulations  repeated  at 
the  rate  of  eight  to  twelve  per  second.  These  observers  concluded  that  this 
was  the  normal  rate  at  which  the  impulses  descend  the  nerve  to  arouse  a 
voluntary  contraction.  One  difficulty  in  this  conclusion  is  that  when  human 
muscle  is  excited  by  eight  to  twelve  stimuU  per  second,  we  obtain,  not  a 
tetanic  contraction  with  a  few  irregularities  superposed  on  it,  but  a  series 
of  single  contractions,  the  so-called  clonus.  In  order  to  produce  a  nearly 
continuous  contraction  we  must  employ  a  vibration  frequency  of  about 
30  per  second.  It  has  been  suggested  to  get  over  this  difficulty  that  under 
normal  circumstances  the  discharge  does  not  travel  along  all  the  nerve  fibres 
at  the  same  time,  so  that  the  difierent  muscle  fibres  composing  the  muscle 
will  be  in  different  phases  of  contraction,  and  there  will  be  never  any  large 
degree  of  relaxation  between  the  individual  contractions  of  the  whole  muscle. 
Von  Kries  has  found  that  the  duration  of  a  muscle  twitch  may  be  lengthened 
by  lengthening  the  duration  of  the  electrical  change  used  to  excite  the  nerve, 
and  has  suggested  that  the  normal  excitatory  process  may  resemble  the 
prolonged  electrical  change  which  can  be  produced  electro-magnetically, 
rather  than  the  short  sudden  shock  represented  by  the  induced  current 
of  an  induction-coil.  Attempts  have  been  made  to  decide  the  question  by 
recording  the  electrical  changes  accompanying  the  natural  contractions 
of  a  muscle,  i.e.  those  excited  reflexly  from  the  central  nervous  system. 
It  was  long  ago  shown  by  Loven  that  a  certain  discontinuity  could  be  seen 
in  records  of  the  electrical  changes  obtained  from  a  frog's  muscle  in  the 
tetanic  spasms  produced  by  an  injection  of  strychnine,  but  according  to 
Burdon  Sanderson  this  discontinuity  represents  a  series  of  spasms  discharged 
from  the  central  nervous  system.  Each  discharge  produces,  not  a  t'svitch, 
but  a  continued  contraction  of  short  duration.  On  photographing  the 
electrical  changes  of  strychnine  spasm  as  obtained  by  a  capillary  electro- 
meter, he  found  that  each  individual  spasm  could  only  be  compared  to  a 
short  tetanus.  The  most  recent  investigations  of  the  question  we  owe  to 
Piper,  who  made  use  of  the  string  galvanometer,  an  instrument  much  more 
delicate  in  the  reproduction  of  rapid  changes  than  is  the  capillary  electro- 
meter. Piper  led  off  two  points  in  the  fore-arm,  one  electrode  being  placed 
about  two  inches  below  the  bend  of  the  elbow,  and  the  other  about'four 
inches  above  the  wrist.     A  single  stimulus  of  the  median  nerve  was  found 


242  PHYSIOLOGY 

by  him  to  give  a  typical  diphasic  variation  in  the  muscles.  When  the 
muscles  were  contracted  voluntarily,  well-marked  oscillations  of  the  galvano- 
meter wire  were  obtained,  indicating  the  existence  in  the  muscle  of  forty- 
eight  to  fifty  complete  diphasic  variations  in  the  second  (Fig.  93).  Piper 
obtained  similar  records  on  leading  off  other  muscles  of  the  body  when  these 
were  placed  voluntarily  in  a  state  of  contraction,  and  he  concludes  therefore 
that  each  voluntary  contraction,  short  or  long,  is  a  tetanus  composed  of 
about  fifty  fused  twitches  per  second.     These  results  would  indicate  that 


Fig.  93.     Electrical  variations  produced  by  voluntary  contractions  of 
human  muscle.     (Piper.) 

the  impulse,  which  normally  travels  down  the  motor  nerve  from  the  anterior 
cornual  cell  to  the  muscle,  is  discontinuous,  and  therefore  that  on  leading 
off  a  motor  nerve  to  a  galvanometer  we  ought  to  obtain  electrical  oscillations 
of  fifty  distinct  stimuh  per  second.  Dittler  has  investigated  by  means  of 
the  string  galvanometer  the  electrical  changes  accompanying  the  ordinary 
contractions  of  the  diaphragm,  and  also  those  occurring  in  the  phrenic 
nerve.  He  finds  that  both  in  the  muscle  and  in  the  nerve  there  is 
evidence  that  each  contraction  is  a  fused  series  of  single  contractions, 
evoked  by  the  discharge  along  the  nerve  of  between  fifty  and  seventy 
excitations  per  second.  So  far  therefore  the  evidence  is  in  favour  of  the 
view  that  voluntary  contraction,  and,  one  must  add,  the  tonic  contractions 
of  all  skeletal  muscles,  are  discontinuous  in  nature  and  analogous  to  the 
tetanus  which  we  may  evoke  artificially  by  rapid  stimulation  either  of 
muscle  or  of  its  motor  nerve. 


SECTION  X 
OTHER  FORMS  OF  CONTRACTILE  TISSUE 

SMOOTH  OR   UNSTRIATED  MUSCLE 

The  little  we  know  about  the  physiology  of  unstriated  muscle  is  derived 
chiefly  from  experiments  on  the  intestine,  ureter,  bladder,  and  retractor 
penis.*  This  tissue  differs  from  voluntary  muscle  in  containing  numerous 
plexuses  of  nerve  fibres  (non-medullated)  and  ganglion-cells,  so  that  in  all 
our  researches  it  is  difficult  to  be  certain  whether  the  results  are  due  to  the 
muscle  fibres  themselves,  or  to  the  nerves  and  nerve-cells  which  are  so  inti- 
mately connected  with  them  ;  especially  as  we  have  as  yet  no  convenient 
drug  Uke  curare,  by  aid  of  which  we  might  discriminate  between  action  on 
muscle  and  action  on  nerve. 

The  differences  between  unstriated  and  voluntary  muscle,  although  at 
first  sight  very  pronounced,  on  further  investigation  prove  to  be  in  most 
cases  differences  of  degree  only,  quahties  and  reactions  which  are  marked 
in  involuntary  muscle  being  also  present  in  a  minor  degree  in  the  more 
highly  differentiated  tissue. 

The  contraction  of  smooth  muscle  is  so  sluggish  that  the  various  stages 
of  latent  period,  shortening,  and  relaxation  can  be  easily  followed  with  the 
eye.  The  latent  period  may  be  from  0-2  to  0-8  second,  and  the  contraction 
may  last  from  three  seconds  to  three  minutes. 

Smooth  muscle  preserves  many  of  the  properties  of  undift'erentiated 
protoplasm,  especially  an  automatic  power  of  contraction,  which  is  regulated 
by  the  condition  of  the  muscle.  Thus  whereas  the  voluntary  muscle  is 
intimately  dependent  on  its  connection  with  the  central  nervous  system, 
and  in  the  absence  of  this  is  reduced  to  a  flabby  inert  tissue,  the  smooth 
muscle,  isolated  from  all  its  nervous  connections,  presents  in  many  cases 
rhythmic  contractions,  and  can  carry  out  a  peripheral  adaptation  to  its 
environment.     These  rhythmic  contractions  are  almost  invariably  observed 

*  The  retractor  penis,  which  is  found  in  the  dog,  cat,  horse,  hedgehog  (but  not  in 
rabbit  or  man),  is  a  thin  band  of  longitudinally  arranged  unstriated  muscle,  which 
is  inserted  at  the  attachment  of  the  prepuce,  and  is  continued  backwards  in  a  sheath  of 
connective  tissue  to  the  bulb,  where  it  divides  into  two  slips,  which  pass  on  eitlier  side 
of  the  anus.  It  is  innervated  from  two  sources,  the  motor  fibres  being  derived  from 
the  lumbar  sympathetic  and  running  to  the  muscle  in  the  internal  pudic  nerve,  while 
the  inhibitory  fibres  run  in  the  pelvic  visceral  nerves  (nervi  erigentes)  and  are  derived 
from  the  second  and  third  sacral  nerve-roots. 

•243 


244  PHYSIOLOGY 

if  the  muscular  tissue  be  subjected  to  a  certain  amount  of  tension,  after 
separation  from  the  central  nervous  system.  The  rhythm  of  the  contrac- 
tions may  vary  from  one  (spleen)  to  twelve  (small  intestine)  contractions 
in  the  minute. 

The  stimuli  for  smooth  muscle  are  essentially  the  same  as  for  striated. 
As  we  should  expect,  however,  from  the  sluggish  response  of  this  kind  of 
contractile  tissue,  the  optimum  rate  of  change  of  current  which  excites  is 
very  much  slower  than  in  the  case  of  striated  muscle.  Thus  in  many  in- 
stances a  single  induction  shock,  even  if  very  strong,  is  powerless  to  excite 
contraction,  and  the  make-induction  shock  of  long  duration  and  low  intensity 
is  always  more  efficacious  than  the  short  sharp  break-induction  current. 
A  still  better  stimulus  is  the  make  or  break  of  a  constant  current.  When 
the  latter  form  of  stimulation  is  used,  response  occurs  at  the  make  sooner 
than  at  the  break,  and,  just  as  in  the  voluntary  muscle,  the  make  excitation 
starts  from  the  cathode  and  the  break  excitation  from  the  anode. 

An  apparent  exception  to  this  statement  is  afforded  by  the  behaviour  of  certain 
forms  of  involuntary  muscle.     In  the  intestine,  in  the  skin  of  worms,  and  in  many 

other  muscular  tubes  the  smooth 
muscle-fibres  are  arranged  in  two 
different  sheets,  one  consisting  of  longi- 
tudinal, the  other  of  circular  fibres. 
If  non-polarisable  electrodes,  connected 
with  a  constant  source  of  ciurent,  be 
applied  to  the  surface  of  the  small 
intestine,  when  the  current  is  made 
K  A  there  will  be  apparently  a  strong  con- 

FiG.  94.  At  the  cathode'K'there  is  a  small  line  traction  of  the  circular  coat  at  the 
of  constriction,  surrounded  by  an  area  of  anode,  which  spreads  up  and  down  the 
relaxation.  At  the  anode  itself  the  muscle  intestine,  and  a  linear  contraction  of 
IS  relaxed,  but  is  strongly  contracted  on  each  . 

side  of  the  anode,  so  that  on  rough  observation  the  longitudinal  coat  at  the  cathode, 
it  would  be  thought  that  contraction  occurred  The  same  result  is  observed  in  the 
at  the  anode  itseK.  earthworm     and    leech.      But    careful 

observation  shows  in  each  case  that  the 
irregularity  is  really  only  apparent,  and  that  in  the  immediate  neighbourhood  of  the 
anode  there  is  relaxation  of  both  coats,  with  a  contraction  of  the  circular  coat  on  each 
side,  and  that  at  the  cathode  there  is  a  contraction  of  both  coats.  The  accompanying 
diagram  (Fig.  94)  will  serve  to  show  the  condition  of  the  circular  coat  at  each  electrode. 

As  a  matter  of  fact,  in  con- 
sequence of  the  arrangement  of 
the  fibres,  we  have  in  the  neigh- 
bourhood of  the  anode  a  number 
of  places  (virtual  cathodes)  where 
the  currc  nt  is  leaving  the  muscle- 
cells  to  enter  inert  conducting  — 
tissues,  and  in  the  same  way  ^ 
there  will  be  in  the  neighbom'- 
hood  of  the  cathode  a  number  of 
virtual  anodes  (Fig.  95).  Thus 
if  we  take  the  ureter  and  lead  a 
current  through  it  while  it  is 
slung  up  in  thread  loops  serving 
as  electrodes,  there  is  contraction  of  both  coats  at  the  cathode  and  relaxation 
of  both  at  the  anode.     If,  however,  the  ureter  be  packed  in  a  pulp  of  blotting-paper 


95.  Diagram  to  show  the  spread  of  current  which 
occurs  when  a  current  is  led  through  a  tube  such  as  the 
ureter  by  means  of  two  electrodes  applied  to  its  surface. 
It  will  be  noticed  that  while  +  E  is  the  anode,  there  are 
immediately  below  and  around  it  a  number  of  cathodes, 
E^,  E^,,  E,^,,  E,^,,  due  to  the  current  leaving  the  muscle  to 
flow  through  indifferent  tissues.     (Biedermann.) 


OTHER  FORMS  OF  CONTRACTILE  TISSUE  245 

moistened  with  normal  saline,  thus  allowing  the  current  to  leave  the  contractile  tissues 
anywhere  along  the  ureter,  we  get  the  same  aberrant  results  of  stimulation  as  are 
obtained  with  the  intestine. 

In  voluntary  muscle,  if  one  stimulus  follows  another  at  an  interval 
which  is  not  too  large,  a  summated  contraction  is  produced  which  is 
greater  in  amphtude  than  that  due  to  a  single  stimulus.  This  summa- 
tion may  be  mechanical  or  physiological,  the  former  being  observed 
when  the  stimulus  is  repeated  during  the  decline  of  the  excitatory  process 
and  being  due  simply  to  the  after-loading  of  a  muscle  by  the  first  contraction. 
It  is  best  marked  when  the  muscle  is  heavily  loaded.  If,  however,  the 
stimuU  be  sent  in  at  sufficiently  short  intervals  so  that  two  stimuli  fall 
within  the  period  of  rise  of  contractile  stress,  an  increased  height  of 
contraction  is  obtained  under  all  conditions,  and  under  isometric 
conditions  the  tension  developed  is  greater  than  that  with  a  single 
stimulus.  If  the  interval  between  two  stimuh  be  so  short  that  the 
second  falls  within  what  we  have  called  the  refractory  period  due  to 
the  first  stimulus,  no  summation  is  obtained,  the  second  stimulus  being 
ineffective. 

In  the  slow  contraction  of  involuntary  muscle  we  could  hardly  expect 
mechanical  summation  to  come  into  play.  Most  types  of  this  tissue  show, 
however,  the  true  summation,  i.e.  the  increased  hberation  of  energy  due 
to  repetition  of  the  stimulus  during  the  rise  of  the  excitatory  condition. 
As  might  be  expected  the  refractory  period  is  also  longer  in  involuntary 
muscle,  since  all  the  processes  of  this  muscle  are  slowed  in  comparison  with 
those  of  voluntary  muscle.  In  certain  types  of  tissue,  and  especially  in 
heart  muscle,  the  refractory  period  lasts  during  the  whole  of  the  period 
of  contraction.  During  this  time  therefore  a  second  shock  ^^^U  be  ineffective. 
As  the  contraction  dies  away  the  muscle  fibre  gradually  recovers  its  sus-- 
ceptibility  to  stimulation,  but  it  does  not  recover  its  full  irritabiUty  until 
it  has  entirely  relaxed.  On  this  account  it  is  impossible  to  obtain  summa- 
tion in  or  to  tetanise  heart  muscle,  the  apphcation  of  interrupted  currents 
to  this  tissue  producing  only  a  series  of  rhythmic  contractions. 

In  all  involuntary  muscle  we  may  observe  summation  of  the  effects  of 
stimuli  even  when  the  individual  stimuh  are  insufficient  to  produce  any 
excitation.  Thus  in  a  muscle  such  as  the  retractor  penis,  we  may  find  a 
strength  of  induction  shock  which,  appUed  singly,  is  just  insufficient  to  evoke 
any  response.  If,  however,  the  shocks  are  repeated  at  intervals  of  a  second, 
it  will  be  found  that  the  first  three  or  four  stimuh  are  ineffective  and  then 
the  muscle  enters  into  a  contraction  which  increases  with  each  succeeding 
stimulus  until  it  has  attained  its  maximum.  There  is  thus  summation 
before  any  contraction  has  occurred,  a  summation  of  stimuli.  Each  stimulus, 
in  fact,  alters  the  state  of  the  contractile  tissus  and  makes  it  more  ready 
to  respond  to  the  next  stimulus,  so  that  the  stimuli  become  more  and  more 
effective.  If  time  is  allowed  for  the  muscle  to  relax  between  successive 
stimuh,  this  summation  is  evidenced  by  a  continually  increasing  height 
of   contraction,  the   so-called    '  staircase.'     The  same    initial  increase   of 


246  PHYSIOLOGY 

efiect  is  observed  when  voluntary  muscle  is  excited  by  continually  recurring 
stimuU  {v.  Fig.  70,  p.  209). 

We  shall  meet  with  other  examples  of  this  summation  of  stimuh  when 
deahng  with  the  physiology  of  the  central  nervous  system.  It  is  indeed  a 
fundamental  phenomenon  in  the  physiology  of  excitation. 

CHEMICAL  STIMULATION.  Strong  salt  solution  excites  contractions 
just  as  in  the  case  of  skeletal  muscle.  Many  drugs,  such  as  physostigmine, 
ergot,  salts  of  lead  and  barium,  digitalis,  may  act  directly  on  smooth  muscle 
and  cause  contraction.  As  one  would  expect,  however,  from  the  greater 
independence  of  the  smooth  muscle,  the  action  of  these  drugs  varies  from 
organ  to  organ,  muscle-fibres,  which  apparently  are  histologically  identical, 
reacting  diversely  according  to  their  origin. 

MECHANICAL  STIMULATION.  Smooth  muscle  may  react  to  a  local 
pinch  or  blow  with  a  local  or  a  general  (propagated)  contraction.  The  most 
important  form  of  mechanical  stimulation  is  that  produced  by  tension. 
The  efiect  of  increasing  the  tension  on  smooth  muscle  may  be  twofold  : 
causing  in  the  first  place  relaxation  and  in  the  second  excitation  with  in- 
creased contraction.  These  two  efiects  may  be  illustrated  by  taking  the 
case  of  the  bladder.  If  this  viscus  (which  is  surrounded  by  a  complete 
coat  of  smooth  muscle)  has  all  its  connections  with  the  central  nervous 
system  severed,  it  is  when  empty  in  a  state  of  tonic  contraction.  If  fluid 
be  injected  into  it  rapidly  there  is  a  great  rise  of  pressure  in  its  cavity,  due 
to  the  forcible  distension.  If,  however,  the  fluid  be  injected  slowly  the 
bladder  muscle  relaxes  to  make  room  for  it,  so  that  a  considerable  amount 
of  fluid  may  be  accommodated  in  the  bladder  without  any  great  rise  of 
pressure.  This  process  of  relaxation  has  its  limit.  If  the  injection  of  fluid 
be  continued  the  walls  begin  to  be  stretched  passively,  and  this  increased 
tension  acts  as  a  stimulus  causing  marked  rhythmic  contractions  of  the 
whole  bladder. 

In  the  same  way  the  response  of  a  smooth  muscle  to  an  electrical  stimulus 
is  much  increased  by  previous  increase  of  the  tension  on  the  muscle  fibres. 

PROPAGATION  OF  THE  EXCITATORY  STATE,  OR  WAVE  OF 
CONTRACTION.  On  stimulating  any  part  of  a  voluntary  muscle  fibre, 
a  wave  of  contraction  is  started  which  travels  to  each  end  of  the  fibre,  but 
no  further.  There  is  no  propagation  from  muscle  fibre  to  muscle  fibre, 
the  synchronous  contraction  of  the  whole  muscle  being  brought  about  by 
simultaneous  excitation  of  all  its  fibres.  It  is  doubtful  whether  this  isolation 
of  the  excitatory  state  is  found  in  smooth  muscle.  As  a  rule  a  stimulus 
applied  to  any  part  of  a  sheet  of  smooth  fibres  may  travel  all  over  the  sheet 
just  as  if  it  were  a  single  fibre.  It  seems  probable  indeed  that  there  is 
protoplasmic  continuity  by  means  of  fine  bridge-like  processes  between 
adjacent  muscle  cells.  And  even  in  the  absence  of  such  bridges  the  propaga- 
tion of  the  contraction  could  be  easily  accounted  for.  Although  in  the  case 
of  voluntary  muscle  the  rule  is  isolated  contraction,  yet  a  very  small  change 
in  the  muscle,  such  as  that  produced  by  partial  drying  or  by  pressure,  is 
sufficient  to  cause  the  contraction  to  spread  from  one  fibre  to  another. 


OTHER  FORMS  OF  CONTRACTILE  TISSUE 


247 


Indeed  by  clamping  two  curarised  sartorius  muscles  together,  as  in  the 
diagram  (Fig.  96),  it  is  found  that  stimulation  of  the  muscle  a  causes  con- 
traction of  the  muscle  b.     The  current  of  action  of  a  in  this  case 
has  served  to  excite  a  contraction  in  b.  a! 

It  must  be  remembered  that  in  all  unstriated  muscle  the  fibres  are  sur- 
rounded by  a  network  of  non  medullated  nerve  fibres.  Some  physiologists  are 
inclined  to  ascribe  to  these  fibres  an  important  part  in  the  propagation  of  the 
contraction  wave.  In  the  case  of  the  heart  muscle,  however,  it  can  be  shown 
almost  conclusively  that  thein'opagation  take  splace  independently  of  nerve 
fibres,  and  i^robably  the  same  is  true  for  many  kinds  of  involuntary  muscle. 

INFLUENCE  OF  TEMPERATURE.  Smooth  muscle  is  extremely  sus- 
ceptible to  changes  of  temperature  ;  as  a  rule  warming  causes  relaxation, 
while  appUcation  of  cold  causes  a  tonic  contraction.  The  condition  of  the 
muscle  at  any  given  time  depends  not  only  on  its  actual  temperature, 
but  also  on  the  rapidity  with  which  this  temperature  has  been  reached. 
Thus  a  rapid  coohng  of  the  retractor  penis  muscle  of  a  dog  from  35°  to  25° 
may  cause  a  contraction  as  extensive  as  would  be  produced  by  a  slow  coohng 
to  5°  C.  On  warming  a  muscle  from  30°  to  50°  C.  it  lengthens  gradually  up 
to  about  40°,  and  it  may  then  undergo  a  marked  heat  contraction  (varying 
in  degree  in  different  muscles)  at  about  50°  C,  which  may  pass  off  at  a 
somewhat  higher  temperature.  It  is  killed  somewhere  between  40°  and 
50°  C.  It  seems  very  doubtful  whether  any  true  rigor  mortis  occurs  in 
smooth  muscle.  The  hard  contracted  appearance  of  the  smooth  muscle 
in  a  recently  dead  animal  is  chiefly  conditioned  by  the  fall  of  temperature. 
On  excising  the  muscle  and  warming  it  up  to  body  temperature  it  may 
again  relax  and  show  signs  of  irritabihty  two  or  three  days  after  the  death 

of  the  animal.  Different  smooth 
muscles,  however,  vary  very  much 
in  their  tenacity  of  life. 

DOUBLE  INNERVATION. 
Voluntary  muscle  is  absolutely 
dependent  for  its  activity  on  the 
central  nervous  system.  Cut  of? 
from  this  it  is  flabby  and  motionless. 
Its  sole  fmiction  is  to  contract 
efficiently  and  smartly  on  receipt 
of  impulses  arriving  along  its  nerve. 
It  is  only  necessary  therefore  that 
these  impulses  should  be  of  one 
character — motor,  and  we  know  that 
each  fibre  of  a  muscle,  such  as  the 
sartorius,  receives  one  ett"erent  nerve 
fibre  terminating  in  an  end-plate. 
In  the  case  of  smooth  muscle  we  have  a  tissue  which  has  an  activity 
and  reactive  power  of  its  own,  and  apart  from  its  innervation  may  be  at 
one  time  in  a  state  of  relaxation,  at  another  in  a  state  of  tonic  contraction. 


Fig.  97.  Tracing  from  tho  retractor  penis  nivisole 
of  the  dog.  showing  lengthening  (inhibition) 
on  stimulation  of  the  nervus  erigens,  and  a 
smart  contraction  on  stimulating  the  pudic 
(motor)  nerve.  (Movements  of  muscle  re- 
duced I.) 


248  PHYSIOLOGY 

In  order  that  the  central  nervous  system  should  have  efficient  control  over 
such  a  tissue,  it  must  be  able  to  influence  it  in  two  directions  :  it  must  be 
able  to  induce  a  contraction  or  increase  a  contraction  already  present,  and 
it  must  also  be  able  to  put  an  end  to  a  spontaneous  contraction,  i.e.  to  induce 
relaxation.  In  order  to  carry  out  these  two  effects,  smooth  muscle  receives 
nerve  fibres  of  two  kinds  from  the  central  nervous  system,  one  kind  motor, 
analogous  to  the  motor  nerves  of  skeletal  muscle,  the  other  kind  inhibitory, 
causing  relaxation  or  cessation  of  a  previous  contraction.  All  these  fibres 
belong  to  the  visceral  or  '  autonomic '  system.  They  are  connected  with 
gangHon-cells  in  their  course  outside  the  central  nervous  system,  and  their 
ultimate  ramifications  in  the  muscle  are  always  non-medullated,  A  typical 
tracing  of  the  opposite  effects  of  these  two  sets  of  nerves  is  given  in  Fig.  97. 

In  the  invertebrata  many  '  voluntary '  striated 
muscles  probably  possess  a  double  innervation. 
Thus  in  the  crayfish  the  adductor  muscle  of  the  claw 
consists  of  striated  muscular  fibres,  every  fibre  of 
which  is  supplied  with  two  kinds  of  nerve  fibres. 
By  exciting  these  fibres  one  may  get,  according  to 
the  conditions  of  the  experiment,  either  contraction 
of  a  relaxed  muscle  or  relaxation  of  a  tonically  con- 
tracted muscle  (Fig.  98). 


AMCEBOID   MOVEMENT 


Fig.    98.     Tracing   of   contraction 
of  adductor  muscle  of   claw   of 

crayfish,  showing  inhibition  re-         Amceboid  movement  is  Seen  in  the  uni- 

sulting  from  stimulation  of  its        ti    i  •  i  ,■,  r.  ^ 

nerve  (at  b)  by  means  of  a  con-  cellular  orgamsms  such   as  the  amoeba  and 

stant  current.     The  break  of  the   in  the  white  blood   corpuscles.      It  can  OCCUr 
current  causes  a  second  smaller         ,  .,,.  ,.        ■,■     -,  r     , 

inhibition.    (BiEDEEMANN.)         ouly    Within   certain    hmits   of   temperature 

(about  0°  C.  to  40°) ;  within  these  limits  it  is 
the  more  active  the  higher  the  temperature.  At  about  45°  the  cell  goes 
into  a  condition  resembhng  heat  rigor. 

The  fluid  in  which  the  corpuscles  are  suspended  is  of  great  importance. 
Distilled  water,  almost  all  salts,  acids  and  alkaUes,  if  strong  enough,  stop  the 
action  and  kill  the  cell. 

The  movements  are  also  stopped  by  CO 2  or  by  absence  of  oxygen. 

Artificial  excitation,  whether  electrical,  chemical,  or  thermal,  causes 
universal  contraction  of  the  corpuscle,  which  therefore  assumes  the  spherical 
form. 

CILIARY  MOVEMENT 

Ciha  are  met  with  in  man  in  nearly  the  whole  of  the  respiratory  passages 
and  the  cavities  opening  into  them,  in  the  generative  organs,  in  the  uterus 
and  Fallopian  tubes  of  the  female,  and  the  epididymis  of  the  male,  and  on  the 
ependyma  of  the  central  canal  of  the  spinal  cord  and  its  continuation  into 
the  cerebral  ventricles. 

The  ciha  (Fig.  99)  are  dehcate  tapering  filaments  which  project  from  the 
hyaline  border  of  the  epithehal  cells.  There  are  about  twenty  or  thirty  to 
each  cell.  The  hyaline  border  is  really  made  up  of  the  enlarged  basal  portions 
of  the  ciha.  -j 


OTHER  FORMS  OF  CONTRACTILE  TISSUE 


249 


111  action  the  cilia  bend  suddenly  down  into  a  hook  or  sickle  form,  and 
then  return  slowly  to  the  erect  position.  This 
movement  is  repeated  many  (twelve  to  twenty) 
times  a  second,  and  thus  serves  to  move  forward 
mucus,  dust,  or  an  ovum,  as  the  case  may  be. 
The  movement  seems  to  be  entirely  automatic, 
and  it  is  quite  unaffected  by  nerves,  at  any  rate 
in  all  the  higher  animals. 

There  is,  however,  a  functional  connection 
between  all  the  cells  of  a  cihated  epithelial 
surface,  so  that  movement  of  the  ciha,  started  in 
one  cell,  spreads  forward  as  a  wave,  just  as, 
when  the  ■\\and  blows,  waves  of  bending  pass 
over  a  field  of  corn. 

The  conditions  of  ciliary  action  are  the  same 
as  those  for  amoeboid  movement  of  naked  cells. 

The   minuteness    of    the    object    has    up   to 
now  prevented   us   from  deciding    whether  the 
cilium  is  itself  actively  contractile,  or  whether  it  is  simply  passively  moved 
by  the  action  of  the  basal  part  situated  in  the  hyaline  border  of  the  cell. 


rro^  nV  rn." 

Fig.    99.       Ciliated   columnar 
epithelium  from  the  trachea 


of   a   rabbit 
mucus-secreting 

(SCHAFER.) 


cells. 


CHAPTER  VI 
NERVE   FIBRES  (CONDUCTING  TISSUES) 


SECTION  I 
THE  STRUCTURE  OF  NERVE  FIBRES 

ON  stimulating  the  nerve  of  a  nerve-muscle  preparation  at  any  part  by 
electrical,  thermal,  or  mechanical  means,  the  stimulus  is  followed,  after 

a  very  short  interval,  by  a  contraction 
of  the  muscle.  This  observation  illus- 
trates the  two  functions  of  nerve  fibres, 
irritability  and  conductivity — that  is  to  say, 
a  suitable  stimulus  can  set  up  changes  in 
any  part  of  the  nerve,  which  are  trans- 
mitted down  the  nerve  without  any  visible 
effects  occurring  in  it,  and  it  is  not  until 
this  nervous  change  has  reached  the 
muscle  that  a  visible  effect  takes  place  in 
the  shape  of  a  contraction.  In  the  animal 
body  a  direct  excitation  of  the  nerve 
fibre  in  its  course  never  takes  place  under 
normal  circumstances.  The  only  func- 
tion the  nerve  fibre  has  to  perform  is  that 
of  conducting  impulses  from  the  sense 
organs  at  the  periphery  to  the  central 
nervous  system,  and  efferent  impulses 
from  this  to  the  muscles  and  other  of 
its  servants.  Hence  it  is  absolutely  es- 
sential that  there  should  be  vital  continuity 
along  the  whole  length  of  the  fibre.  Damage 
to  any  part,  such  as  by  crushing,  heat,  or 
any  other  injurious  condition,  infallibly 
causes  a  block  to  the  passage  of  an  im- 
pulse. 

A  nerve  fibre  is  essentially  a  long  pro- 
cess or  arm  of  a  nerve-cell  (Fig.  100).     The 

Fig.  100.    Diagram  of  a  motor  nerve-  ^ell  may  either  be  situated  on  the  surface  of 
cell   with  its   nerve   fibre.      (After     ,      ,      t  .  ■      ,t      ^  ■   ^ 

Bakkbr.)  the  body  or,  as  m  most  cases  m  the  higher 

a.h,  axon  hillock ;     d,  dendrites ;  animals,    may    be    withdrawn    from    the 
a.x,   axis   cylinder ;    m,    medullary  c  •    ,  •    i       n     j_-  <•       n  ^ 

sheath-  n.ii,  node  of  Kanvier.  surtace  mto  a  special  collection  01  cells  sucn 

250 


THE  STRUCTURE  OF  NERVE  FIBRES 


251 


as  the  posterior  root  ganglion,  or  may  be  one  of  the  mass  of  cells  and  inter- 
lacing processes  making  up  a  central  nervous  system.  All  nerves  are  alike 
in  possessing  as  their  conducting  part  the  continuous  strand  of  protoplasm 
produced  from  the  nerve-cell  and  known  as  the  axon  or  axis  cyhnder.  By 
special  methods  the  axon  may  be  shown  to  be  made  up  of  fibrillse  or 
neuro-fibrils,  embedded  in  a  more  fluid  material  (Fig.  101).     These  neuro- 


FiG.  101.     Medullcatcd  nerve  fibres,  showing  continuity  of  the  neuro-fibrils  across 
the  node  of  Ranvier.     (Bethe.) 
a,  longitudinal ;   h,  transverse  section. 

fibrils  are  supposed  to  be  continuous  throughout  the  cell  and  the  axis 
cyhnder  and  to  represent  the  essential  conducting  constituents  of  the  nerve. 
In  the  course  of  growth  the  nerves  develop  certain  histological  differences, 
which  appear  to  bear  some  relation  to  the  nature  of  the  processes  they  con- 
duct or  to  the  character  of  their  parent  cell.  Thus  all  the  fibres  which  are 
given  off  from  and  which  enter  the  central  nervous  system,  i.e.  the  brain  and 
spinal  cord,  belong  to  the  class  known  as  medullated.  In  this  type  the 
conducting  core  or  axis  cyhnder  is  surrounded  with  a  layer  of  apparently 
insulating  material  known  as  myehn,  forming  the  medullary  sheath,  or  the 
sheath  of  Schwann.  This  sheath  consists  of  a  fatty  material  composed  largely 
of  lecithin,  and  staining  black  with  osmic  acid,  supported  in  the  interstices 
of  a  network  formed  of  a  horny  substance  knOwn  as  neurokeratin.  The 
medullary  sheath  is  surrounded  by  a  structureless  membrane,  the  primitive 
sheath  or  neurilemma.  At  regular  intervals  a  break  occurs  in  the  medullary 
sheath,  the  neurilemma  coming  in  close  contact  with  the  axis  cyhnder.     This 


252  PHYSIOLOGY 

break  is  the  node  of  Ranvier,  the  intervening  portions  of  medullated  nerve 
being  the  internodes.  In  each  internode,  lying  closely  under  the  neurilemma, 
is  an  oval  nucleus  embedded  in  a  little  granular  protoplasm.  The  medullated 
nerve  fibres  vary  considerably  in  diameter,  the  largest  fibres  being  distributed 
to  the  muscles  and  skin,  the  smallest  carrying  impulses  from  the  central 
nervous  system  to  the  viscera.  The  latter  all  come  to  an  end  in  some  collec- 
tion of  ganghon-cells  of  the  sympathetic  chain  or  peripheral  ganglia,  the 
impulses  being  carried  on  to  their  destination  by  a  fresh  relay  of  non- 
medullated  nerve  fibres. 

The  non- medullated  fibres  (Fig.  102)  differ  from  the  medullated  simply 
in  the  absence  of  a  medullary  sheath.  They  possess,  in  many  cases  at  any 
rate,  a  primitive  sheath,  under  which  we  find  nuclei  lying  closely  on  the  side 


Fig.  102.     Non-meduUated  nerve  fibres.     (Schaper.) 

of  the  fibre  and  bulging  out  the  sheath.  In  their  ultimate  ramifications 
they  tend  to  form  close  networks  or  plexuses  and  appear  to  lose  the  last 
traces  of  a  sheath. 

The  medullated  nerves  are  bound  together  by  connective  tissue  (endo- 
neurium)  into  small  bundles,  which  are  again  united  by  tougher  connective 
tissue  into  larger  nerve-trunks.  These  fibres  as  a  rule  branch  only  when  in 
close  proximity  to  their  destination,  and  then  the  branching  always  occurs  at 
a  node  of  Ranvier. 

As  to  the  functions  of  the  myehn  sheath  in  the  medullated  nerve  fibre 
very  httle  is  known.  It  does  not  make  its  appearance  until  the  axis  cylinder 
is  formed,  and  is  apparently  derived  from  a  series  of  cells  which  grow  out  from 
the  spongioblasts  of  the  central  nervous  system  and  form  a  chain  surrounding 
the  out-growing  axons.  In  the  regeneration  of  a  nerve  fibre  after  section 
the  myehn  sheath  appears  later  than  the  axon  in  the  peripheral  part  of  the 
nerve.  It  has  been  supposed  by  some  to  act  as  a  sort  of  insulator  ensuring 
isolated  conduction  within  any  given  nerve  fibre.  We  have,  however,  no 
proof  that  equally  isolated  conduction  is  not  possible  in  the  non- medullated 
fibres  of  the  visceral  system,  although  it  is  certainly  true  that  a  finer 
ordering  of  movements  is  required  in  the  skeletal  muscles  than  in  the 
visceral  unstriated  muscles.  Moreover  in  the  central  nervous  system  the 
main  tracts  cannot  be  shown  to  be  functional  before  the  date  at  which  they 
acquire  their  medullary  sheaths,  suggesting  that  previously  any  impulse 
making  its  way  along  the  tract  underwent  dissipation  before  arriving  at  its 
destination.  It  is  possible  too  that  the  myehn  sheath  may  serve  as  a  source 
of  nutrition  to  the  enclosed  axis  cylinder,  which,  in  the  greater  part  of  its 
course,  is  far  removed  from  its  trophic  centre,  namely,  the  cell  of  which  it  is 
an  outgrowth.  This  trophic  function  of  the  myehn  sheath  has  a  certain  basis 
of  fact  in  that  the  myelin  sheath  is  as  a  rule  larger  in  those  fibres  which  take 
the  longer  course. 


SECTION  II 

PROPAGATION   ALONG  NERVE  FIBRES 

The  velocity  of  propagation  along  a  nerve  fibre  may  be  measured,  although 
in  early  times  it  was  thought  to  be  as  instantaneous  as  the  lightning  flash. 
To  measure  the  velocity  of  propagation  in  a  motor  nerve,  a  frog's  gastroc- 
nemius is  prepared,  with  a  long  piece  of  sciatic  nerve  attached.  The  muscle 
is  arranged  (Fig.  103)  so  that  its  contraction  may  be  recorded  on  a  rapidly 
moving  surface,  on  which  are  also  recorded,  by  means  of  electro-magnetic 


Fig, 


103.  Diagram  of  arrangement  of  experiment  for  the  determination  of  the 
velocity  of  transmission  of  a  motor  impulse  down  a  nerve. 
The  battery  current  passes  through  the  primary  coil  of  the  inductorium  c, 
and  a  '  kick  over  '  key  k.  By  means  of  the  switch  s,  the  break  shock  in  the 
secondary  cu'cuit  can  be  sent  through  the  nerve  n,  either  at  b  or  at  a.  The 
muscle  m  is  arranged  to  write  on  the  blackened  surface  of  a  trigger  or  pendulum 
myograph,  and  is  excited  during  the  passage  of  the  recording  surface  by  the 
automatic  opening  of  the  key  k.     (The  time-marker  is  not  shown.) 


signals,  the  moment  at  which  the  stimulus  is  sent  into  the  nerve,  and  also  a 
time-marking  showing  .,  1 ,,  sec.  Tracings  are  now  taken  of  the  contraction 
of  the  muscle  :  first,  when  the  nerve  is  stimulated  at  its  extreme  upper  end  ; 
secondly,  as  close  as  possible  to  the  muscle.  It  will  be  found  that  the  latent 
period,  which  elapses  between  the  point  at  which  the  stimulus  is  sent  into 
the  nerve  and  the  point  at  which  the  lever  begins  to  rise,  is  rather  longer  in  the 
first  case  than  in  the  second.  The  dift'erence  in  the  two  latent  periods  gives 
the  time  that  the  nervous  impulse  has  taken  to  travel  down  the  length  of 
nerve  between  the  two  stimulated  points.  Calculated  in  this  way,  the 
velocity  of  propagation  in  frog's  nerve  is  about  28  metres  per  second. 

In  man  and  in  warm-blooded  animals  the  velocity  has  been  variously 
estimated  at  from  60  to  120  metres  per  second.  The  higher  of  these  figures 
is  probably  nearer  the  truth. 

253 


254 


PHYSIOLOGY 


On  the  other  hand,  in  invertebrata  the  velocity  of  propagation  along  nerve  fibres 
may  be  quite  slow.  The  following  Table  represents  the  velocity  of  transmission  along 
a  number  of  different  fibres,  as  determined  by  Carlson,  compared  with  the  duration  of 
a  single  muscle-twitch  in  the  same  animal. 


Species 

Muscle 

Nerve 

Contrac- 

Rate ot    1 

Muscle 

tion 
time  in 
seconds 

Nerve 

the  impulse 
in  metres 
per  second 

Frog 

Gastrocnemius   . 

\0-10 

Sciatic 

(medullated) 

27-00 

Snake 

Hyoglossus 

0-15 

Hyoglossal 
(medullated) 

14-004 

Lobster     . 

Adductor  of 

0-25 

Ambulacral 

12-00 

(Homarus) 

forceps 

(non-meduUated) 

Hagfish     . 

Retractor  of  jaw 

0-18 

Mandibular 

(non-medullated) 

4-50 

Limvdus    . 

Adductor  of 
forceps 

1-00 

Ambulacral 

(non-medullated) 

3-25 

Octopus     . 

Mantle 

0-50 

Pallial 

(non-medullated) 

2-00 

Slug  (Limax)     . 

Foot 

4-00 

Pedal 

(non-medullated) 

1-25 

Limulus     . 

Heart 

2-25 

Nerve  plexus  in  heart 
(non-medullated) 

0-40 

The  velocity  of  propagation  in  sensory  nerves  is  more  difficult  to  deter- 
mine owing  to  the  fact  that  a  sensory  impulse,  on  arrival  at  the  receiving 
organ — i.e.  some  part  of  the  central  nervous  system — does  not  at  once  give 
rise  to  some  definite  recordable  mechanical  change,  such  as  a  muscular  con- 
traction. There  is  another  method  of  determining  the  velocity  of  conduction, 
which  may  be  used  also  with  sensory  fibres.  The  passage  of  a  nerve- 
impulse  down  a  nerve,  just  as  the  passage  of  a  wave  of  contraction  along  a 
muscle  fibre,  is  immediately  preceded  or  accompanied  by  an  electrical  change, 
which  also  travels  along  the  nerve  as  a  wave  of  '  negativity.'  The  velocity 
of  propagation  of  this  wave  may  be  measured,  and  is  found  to  give  the  same 
numbers  as  the  velocity  determined  by  the  preceding  method. 

The  existence  of  this  electrical  change  enables  us  to  show  that  a  nerve- 
impulse,  excited  at  any  point  in  the  course  of  a  nerve  fibre,  travels  in  both 
directions  along  the  fibre.  The  power  of  nerves  to  transmit  impulses  in  either 
direction  is  shown  further  by  the  experiment  known  as  Kiihne's  gracihs 
experiment.  The  gracihs  muscle  of  the  frog  is  separated  into  two  portions 
by  a  tendinous  intersection,  so  that  there  is  no  muscular  continuity  between 
the  two  halves.  The  nerve  to  the  muscle  divides  into  two  branches,  one 
to  each  half,  and  at  the  point  of  junction  there  is  division  of  the  axis  cylinders 
themselves.  If  the  section  a  in  the  diagram  (Fig.  104),  which  is  quite  isolated 
from  the  rest  of  the  muscle,  be  stimulated,  as  by  snipping  it  with  scissors, 


PROPAGATION  ALONG  NERVE  FIBRES 


255 


the  whole  muscle  contracts.  If  the  portion  of  the  muscle  which  is  free  from 
nerve  fibres  be  stimulated  in  the  same  way,  the  contraction  is  limited  to 
the  fibres  directly  stimulated,  showing  that  in  the  first  case  the  stimulus 
excited  nerve  fibres  which  transmitted  the  impulse  up  the  nerve  to  the  point 
of  division  and  then  down  again  to  the  other  half  of  the  muscle. 

Since  nerves  have  this  power  of  conduction  in  both  directions,  it  might 
be  thought  that  a  single  set  of  nerve  fibres  might  very  well  subserve  both 
afferent  and  efferent  functions,  at  one  time  conducting 
sensory  impulses  from  periphery  to  cord,  at  another  time 
motor  impulses  from  cord  to  muscles.  But  this  is  not  the 
case.  As  a  matter  of  fact  we  find  in  the  body  a  marked 
differentiation  of  function  between  various  nerve  fibres. 
Thus  Bell  and  Majendie  showed  that  the  spinal  roots 
might  be  divided  into  afferent  and  efferent,  the  anterior 
roots  carrying  only  impulses  from  spinal  cord  to  periphery, 
while  the  posterior  roots  carried  impulses  from  periphery 
to  central  nervous  system.  The  law  known  by  the  name 
of  these  observers  states  indeed  that  a  nerve  fibre  cannot 
be  both  motor  and  sensory.  We  may  find  both  kinds  of 
fibres  joined  together  into  a  single  nerve-trmik,  but  the 
fibres  in  each  case  are  isolated  and  conduct  impulses  only 
in  one  or  other  direction.  Under  normal  conditions  the  afferent  fibres  are 
excited  only  at  their  endings  on  the  surface  of  the  body,  while  the  eft'erent 
fibres  are  excited  only  at  their  origin  from  the  spinal  cord.  The  difference 
in  the  function  of  different  nerve  fibres  depends  therefore  not  so  much 
on  the  structure  of  the  nerve  fibre  itself  as  on  the  connections  of  the  fibre. 
We  can  show  this  experimentally  by  grafting  one  set  of  nerve  fibres  on 
to  another.  If  the  cervical  sympathetic  be  united  to  the  Ungual  nerve, 
stimulation  of  the  spnpathetic,  instead  of  causing,  as  usual,  constriction 
of  the  vessels  of  the  head  and  neck,  will  cause  dilatation  of  the  vessels  of  the 
tongue  and  secretion  of  watery  saliva.  In  the  same  way  the  finer  functional 
differences  between  the  various  forms  of  sensory  nerves  seem  to  be  deter- 
mined by  their  connections  within  the  central  nervous  system.  Stimulation 
of  the  optic  nerve  by  any  means  whatsoever  evokes  a  sensation  of  light. 
One  and  the  same  stimulus  applied  to  different  nerves  will  evoke  different 
sensations,  e.g.  a  tuning-fork  applied  to  the  skin  will  give  a  sensation  of 
vibration,  to  the  ear  a  sensation  of  sound.  We  shall  have  occasion  to  return 
to  this  question  of  the  restricted  function  of  nerve  fibres  when  we  deal  with 
Miiller's  '  law  of  specific  irritability  '  in  the  chapter  on  Sensations. 


Fig.  104. 

Kiihne's  gracilis 

experiment. 


SECTION  III 

EVENTS   ACCOMPANYING  THE  PASSAGE  OF  A 
NERVOUS  IMPULSE 

In  muscle  we  saw  that  the  passage  of  an  excitatory  wave  was  accompanied 
or  followed  by  electrical  changes,  production  of  heat,  and  mechanical  change, 
all  pointing  to  an  evolution  of  energy  from  the  explosive  breaking-down  of 
contractile  material. 

In  nerve,  however,  which  serves  merely  as  a  conducting  medium,  we 
should  not  expect  so  much  expenditure  of  energy,  or  in  fact  any  expenditure 
at  all.  All  that  is  necessary  is  that  each  section  of  the  nerve  should  transmit 
to  the  next  section  just  so  much  kinetic  energy  as  it  has  received  from 
the  section  above  it.  And  experiment  bears  out  this  conclusion.  The 
most  refined  methods  have  failed  to  detect  the  slightest  development  of 
heat  in  a  nerve  during  the  passage  of  an  excitatory  process,  and  we  know 
already  that  there  is  no  mechanical  change  in  the  nerve.  The  only  physical 
change  in  a  nerve  under  these  circumstances  is  the  development  of  a  current 
of  action.  A  nerve  becomes,  when  excited  at  any  point,  negative  at  this 
point  to  all  other  parts  of  the  nerve,  and,  just  as  in  muscle,  this  '  negativity  ' 
is  propagated  in  the  form  of  a  wave  in  both  directions  along  the  nerve. 

That  the  excitatory  process  in  nerves  is  probably  accompanied  by  certain 
small  chemical  changes  is  indicated  by  the  facts  that,  in  the  complete 
absence  of  oxygen,  the  nerve  fibres  lose  their  irritability,  and  that  this  loss 
of  irritability  is  hastened  by  repeated  stimulation  of  the  nerve.  When  the 
irritability  has  been  abolished  by  stimulation  in  the  absence  of  oxygen,  it 
may  be  restored  within  a  few  minutes  by  readmission  of  oxygen  to  the  nerve. 

If  we  connect  a  galvanometer  to  two  points  of  an  uninjured  nerve,  no 
current  is  observed,  all  points  of  a  living  nerve  at  rest  being  isoelectric.  On 
making  a  cross-section  of  the  nerve  at  one  leading-ofi  point,  a  current  is  at 
once  set  up,  which  passes  from  the  surface  through  the  galvanometer  to  the 
cross-section.  This  is  a  demarcation  current,  set  up  at  the  junction  between 
living  and  dying  nerve.  This  current  rapidly  diminishes  in  strength  and 
finally  disappears,  owing  partly  to  the  fact  that  the  dying  process  started 
in  the  nerve  by  the  section  extends  only  as  far  as  the  next  node  of  Ranvier  and 
there  ceases,  so  that  after  a  short  time  the  electrode  apphed  to  the  cross- 
section  is  simply  leading  off  an  intact  living  axis  cyhnder  through  the  dead 
portion  of  the  nerve,  which  acts  as  an  ordinary  moist  conductor.  On  making 
a  fresh  section  just  above  the  previous  one,  the  process  of  dying  is  again  set 

256 


EVENTS  ACCOMPANYING  A  NERVOUS  IMPULSE         257 

up,  and  the  demarcation  current  is  restored  to  its  original  strength.  If, 
while  the  demarcation  current  is  at  its  height,  we  stimulate  the  other  end  of 
the  nerve  with  an  interrupted  current,  the  needle  of  the  galvanometer  swings 
back  towards  zero,  i.e.  there  is  a  negative  variation  of  the  resting  current. 

In  order  to  demonstrate  the  wave-hke  progression  of  the  electrical  change 
from  the  excited  spot  along  the  nerve,  it  is  necessary,  as  in  the  case  of  muscle, 
to  make  use  of  a  very  sensitive  capillary  electrometer  or  a  string  galvano- 
meter. It  is  then  found  that  the  change  progresses  along  the  nerve  at  the 
same  rate  as  the  nervous  impulse,  i.e.  28  to  33  metres  per  second  in  the  frog. 
But  it  lasts  only  an  extremely  short  interval  of  time  at  each  spot,  ^^z.  six  to 
eight  ten-thousandths  of  a  second.  Thus  the  length  of  the  excitatory  wave 
in  nerve  is  about  18  mm. 


SECTION  IV 


CONDITIONS  AFFECTING  THE  PASSAGE  OF  A 
NERVOUS  IMPULSE 

TEMPERATURE.     Below  a  certain  temperature  the  propagation  of  the 
excitatory  process  in  the  nerve  is  absolutely  abohshed.    The  exact  tempera- 
ture at  which  this  occurs  varies  according  as  we  use  a  warm-  or  a  cold- 
I  blooded  animal.     In  the  frog  it  is  necessary 

to  cool  the  nerve  below  0°  C.  before  con- 

i      ^      .^  ^ iL  duction  is  abohshed,  whereas  in  the  mammal 

I    I  it  is  sufficient  to  cool  the  nerve  to  somewhere 

t— I  between   0°    and   5°    C.     Since    coohng   the 

nerve  does  not  excite  it,  this  procedure  forms  a 
convenient  method  for  blocking  the  passage 
of  impulses  along  a  nerve  without  using 
the  irritating  procedure  of  section.  On 
warming  the  nerve  again  the  conductivity 
returns.  The  rapidity  with  which  the  excita- 
tory process  is  propagated  along  either  a  nerve 
or  a  muscle  fibre  depends  on  the  temperature. 
Thus  the  mean  rate  of  conduction  in  the 
frog's  nerve  at  8°  to  9°  C.  is  about  16  metres 
per  second.  The  temperature  coefficient 
of   the   velocity    of   nerve   propagation,    i.e. 

velocity  at  Tn  +  10  ,       ,         -        tit 

—_ has  been  found  by  Lucas 

velocity  at  Tn 

to  be  about  1-79.  The  same  value  was 
found  by  Maxwell  for  conduction  in  molluscan 
nerve,  and  in  frog's  striated  muscle  Woolley 
found  the  temperature  coefficient  for  con- 
duction of  the  excitatory  process  to  vary  between  1-8  and  2. 

An  ingenious  method  (Fig.  105)  has  been  used  by  Keith  Lucas  for  the  determination 
of  the  conduction  rates  in  nerve  at  different  temperatures.  The  glass  vessel  repre- 
sented in  the  figure  is  filled  with  Ringer's  solution,  in  which  the  whole  nerve-muscle 
preparation  is  immersed.  The  muscle  used  was  the  flexor  longus  digitorum,  so  that 
the  whole  length  of  the  sciatic,  tibial,  and  sural  nerves  could  be  used.  The  nerve  is 
passed  up  through  the  constrictions  in  the  inner  glass  vessels  at  c  and  D,  and  is  attached 
to  the  thread  e.     f,  i,  and  G  are  three  non-polarisable  electrodes  composed  of  porous 

258 


CONDITIONS  AFFECTING  A  NERVOUS  IMPULSE 


259 


aii|||| 

iiiifiiiiiiiii  iiiiifiirin 

c 

clay,  containing  saturated  zinc  sulphate,  in  which  a  zinc  rod  is  immersed.  If  the  current 
is  passed  in  at  G  and  out  at  F  the  effective  cathode  is  at  the  lower  end  of  the  constriction 
c,  and  similarly  if  the  current  is  passed  in  at  i  and  out  at  G,  the  effective  cathode  is  at 
D.  The  tendon  of  the  muscle  A  is  attached  by  a  thin  glass  rod  H  to  a  very  light  recording 
lever,  the  movement  of  which  is  magnified  by  placing  it  in  the  focal  plane  of  a  projecting 
eye-piece  and  recording  its  image  on  a  moving  sensitive  plate.  The  whole  apparatus,  with 
the  exception  of  the  glass  rod  at  H,  can  be  immersed  in  a  water  bath  at  any  given  tempera- 
ture. Two  records  are  taken  with  the  whole  apparatus,  first  stimulating  at  c,  and 
secondly  stimulating  at  d.  The  difference  between  the  latent  periods  in  these  two 
cases  is  the  time  taken  for  the  excitatory  wave  to  travel  from  d  to  c.  The  rate  of 
propagation  is  similarly 
recorded  when  the  water 
bath  is  i-aised  to  18°  C. 
or  to  any  desired  tempera- 
ture. Since  we  are  only 
dealing  with  differences 
in  latent  periods  the  effect 
of  the  rise  of  temperature 
on  the  latent  period  of  the 
muscle  itself  does  not 
affect  the  determinations. 

THE  INFLUENCE 
OF  FATIGUE.  In  the 
description  of  the 
phenomena  of  mus- 
cular fatigue  given  in  ^j^  iqq 
the  last  chapter  it  was 
assumed  that  the 
muscle  was  being  ex- 
cited directly.  The  same  phenomena  are  observed  when  the  muscle 
is  excited  through  its  nerve,  though  in  this  case  fatigue  comes  on  much 
more  quickly.  If,  after  the  muscle  has  been  excited  in  this  way  until 
exhausted,  it  be  excited  directly,  it  will  respond  with  a  contraction  nearly  as 
high  as  at  the  beginning  of  the  experiment.  We  see  therefore  that  the 
nervous  structures  are  more  susceptible  to  the  influences  causing  fatigue 
than  the  muscle  itself,  and  it  can  be  shown  that  the  weak  point  in  the  nerve- 
muscle  preparation  is  not  the  nerve,  but  the  end-plates.  In  fact  it  is  not 
possible  to  demonstrate  any  phenomena  of  fatigue  in  the  nerve-trunk.* 
This  fact  can  be  shown  in  mammals  by  poisoning  the  animal  with  curare,  and 
then  stimulating  a  motor-nerve  continuously  while  the  animal  is  kept  alive 
by  means  of  artificial  respiration.  As  the  effect  of  the  curare  on  the  end- 
plates  begins  to  wear  off  in  consequence  of  its  excretion,  the  muscles  supplied 
by  the  stimulated  nerve  enter  into  tetanus.  The  action  of  the  curare  may  be 
cut  short  at  any  time  by  the  injection  of  salicylate  of  physostigmine,  when 
the  muscles  will  at  once  begin  to  react  to  the  excitation. 

The  same  fact  may  be  shown  on  the  excised  nerve-muscle  preparation 
of  the  frog.  The  gastrocnemii  of  the  two  sides  with  the  sciatic  nerves  are 
dissected  out,  and  an  exciting  circuit  is  so  arranged  that  the  interrupted 

*  Unless  it  be  asphyxiated  by  total  deprivation  of  oxygen. 


Curve    of   muscle-twitch    obtained    by   forcgoinc 
method.     (Keith  Lucas.) 
moment  of  excitation,     b  =  movement  of  muscle, 
c  =  time-marker. 


260 


PHYSIOLOaY 


secondary  currents  pass  through  the  upper  ends  of  both  nerves  in  series  (Fig. 
107).  At  the  same  time  a  constant  cell  is  connected  with  two  non-polarisable 
electrodes  {np,  np)  placed  on  the  nerve  of  b,  so  that  a  current  runs  in  the 
nerve  in  an  ascending  direction.  The  effect  of  passing  a  constant  current 
through  a  nerve  is  to  block  the  passage  of  impulses  through  the  part  traversed 

by  the  current.  When  the  con- 
stant polarising  current  is  made, 
the  muscle  may  give  a  single 
:^  twitch,  and  then  remains  quies- 
cent. The  exciting  current  is 
then  sent  through  both  nerves  by 
the   electrodes   e,   and  e,.      The 


1     "-L^"^     '^2- 

muscle  A  enters  into  tetanus, 
which  gradually  subsides  owing 
to  "fatigue."  When  A  no  longer 
responds  to  the  stimulation,  the 
constant  current  through  the  nerve 
of  B  is  broken.  B  at  once  enters 
into  tetanus,  which  lasts  as  long 
as  the  contraction  did  in  the  case 
of  A,  and  gradually  subsides  as 
fatigue  comes  on.  Since  both 
nerves  have  been  excited  through- 
out, it  is  evident  that  the  fatigue 

does  not  affect  the  nerve-trunk.     We  have  already  seen  that  a  muscle 

will  respond  to  direct  stimulation  when  stimulation  of  its  nerve  is  without 

effect,  and  must  therefore  conclude  that  the  first  seat  of  fatigue  is  the  junction 

of  nerve  and  muscle,  i.e.  the  end-plates. 

In  the  normal  intact  animal  the  break  in  the  neuro-muscular  chain  which 

is  the  expression  of  fatigue  occurs  still  higher  up,  i.e.  in  the  central  nervous 

system,   and   is    probably   due    to    some 

reflex    inhibition    of    the    central    motor 

apparatus  from  the  muscle  itseK.     Thus 

after  complete  fatigue  has  been  produced 

in  a  muscle  so   far  as  regards  voluntary 

efforts,  direct  stimulation  of  the  muscle 

itself  or  its  nerve  will  produce  a  contrac- 
tion as  great  as  would  have  been  the  case 

at  the  beginning  of  the  experiment. 

THE   INFLUENCE  OF   DRUGS.      The 

most  important  drugs  with  an  influence 

on  nerve  fibres  are  those  belonging  to  the 

class  of  anaesthetics.     Of 

chloroform,  and  alcohol. 

The  action  of  any  of  these  substances  on  the  excitability  and  conductivity  of  a  nerve 
maybe  studied  by  means  of  the  simple  apparatus  represented  in  Fig.  108.     The  nerve 


A 

Fig. 107.     Arrangement  of  experiment  for  demon- 
^  strating  the    absence  of  fatigue  in  medullated 
nerve  fibres. 
EC,  exciting  circuit ;   cp,  polarising  circuit. 


Fig.  108. 
these  we  may  mention  carbon  dioxide,  ether, 


CONDITIONS  AFFECTING  A  NERVOUS  IMPULSE  261 

of  a  nerve-muscle  preparation  is  passed  through  a  glass  tube  which  is  made  air-tight  by 
plugs  of  normal  saline  clay  surrounding  the  nerve  at  the  two  ends  of  the  tube.  By  means 
of  two  lateral  tubulures  a  current  of  CO2,  or  air  charged  with  vapour  of  ether  or  other 
narcotic,  can  be  passed  through  the  tube.  The  nerve  is  armed  with  two  pairs  of  elec- 
trodes which  are  stimulated  alternately,  the  pair  within  the  tube  serving  to  test  the 
action  of  the  drug  on  the  excitability,  while  the  pair  outside  the  tube  show  the 
presence  or  absence  of  any  effect  on  the  conducting  potver  of  the  nerve  below  it. 

Of  the  gases  and  vapours  mentioned  above,  COg  and  ether  both  diminish 
and  finally  aboUshTthe  excitability  and  conductivity  of  the  nerve  fibres. 
The  conductivity,  however,  persists  after  all  trace  of  excitability  has  dis- 
appeared, before  in  its  turn  being  also  abohshed.     On  removing  the  gas 


Fig.  109.  Tracing  to  show  the  effect  of  ether  on  excitability  and  conduclivity  of  nerve. 
Nerve  excited  by  single  induction  shocks  alternately  within  and  above  ether.  cbanib:'r.  The 
vertical  lines  indicate  contractions  of  the  muscle  (gastrocnemius.)  The  lower  line  indicates 
the  periods  during  which  the  nerve  was  exposed  to  the  action  of  ether. 

A,  disappearance  of  excitability  ;  B,  reappearance  of  excitabilit;/ ;  c,  disappearance  of 
conductivity  ;  n,  reappearance  of  conductivity.'    (From  a  tracing  kindly  lent  by  Prof.  Gotch.  ) 

or  vapour  by  blowing  air  over  the  nerve,  the  conductivity  and  excitabihty 
gradually  return  in  the  reverse  order  to  their  disappearance  (Fig.  109). 

Alcohol  is  said  to  increase  the  excitabihty  or  leave  it  unaffected,  while 
diminishing  the  conductivity  of  the  nerve. 

Chloroform  rapidly  abolishes  both  excitabihty  and  conductivity.  It 
is  a  much  more  severe  poison  than  the  drugs  just  mentioned,  so  that  in  many 
cases  its  effects  are  permanent,  and  no,  or  only  a  very  partial,  recovery  of  the 
nerve  is  obtained  on  removal  of  the  chloroform  vapour  from  the  apparatus. 


SECTION  V 

THE  EXCITATION  OF  NERVE  FIBRES 

Many  different  forms  of  stimuli  may  be  used  to  arouse  the  activity  of  an 
excitable  tissue  such  as  muscle  or  nerve.  Thus  we  may  use  thermal,  mechani- 
cal, or  chemical  stimuH.  If  the  temperature  of  a  motor  nerve  be  gradually 
raised,  no  effect  is  noticed  till  about  40°  C.  is  reached,  when  the  muscle  may 
enter  into  weak  quivering  contractions.  Sudden  warming  of  the  nerve 
always  gives  rise  to  excitation.  At  about  45°  C.  the  nerve  loses  its  irritabihty 
and  dies.  On  the  other  hand,  a  nerve  may  be  rapidly  cooled  without  any 
excitation  taking  place. 

A  nerve  may  be  excited  mechanically  by  crushing  or  cutting.  These 
methods  destroy  the  nerve.  It  is  possible  to  excite  a  nerve  mechanically, 
without  any  serious  injury  to  it,  by  carefully  graduated  taps,  and  this  method 
has  been  used  in  investigating  the  phenomena  of  electronus. 

All  chemical  stimuh  apphed  to  the  nerve  have  a  speedy  effect  in  destroying 
its  irritabihty.  The  chemical  stimuli  most  used  are  strong  salt  solutions, 
glycerin,  or  weak  acids.  If  any  one  of  these  be  appUed  to  a  motor  nerve,  the 
muscle  enters  into  an  irregular  tetanus,  which  lasts  till  the  irritabihty  of  the 
nerve  is  destroyed  at  the  part  stimulated. 

None  of  these  forms  of  stimuH  can  be  adequately  controlled  either  as  to 
strength  or  duration.  Moreover,  owing  to  their  destructive  effects,  any 
repetition  of  the  stimulus  will  fall  on  a  nerve  or  muscle  more  or  less  altered 
by  the  first  stimulus.  We  are  therefore  justified  in  the  use  of  electrical 
stimuH  not  only  for  arousing  the  activity  of  excitable  tissues,  but  also  for 
determining  the  conditions  of  excitation  of  muscle  and  nerve.  For  this  pur- 
pose we  may  use  either  the  make  and  break  of  a  constant  current,  the  induced 
current  of  short  duration  produced  in  a  secondary  coil  of  an  inductorium 
by  the  make  or  break  of  the  primary  circuit,  or  the  discharge  of  a  condenser. 

The  last-named  method  of  stimulation  is  especially  useful  when  we  desire  to  deter- 
mine the  total  amount  of  energy  involved  in  the  electrical  stimulation  of  a  nerve  or 
muscle.  The  arrangement  of  such  an  experiment  is  shown  in  Fig.  110.  By  means 
of  the  switch  S  the  condenser  can  be  put  into  connection  either  with  the  battery  from 
which  it  receives  its  charge  or  with  the  nerve  through  which  it  can  discharge.  By 
knowing  the  capacity  of  the  condenser  and  the  electromotive  force  by  which  it  is 
charged,  we  can  estimate  the  energy  of  the  charge  sent  through  the  nerve. 

E  (energy  in  ergs)*  =  5FV^ 
(F  =  capacity  in  microfarads  ;    V  =  electromotive  force  in  volts). 

*  An  erg  is  the  amount  of  work  producad  or  energy  expended  by  the  action  of 
on3  dym  through  oub  cantimstre.  A  dyne  is  the  force  which  will  give  to  a  mass  of 
on3  gram  an  acceleration  of  one  centimetre  per  second  per  second. 

262 


THE  EXCITATION  OF  NERVE  FIBRES 


263 


.^^^ 


In  this  way  it  has  been  found  that  the  energy  of  a  minimal  effective  stimulus  for  frog's 
nerve  is  about  jo^j-jj  of  an  erg. 

The  amount  of  energy  necessary  to  excite  the  nerve  will  vary  with  the  rate  at  which 
the  condenser  is  allowed  to  discharge  through  the  nerve.  Its  rate  can  be  modified 
by  altering  the  resistance  in  the  discharging  circuit  or  by  altering  the  electromotive 
force  of  the  charge.  Tliis  method  has  been  adopted  by  Waller  in  determining  the  rate  of 
change  at  which  excitation  is  obtained  with  a  minimal  exj^en- 
diture  of  energy,  which  he  calls  the  "  characteristic  "  of  the 
tissue  in  question.  To  this  point  we  shall  have  occasion  to 
refer  later. 

When  using  the  make  and  break  of  a  constant 
current  as  a  stimulus,  the  first  fact  of  importance  is 
the  relation  of  the  seat  of  excitation  to  the  poles 
by  which  the  current  is  led  into  or  out  of  the  ex- 
citable tissue.     We  have  already  seen  that  when  a 
current  is   passed   through  a   muscle   or  nerve   the 
muscle  contracts  only  at  make  or  at  break 
of  the  current,  no  propagated  excitatory  effect 
being  produced  during  the  passage  of  the  cur- 
rent.  The  excitation  at  make  is  obtained  with 
a  smaller  current  than  the    excitation   at 
break. 

Besides  this  difference  in  intensity,  there 
is  a  difference  in  the  point  from  which 
excitation  starts.  A  make  contraction  starts 
from  the  cathode,  a  break  contraction  from 
the  anode.     This  is  well  shown  by  the  two  following  experiments  : 

{a)  A  curarised  sartorius  muscle  of  the  frog  (Fig.  Ill),  with  its  bony 
insertions  still  attached,  is  fastened  at  the  two  ends  to  two  electrodes,  which 
are  able  to  swing  when  the  muscle  contracts,  and  are  attached  by  threads 
to  levers  which  serve  to  record  the  contraction.     The  middle  of  the  muscle  is 

then  fixed  by  clamping   it  lightly. 
A  circuit  is  arranged  so  that  a  con- 
stant current  can  be  sent  through  the 
electrodes  and  the  whole  length  of  the 
muscle.     It  is  found,  on  making  the 
ciu:rent,  that  the  lever  attached  to 
the  cathode— that  is,  to  the  electrode 
by   which   the    current    leaves    the 
muscle- — rises  before  the  other  lever.     On  the  other  hand,  on  breaking  the 
current  the  lever  at  the  anode  rises  first,  showing  that  the  anodic  half  of 
the  muscle  contracts  before  the  cathodic  half. 

(6)  The  irritability  of  a  muscle,  i.e.  its  power  of  responding  to  a  stimulus 
by  contracting,  is  intimately  dependent  on  the  hfe  of  the  muscle.  If  the 
muscle  be  injured  or  killed  at  any  spot,  its  irritability  at  this  spot  will  be 
therefore  diminished  or  destroyed.  Hence,  if  we  stimulate  a  muscle  at  the 
injured  spot,  no  contraction  will  ensue.      This  fact  may  be  used  to  demon- 


FiG.  110.  Arrangement  of  apparatus 
for  the  excitation  of  a  nerve  by 
means  of  condenser  discharges. 

B,  battery ;  K,  rheochord;  c,  rider 
of  rheochord  ;  s,  switch  (Pohl's  re- 
verser  without  cross  wires) ;  c,  con- 
denser ;  ?i,  nerve ;  7n,  muscle ;  e,  non- 
polarisable  electrodes. 


,^-<5 


Fia. 


111.     Sai-torius  clamped  in  middle  and 

attached  to  levers  at  either  end. 


264  PHYSIOLOGY 

strate  the  production  of  excitation  at  cathode  on  make,  and  at  anode  on 

break  of  a  constant  current. 

A  muscle  with  parallel  fibres,  such  as  the  sartorius,  is  injured  at  one 

end,  and  a  constant  current  passed,  first  from  the  injured  to  the  uninjured 

end,  and  then  in  the  reverse  direction  (Fig.  112).     It  is  found  in  the  former 

case,  when  the  anode  is  on  the  injured  part  (which  is  therefore  less  excitable), 

I    vu  J  -,„^^»/;^'....„j\  that  break  of  the  current  is  ineffec- 

Uathode    ^  anoae(injurecl) 

tive,  and  in  the  latter,   when  the 
contraction  at  make.  ,n     i     •  ,l■•^        £ 

cathode  is  on  the  injured  surface, 

that  the  make  stimulus  is  inefiec- 

,     ,  tive,  shomnff  that  the  part  excited 

anode         m  kathode  (injured)  j    ?    xi,        xi,    j       ^        i 

===—-=—  ^  corresponds  to  the  cathode  at  make 

\S  I  ^   ~      n  ,30  <  r>  a   rna.  e.  ^^^  ^^  ^^^  anode  at  break. 

^^1'--^'^  With   a   current   of    very  short 

.^      , ,  „     ^  ■'.  ,        ,      ^    .    p ,     n  duration  no  excitation  is  produced 

Fig.  112.     Diagram  to  show  the  effect  oi  local  .     ,        .  ,       , 

injury  on  the  excitability  of  a  muscle,     b,  at    break.      Every  induction  shock 

battery;    m,   muscle.    The  arrows  indicate  ^^^^    ^^    therefore  regarded    as    a 
the  direction  oi  the  current.                                                     .  " 

make  stimulus,  and  when  such  a 
shock  is  led  through  a  muscle  the  contraction  in  each  case  will  start  at 
the  cathode,  i.e.  the  point  at  which  the  induction  shock  leaves  the  muscle. 
The  results  of  stimulating  nerve  fibres  are  similar  to  those  obtained  by 
stimulating  muscle  fibres  directly. 

Under  normal  circumstances,  if  a  constant  current  be  passed  through  the 
nerve  of  a  nerve-muscle  preparation  for  a  short  time,  the  muscle  responds 
only  at  the  make  and  the  break  of  the  current,  remaining  perfectly  quiescent 
all  the  time  the  current  is  passing.  If  the  nerve  be  in  a  very  excitable 
condition,  it  is  possible  that  the  muscle  may  be  thrown  into  a  tetanus  or 
continued  contraction  during  the  whole  time  that  the  current  is  passing 
('  closing  tetanus ').  On  the  other  hand,  if  a  strong  ascending  current  be 
passed  through  the  nerve  for  a  considerable  time,  the  muscle  when  the 
current  is  broken  may  go  into  continued  contraction,  which  may  last  some 
time.  Normally,  however,  the  muscle  simply  responds  mth  a  single  twitch 
at  the  make  and  break  of  the  current,  although,  on  investigating  the  condition 
of  the  nerve  during  the  passage  of  the  current,  we  find  that  it  is  considerably 
modified.  This  modification  in  the  condition  of  the  nerve  is  spoken  of  as 
electrotonus,  and  includes  changes  in  its  irritabihty  and  its  electrical  condition. 

To  investigate  these  changes  the  following  apparatus  is  necessary :  two  constant 
batteries,  induction-coil,  a  reverser  and  keys,  a  pair  of  non-polarisable  electrodes, 
and  a  pair  of  ordinary  platinum  electrodes.  Fig.  113  represents  roughly  the  arrange- 
ment of  the  experiment.  A  constant  current  from  the  battery  is  led  tlirough  a  part 
of  the  nerve  by  means  of  non-polarisable  electrodes,  which  are  about  one  inch  apart. 
In  this  circuit  we  put  a  reverser,  by  means  of  which  the  direction  of  the  current  of 
the  nerve  may  be  changed  at  will,  and  a  key  to  make  or  break  the  current.  This  is  the 
polarising  circuit.  The  other  battery  is  arranged  in  the  primary  circuit  of  the  coil,  a  key 
being  interposed,  so  that  we  may  use  make  or  break  induction  shocks,  which  are  ap- 
plied to  the  nerve  by  means  of  the  small  platinum  electrodes.  The  tendon  of  the 
muscle  is  cormected  by  a  thread  with  a  lever,  which  is  arranged  to  write  on  a  smoked 
surface,  so  that  the  height  of  the  contraction  can  be  recorded. 


^HE  EXCITATION  OF  NERVE  FIBRES 


265 


We  first  find  the  position  of  the  secondary  coil,  at  which  the  break  induction  shock 
is  a  submaxiiual  stimulus,  and  we  employ  this  strength  of  stimulus  throughout  the 
experiment.  The  make  induction  shock  is  prevented  from  acting  on  the  nerve  by  closing 
a  shortcircuiting  key  in  the  circuit  of  the  secondary  coil.  The  nerve  is  now  stimulated 
at  various  points  with  a  single  break  induction  shock,  and  the  contractions  recorded. 
The  heights  of  these  contractions  serve  to  indicate  the  irritability  of  the  nerve  at  the 
point  stimulated.  We  now  throw  the  polarising  current  into  the'  nerve.  At  the  make 
of  this  current  the  muscle  will  prob- 
ably respond  with  a  twitch  which  is 
not  recorded.  We  then  test  once  more 
the  irritability  of  different  points  of 
the  nerve,  and  we  find  that,  when 
the  stimulus  is  ai^plied  near  a,  the 
point  where  the  current  enters  the 
nerve  (anode),  the  stimulus,  which 
before  gave  a  moderately  large  con- 
traction of  the  muscle,  now  has  either 
no  eft'ect  or  else  produces  a  very  weak 
contraction.  On  the  other  hand,  in 
the  region  of  the  cathode  the  stimulus, 
which  before  was  submaximal,  has 
now  become  maximal,  as  is  shown  by 
the  increase  in  the  height  of  the  con- 
traction evoked  by  the  induction 
shock. 

We  now  reverse  the  direction  of 
the  polarising  current,  so  that  the 
current  of  the  nerve  runs  from  k  to  a. 
a  reversal  of  the  changes  in  the  nerve 


Fig, 


113.      Arrangement  of  apparatus  for  showing 
electrotonic  changes  in  irritabiUty. 
e,  exciting  current ;   p,  polarising  current ; 
r,  Pohl's  reverser. 


With  this  reversal  of  current  there  is  also 
;  that  is  to  say,  the  normally  submaximal 
stimulus  is  maximal  when  applied  near  a,  and  minimal  when  applied  near  k.  On 
break  of  the  polarising  current  the  condition  of  the  nerve  retui'ns  to  normal,  and 
the  submaximal  stimulus  is  once  more  submaximal  throughout. 

This  retm'n  to  normal  conditions,  however,  is  not  immediate,  since  the  fii'st  effect 
of  breaking  the  current  is  a  swing-back,  so  to  speak,  past  the  normal,  the  diminished 
irritability  at  the  anode  giving  place  to  an  increased  irritabilitj^  which  only  gradually 
subsides.  In  the  same  \vaj%  immediately  after  the  polarising  current  has  ceased  to 
flow,  the  neighbourhood  of  the  cathode  acquires  a  condition  of  diminished  irritability, 
and  this  only  gradually  gives  place  to  a  normal  condition. 

This  experiment  teaches  us  that,  when  a  constant  current  is  passed 
through  a  nerve,  there  is  increase  in  the  irritabihty  in  the  nerve  near  the 
cathode,  and  a  diminution  in  irritabihty  near  the  anode.  These  conditions 
of  increased  and  diminished  irritabihty  are  spoken  of  as  catelectrotomis  and 
anelectronus  respectively.  In  muscle  we  have  seen  that  a  make  contraction 
always  starts  from  the  cathode,  and  a  break  contraction  from  the  anode. 
Now  the  event  that  takes  place  at  the  cathode  on  make  and  at  the  anode  on 
break  of  a  constant  current  is,  as  the  last  experiment  shows  us,  a  rise  in 
irritability,  in  the  former  case  from  normal  to  above  normal,  in  the  latter 
from  subnormal  to  normal.  Hence  we  may  say  that  the  excitation  is  caused 
by  a  sudden  rise  of  irritability,  which  may  be  due  either  to  a  sudden  appear- 
ance of  catelectrotomis,  or  a  sudden  disappearance  of  anelectrotonus.  I 
have  said  sudden  because  the  steepness  of  the  rise  of  irritability  is  a  necessary 
factor  in  causing  excitition.  If  the  polarising  current  passing  through 
a  nerve  be  slowly  and  grcidiuilly  increased  to  considerable  strength,  it  will 

9* 


266 


PHYSIOLOGY 


give  rise  to  no  contraction.  The  degree  of  suddenness  of  the  rise,  which  is 
most  beneficial  in  causing  contraction,  varies  with  the  nature  of  the  tissue 
stimulated.  Thus  it  is  more  rapid  in  nerve  than  in  muscle,  and  in  pale 
muscle  than  in  red  muscle,  and  in  voluntary  muscle  than  in  unstriated 
muscle. 

It  is  evident  that  there  must  be,  somewhere  between  the  anode  and 
cathode,  an  indifierent  point- — that  is  to  say,  a  region  where  the  irritability 


Fig.  114.  Diagram  to  show  the  variations  of  irritability  in  a  nerve  during  the  passage 
of  polarising  currents  of  different  strengths.  The  degree  of  change  is  represented  by  the 
distance  of  the  curves  from  the  base  line  ;  the  part  of  the  curve  below  the  line  signifying 
decrease,  that  above  the  line  increase  of  irritability. 

A,  anode  ;  b,  cathode  ;  ?/i,  effect  of  weak  current ;  y^,  medium  current ;  y^,  strong  current. 
It  will  be  noticed  that  the  indifferent  point,  x,  where  the  curve  crosses  the  horizontal  line, 
approaches  nearer  and  nearer  the  cathode  as  the  current  is  increased  in  strength.  (From 
Foster,  after  Pflttgbr.) 


is  neither  increased  nor  diminished.  We  find  experimentally  that  this  in- 
difierent point  is  nearer  the  anode  when  the  polarising  current  is  weak,  and 
approaches  the  cathode  as  the  current  is  strengthened,  so  that  with  very 
strong  currents  nearly  the  whole  intrapolar  length  is  in  a  condition  of  an- 
electrotonus  (Fig.  114).  When  a  strong  polarising  current  is  used,  the  de- 
pression of  irritabihty  at  the  anode  is  so  marked  that  no  impulse  can  pass 

ascending   current 

make  excitation  blocked 
at  anode. 


kath. 


break  excitation  at  anode 
blocked  at  kathode. 


Fig. 


115.     Diagram  to  show  the  blocking  effect  of  a  strong  constant  current 
passed  through  the  nerve  of  a  nerve-muscle  preparation. 


this  region.  Thus  if  we  send  a  very  strong  ascending  current  through  the 
nerve,  there  is  no  contraction  at  make.  This  is  owing  to  the  fact  that  the 
impulse  started  at  the  cathode  on  make  of  the  current  cannot  reach  the 
muscle,  its  passage  down  the  nerve  being  blocked  in  the  region  of  the  anode 
(Fig.  115,  A). 

The  results  of  stimulating  motor  nerves  by  means  of  constant  currents  were  studied 
by  Pfliiger  and,  embodied  in  a  Table,  make  up  what  is  known  as  Pfliiger's  law.  The 
result  of  stimulating  varies  with  the  strength  of  a  current. 


THE  EXCITATION  OF  NERVE  FIBRES 

Law  of  Contraction 


267 


strength  of  current 

Ascending 

Descending 

Make                   Break 

Make                 Break 

Weak       . 

c                      0 

c                   0 

Medium   . 

c                       c 

C                   c 

Strong      . 

0                  Cor  T 

CorT                0 

c  =  contraction.     C  =  strong  contraction.     T  =  tetanus.     O  =  no  eli'ect. 

With  the  weakest  currents  excitation  occurs  only  at  make,  since  a  make-stimulus, 
i.e.  the  rise  of  catelectrotonus,  is  always  more  effectual  than  a  break-stimulus,  i.e.  the 
disappsarance  of  anelectrotonus.  With  currents  of  moderate  strength  excitation 
occurs  both  at  make  and  break,  bsing  better  marked  at  make,  especially  in  the  case  of 


Fig.  116.     Arrangement  of  experiment  to  demonstrate  Pfliiger's  law  of  contraction. 

descending  currents.  With  very  strong  currents  we  get  a  contraction  at  make  only 
when  the  current  is  descending,  since,  when  the  cm'rent  is  ascending,  the  excitation 
started  at  the  cathode  cannot  pass  the  block  at  the  anode.  For  the  same  reason  a 
break  contraction  is  obtained  only  with  an  ascending  current,  since  at  the  break  of 
a  descending  current  there  is  a  swingback  of  the  nerve  at  the  cathode  to  a  condition 
of  diminished  irritability,  which  effectually  blocks  the  excitation  started  higher  up 
the  nerve  at  the  anode. 

The  arrangement  of  the  experiment  for  demonstrating  Pfliiger's  law  is  shown  in 
Fig.  116.  The  strength  of  the  current  is  graduated  by  means  of  the  rheochord,  the 
current  being  led  into  the  nerve  by  means  of  nonpolarisable  electrodes.  It  is  extremely 
important  in  these  experiments  to  avoid  any  injury  or  drying  of  the  nerves  at  either  of 
the  two  electrodes,  since  the  excitatory  effect  either  at  make  or  break  would  be  abolished 
by  local  injury. 

These  results,  worked  out  chiefly  on  motor  nerves,  have  been  con- 
firmed as  far  as  possible  experimentally  on  sensory  nerve,  and  on  muscle 
and  contractile  tissues  generally,  and  probably  hold  good  for  all  irritable 
Uving  tissues. 

It  is  said  that  an  anelectrotonus  takes  some  time  to  attain  its  full  height, 
and  a  catelectrotonus  reaches  its  maximum  almost  directly  after  the  current 
is  made,  and  that  it  is  on  this  account  that  a  current  of  very  short  duration 
excites  only  at  the  make,  the  break  occurring  before  the  anelectrotonus  is 
developed  enough  for  its  disappearance  to  cause  a  stimukis. 

Other  things  being  equal,  a  current  of  given  strength  causes  a  stronger 


268 


PHYSIOLOGY 


on  excitation  has  been  suggested  by  Gotch. 

s 


excitation  the  greater  the  length  of  nerve  that  it  flows  through.  It  must 
be  remembered,  however,  that  the  nerve  oilers  considerable  resistance  to  the 
passage  of  the  current,  and  so,  to  keep  the  current  constant  while  increasing 
the  length  of  intrapolar  nerve,  we  must  largely  increase  the  electromotive 
force  employed. 

A  very  convenient  method  of  showing  the  effect  of  the  length  of  intrapolar  nerve 

The  two  sciatic  nerves  of  a  frog  are  dissected 
out,  one  of  them  being  in  connection  with 
the  gastrocnemius.  These  are  first  arranged 
as  in  Fig.  117.  a.  h,  and  c  are  three 
non-polarisable  electrodes,  the  terminals  of 
a  constant  battery  being  connected  to  a  and 
c.  The  position  of  the  rider  on  the  rheo- 
chordis  then  ascertained  at  which  make  of 
the  current  just  excites  contraction  in  the 
muscle  of  nerve  2,  the  current  in  this  case 
passing  from  a  to  6  along  nerve  1,  and 
from  6  to  c  along  a  small  piece  of  nerve  2. 
We  will  suppose  that  eleven  units  of 
current  are  necessary  to  produce  excita- 
tion, h  is  then  withdrawn  and  the  nerve 
2  laid  on  a  (Fig.  117,  b),  so  that  the 
current  can  now  pass  from  a  to  c  entirely 
through  a  long  stretch  of  nerve  2.  On 
again  seeking  the  minimal  stimulus,  it 
will  be  found  that  a  smaller  current  is 
sufficient  to  excite,  contraction  being 
obtained  with  seven  units.  Since  the 
length  of  nerve  traversed,  and  therefore  the  resistance  to  the  current,  are  the  same 
in  both  cases,  it  is  evident  that  a  current  is  more  effective  the  greater  the  length  of 
excited  nerve  that  it  traverses. 

A  nerve  cannot  be  excited  by  currents  passed  transversely  across  it,  since 
in  such  cases  the  anode  and  cathode  he  so  close  to  one  another  in  a  nerve- 
fibril,  as  it  is  traversed  by  a  current,  that  their  effects  counteract  one  another. 

ELECTRICAL  STIMULI  AS  APPLIED  TO  HUMAN  NERVES 
When  we  attempt  to  apply  the  results  gained  on  frog's  nerves  to  man, 
we  are  met  at  once  by  the  difficulty  that  we  cannot  dissect  out  the  nerves 
and  apply  stimuh  to  them  directly.  So  usually  unipolar  excitation  is  used,  one 
electrode,  either  anode  or  cathode,  being  apphed  to  the  skin  over  the  nerve  to 
be  stimulated,  and  the  other  to  some  indifferent  point,  such  as  the  back.  It  is 
evident  under  these  circumstances  that  the  current  is  concentrated  as  it 
leaves  the  anode  and  reaches  the  cathode,  and  diffuses  widely  in  the  body, 
seeking  the  lines  of  least  resistance.  Thus  it  is  impossible  to  get  pure  anodic 
or  cathodic  effects.  If  the  anode  be  applied  over  the  nerve,  the  current 
enters  by  a  series  of  points  (the  polar  zone),  and  leaves  by  a  second  series 
(the  peripolar  zone).  The  polar  zone  will  thus  be  in  the  condition  of  anelec- 
trotonus,  and  the  peripolar  zone  in  that  of  catelectrotonus.  The  current, 
however,  will  be  more  concentrated  at  the  polar  than  at  the  peripolar  zone, 
and  so  the  former  effect  will  predominate.     These  restrictions  in  the  apphca- 


THE  EXCITATION  OP  NERVE  FIBRES 


269 


tion  of  the  current  cause  slight  apparent  irregularities  in  the  law  of  contrac- 
tion as  tested  on  man. 

In  stimulating  the  nerv^es  of  man  for  the  purpose  of  determining  the  con- 
ditions of  the  different  muscles,  we  may  use  either  induced  currents  (generally 
called  faradic  stimulation)  or  the  make  and  break  of  a  battery  current  (galvanic 
stimulation).  The  electrodes  are  covered  with 
chamois  leather  moistened  with  salt  solution 
in  order  to  diminish  the  resistance  of  the  skin. 
When  it  is  desired  to  stimulate  any  given  muscle 
the  stimulating  electrode  is  brought  as  nearly  as 
possible  over  the  spot  where  the  muscle  receives 
its  motor  nerve.  These  '  motor  points  '  have  been 
mapped  out,  and  reference  is  generally  made  to  a 
diagram  in  determining  the  point  for  any  given 
muscle.  By  reversing  the  current  the  stimulating 
electrode  may  be  made  either  anode  or  cathode. 
It  is  found  that  stimulation  occurs  most  easily 
on  closure  of  the  current  when  the  stimulating 
electrode  is  the  cathode  ;  with  the  greatest  diffi- 
culty when  the  current  is  broken  and  the  stimu- 
lating electrode  is  the  cathode.  These  different 
contractions  are  generally  represented  by  capital 
letters,  and  the  usual  relationship  is  ex- 
pressed by  the  statement  that  CCC  is  obtained 
most    easily,    then    ACC    and    AOC,    and    finally 


COC. 


CCC  ==  cathodal  closing  contraction. 
,  ACC  =  anodal  closing  contraction. 
AOC  =  anodal  opening  contraction. 
COC  ==  cathodal  opening  contraction. 


Fig.  118.  Electrodes  applied  to 
the  skin  over  a  nerve-trunk.  In 
A  the  polar  area  is  anelectrotonic 
and  the  peripolar  catelectro- 
tonic.  The  former  condition 
therefore  preponderates,  since 
the  current  here  is  more  con- 
centrated. In  B  the  conditions 
arc  reversed,  the  polar  zone 
corresponding  in  this  case  to  the 
cathode.     (Wallee.) 


When  the  motor  nerve  to  a  muscle  has  under- 
gone degeneration  the  muscle  also  begins  to 
degenerate,  and  we  find  certain  alterations  in  its  response  to  artificial  stimu- 
lation. In  the  first  place,  the  muscle  may  fail  to  respond  to  induction  shocks,  while  it 
may  show  an  increased  irritability  for  galvanic  shocks.  In  the  .second  place,  qualita- 
tive alterations  in  irritability  may  be  present,  so  that  ACC  may  be  obtained  witli  a 
smaller  current  than  CCC.  These  alterations  are  spoken  of  as  the  '  reaction  of  degenera - 
tion.' 


SECTION  VI 


THE   CONDITIONS  WHICH   DETERMINE  ELECTRICAL 

STIMULATION 

Foe,  every  tissue  traversed  by  a  current  there  is  a  minimum  rate  of  change 
at  which  the  current  through  the  tissue  must  be  increased  or  diminished  in 
order  to  cause  excitation.  If  instead  of  suddenly 
making  and  breaking  the  current  passing  through  an 
irritable  structure  we  carry  out  the  change  gradually, 
no  excitatory  effect  is  produced,  even  although  the 
current  may  finally  attain  a  considerable  strength. 
This  fact  may  be  demonstrated  by  the  use  of  an  appara- 
tus known  as  the  rheonome. 

A  useful  form  of  rheonome  is  that  devised  by  Lucas  (Fig.  119). 
Two  zinc  plates  d  and  E,  immersed  in  a  saturated  solution  of 
zinc  sulphate  contained  in  a  rectangular  cell,  are  separated  from 
one  another  by  a  vulcanite  diaphragm.  In  the  diaphragm  is  a 
hole  G  by  which  the  two  sides  of  the  vessels  are  connected.  This 
hole  can  be  closed  at  any  desired  rate  by  a  shutter  f.  When  the 
hole  is  closed  no  current  can  pass  between  the  plates,  and  the 
amount  which  can  pass  will  depend  on  the  extent  to  which  the 
shutter  has  been  raised.  By  giving  the  hole  the  right  shape  it  is 
possible  to  diminish  the  resistance  of  the  apparatus  regularly.  If 
this  rheonome  be  placed  in  circuit  with  a  battery  and  an  excitable 
tissue,  such  as  the  nerve  of  a  nerve-muscle  preparation,  we  can 
make  a  current  or  break  a  current  through  the  tissue  at  any 
desired  rate.  Thus  the  course  of  the  current  through  the  tissue 
will  be  represented,  not  by  a  vertical  line,  but  by  a  sloping  line 
which  may  be  given  any  desired  degree  of  steepness  (Fig.  120). 

If  the  current  be  slowly  increased  through  the 
nerve  or  be  slowly  cut  off  from  the  nerve,  no  excitatory 
efiect  takes  place,  while  quickly  opening  or  closing  the 
slmtter  will  cause  excitation.  It  might  be  concluded 
that   the   excitatory  effect  of  a  current  increases  with 

1.  The  intensity  of  the  current. 

2.  The  rate  of  change  of  the  current. 

The  second  of  these  conditions  needs,  however,  some  correction.  As  we 
increase  the  rate  of  change  of  current,  by  employing  in  the  case  of  induced 
currents  more  and  more  rapid  alternations,  we  find  that  the  excitatory  effect, 

270 


Fig.  119. 
Rheonome  of 
Keith  Lucas. 


ELECTRICAL  STIMULATION 


271 


instead  of  increasing,  begins  to  diminish,  and  finally  disappears,  so  that  high- 
frequency  currents  of  enormous  tension  can,  as  in  Tesla's  experiments,  be 
led  through  the  body  without  any  apparent  physiological  effect.  On  the 
other  hand,  by  using  more  sluggish  forms  of  irritable  tissue,  we  may  find  that 
even  induction  shocks  are  too  rapid  for  effective  excitation.  Thus  the  red 
muscles  of  the  slow-moving  tortoise  react  better  to  the  slow  make  than  to  the 
sudden  break  induction  shock,  and  many  forms  of  unstriated  muscle  are 
unaffected  by  either  make  or  break  shock.  There  is  in  fact  for  each  tissue 
an  optimum  rate  of  change  varying  with  the  character  of  the  tissue,  at  which 
the  current  necessary  to  produce  a  response  is  at  a  minimum.  This  optimum 
rate  of  change  is  spoken  of  by  Waller  as  the  '  characteristic  '  of  an  irritable 
tissue. 

A  further  investigation  of  the  time  relations  of  electrical  stimuli  by 
Keith  Lucas  has  thrown  important  light  on  the  character  of  the  excitatory 


Tig.  120.  String  galvanometer  records  of  the  change  of  current  obtained  by 
opening  the  diaphi'agm  in  the  rheonome  (Fig.  119)  at  different  rates.  (K. 
Lucas.) 

response  itself.  The  difference  between  various  excitable  tissues  is  perhaps 
best  brought  out  by  finding  the  minimum  strength  of  current  which  will 
excite  at  make  and  then  determining  how  much  this  current  must  be  in- 
creased when  it  is  broken  at  a  very  short  interval  of  time  after  it  has  been 
made.  The  following  Table  represents  the  relation  between  duration  and 
strength  of  current  necessary  to  stimulate  in  the  case  of  the  sciatic  nerve 
of  the  toad  : 


Duration  of  current  (sec.) 

Strength  of  current  (volts) 

CO 

•086 

■0070 

•091 

■0035 

•119 

•00087 

•179 

•00043 

•245 

If  we  slightly  alter  the  use  by  Waller  of  the  word  '  characteristic  '  we 
may  take  as  the  characteristic  of  the  tissue  the  duration  of  the  stimulus 
at  which  the  current  necessary  to  stimulate  was  just  double  the  minimum. 
In  the  above  case  the  minimal  stimulating  current  was  approximately 
doubled  when  the  duration  of  the  current  was  limited  to  about  -001  sec. 
From  a  number  of  experiments  of  this  description,  Lucas  gives  the  following 
as  the  characteristic,  or  what  he  terms  the  "  excitation  times,"  of  muscle 
and  of  nerve  : 


272  PHYSIOLOGY 

Muscle .     -017     sec. 

Nerve  fibre       .......     -003       ,, 

Nerve-ending  (or  intermediary  substance)    .  .     -00005    ,, 

Similar  differences  are  obtained  when  we  attempt  to  determine  by  means  of  the 
rheonome  the  minimal  gradient  of  current  necessary  to  excite  a  nerve.  In  the  case 
of  the  toad's  nerve  the  minimal  gradient  must  be  ten  times  as  steep  as  in  the  case  of 
the  toad's  muscle,  and  is  such  that  in  one  second  the  current  must  reach  a  strength 
forty-five  times  the  minimal  strength  which  is  necessary  to  excite  when  the  current 
is  made  instantaneously.  In  the  frog's  nerve  the  minimal  gradient  is  still  steeper, 
so  that  in  one  second  the  current  must  reach  sixty  times  the  strength  of  the  minimal 
exciting  current.  We  may  interpret  these  results  as  signifying  that  the  excitatory 
state  produced  in  an  irritable  tissue  involves  the  production  of  some  change  which 
passes  away  spontaneously.  The  rate  of  production  of  the  change,  and  still  more  the 
rate  of  its  spontaneous  disappearance,  differ  from  tissue  to  tissue.  If  the  gradient 
of  a  current  which  is  made  through  the  tissue  is  too  slight,  the  spontaneous  disappearance 
of  the  excitatory  change  goes  on  as  rapidly  as  the  production  in  consequence  of  the 
rise  of  current.  No  excitation  therefore  takes  place.  The  "  excitation  time  "  of  the 
tissue  will  thus  be  proportional  to  the  duration  of  the  excitatory  change  produced  in 
the  tissue  as  a  result  of  the  stimulus.  We  may  compare  the  excitation  time  of  three 
tissues  with  the  duration  of  the  electrical  change  produced  in  the  same  tissues  by  a 
single  stimulus. 

The  excitation  times  were  : 

Frog's  nerve  fibre  .....       -003   sec. 

Muscle  fibre  of  sartorius         .  .  .  .       -017     „ 

Ventricular  muscle  of  frog      ....     2-000     „ 

In  the  case  of  muscle,  according  to  Burdon  Sanderson,  the  electrical  change  reaches 
its  culminating-point  in  -0025  sec,  and  may  take  perhaps  eight  times  this  interval 
before  it  dies  away.  In  the  cardiac  muscle  of  the  tortoise  Sanderson  found  the  electrical 
change  to  last  between  two  and  three  seconds. 

SUMMATION  OF  STIMULI.  Closely  associated  with  the  excitation 
time  of  the  tissues  are  the  phenomena  of  '  summation  of  stimuli '  and  '  re- 
fractory period.'  If  two  subminimal  stimuli  are  sent  in  within  a  sufficiently 
short  interval  of  time,  their  effect  is  summated,  so  that  two  stimuh,  each 
of  which  would  be  ineffective,  may  together  produce  an  excitation.  In 
the  case  of  striated  muscles,  in  order  that  mechanical  summation  of  con- 
traction may  take  place,  the  second  stimulus  must  become  efiiective  before 
the  muscle  has  completely  relaxed ;  the  second  contraction,  that  is  to  say, 
starts  from  the  height  to  which  the  first  contraction  has  brought  the  muscle. 
A  similar  condition  of  things  appears  to  hold  for  summation  of  stimuli,  if 
we  substitute  for  mechanical  change  in  muscle  the  molecular  change  which 
accompanies  the  excitatory  state.  For  summation  of  two  stimuh  to  take 
place,  the  second  stimulus  must  occur  at  a  time  before  the  condition  excited 
by  the  first  stimulus  has  passed  away.  The  maximum  time  at  which  summa- 
tion of  two  stimuli  can  take  place  will  therefore  vary  from  tissue  to  tissue 
and  will  bear  a  relation  to  what  we  have  designated  the  '  excitation  time ' 
of  the  tissue  and  also  to  the  rapidity  of  current  gradient  necessary  to  excite 
the  tissue.  This  will  be  evident  if  we  compare  the  maximum  summation 
intervals  for  different  tissues  with  the  excitation  time  of  the  same  tissues. 


ELECTRICAL  STIMULATION  273 

stimulating  current  5 ';'  above  minimal  stimulus 


Summation  interval 

'.'  Excitation  time" 

sec. 

sec. 

•OUUo 

•U03 

•0015 

•017 

•0080 

2-000 

Frog's  nerve 

,,       sartorius 
„       heart 

REFRACTORY  PERIOD.  The  phenomenon  of  a  refractory  period 
has  long  been  known  in  connection  with  the  heart  muscle  and  has  often 
been  regarded  as  characteristic  of  this  muscle.  If,  in  the  isolated  ventricle, 
a  beat  be  evoked  by  a  single  minimal  stimulus,  subsequent  repetition  of 
the  stimulus  during  the  course  of  the  contraction  is  ineffective,  and  becomes 
effective  only  when  the  contraction  has  passed  away.  The  heart  is  said  to 
be  refractory  to  stimuli  during  this  period.  The  duration  of  the  refractory 
period  is  a  question  of  the  strength  of  the  stimulus  used.  With  strong 
stimuli  the  heart  may  be  made  to  contract  when  the  relaxation  has  only 
progressed  half  way,  and  with  very  strong  stimuli  one  contraction  may 
be  made  to  follow  the  last  at  such  a  short  interval  that  hardly  any  trace 
of  relaxation  is  observable  between  the  beats.  The  phenomenon  seems  to 
be  common  to  all  excitable  tissues.  Thus  if  two  stimuli  are  applied  to  a 
nerve  within  a  sufficiently  brief  interval,  the  second  stimulus  is  ineffective, 
so  far  as  can  be  determined  by  the  response  of  an  attached  muscle  or  by 
means  of  a  capillary  electrometer.  The  period  is  longer  the  lower  the 
temperature  and  varies  from  •OOOG  sec.  at  40°  C.  to  ^002  sec.  at  12°  C.  This 
critical  interval  is  lengthened  if  the  irritabihty  of  the  nerve  is  depressed 
by  narcotics.  We  may  ascribe  it  to  the  second  stimulus  being  appUed 
before  the  excitatory  change  due  to  the  first  stimulus  has  reached  its 
culminating-point. 

THE  EFFECT  OF  TEMPERATURE  ON  EXCITABILITY.  It  was 
found  by  Gotch  that  the  excitabihty  of  a  nerve  within  certain  hniits  was 
increased  by  cooHng  the  nerve  and  diminished  by  raising  its  temperatm-e 
(Fig.  121).  Thus,  if  a  frog  be  cooled  to  2°  C.  or  3°  C.  for  a  day,  it  will  be 
found  that  simple  section  of  the  sciatic  nerve  may  suffice  to  send  the  gastroc- 
nemius into  continued  contraction,  and  under  these  circumstances  '  closing 
tetanus  '  may  be  obtained  with  the  greatest  ease.  This  increase  of  excita- 
bihty does  not  apply  to  all  kinds  of  stimuh.  In  the  case  of  nerve  its  irri- 
tability was  found  to  be  increased  by  warming,  and  diminished  by  cooling 
for  induction  shocks  and  for  all  galvanic  currents  of  less  duration  than 
•005  sec.  In  skeletal  muscle  Gotch  found  the  excitabihty  for  all  forms  of 
stimuli  increased  by  cooUng.  Lucas  has  show^n  that  these  paradoxical 
effects  in  nerve,  namely,  increase  of  excitabihty  towards  currents  of  long 
duration  and  the  simultaneous  decrease  towards  currents  of  short  duration, 
are  conditioned  by  two  opposed  changes  in  the  tissue.  The  fall  of  tempera- 
ture delays  the  subsidence  of  the  excitatory  process,  but  at  the  same  time 
renders  more  difficult  the  initiation  of  a  propagated  distm-bance.  The  first 
of  these  effects  reduces  the  current  required  for  excitation  in  a  ratio  which 
is  greater  the  greater  the  duration  of  the  cm-rent.     The  latter  increases  the 


274 


PHYSIOLOGY 


current  required  in  the  same  ratio  for  all  durations.  If  then  the  change  of 
temperature  is  such  that  the  two  opposite  effects  are  exactly  balanced  at  a 
certain  medium  duration  of  current,  it  follows  that  for  currents  of  longer 
duration  the  net  result  will  be  to  reduce  the  current  required  for  excitation, 
while  for  currents  of  shorter  duration  the  net  result  will  be  to  increase  the 
current  required.  The  effect  of  temperature  therefore  on  the  minimum 
exciting  current  will  vary  from  tissue  to  tissue  according  as  the  two  factors, 
rate  of  subsidence  of  excitatory  change  and  the  initiation  of  a  propagated 


Fig.  121.  Tracing  of  muscle  contractions  to  show  effect  of  cooling  a  nerve  on 
its  excitability.  The  lower  line  indicates  the  changes  in  temperature  of  the 
excited  part  of  the  nerve.  The  muscle  responded  only  when  the  nerve  was 
cooled,   the  stimulus    becoming    ineffectual  when  the   nerve  was  warmed. 

(GOTCH.) 

disturbance  as  a  result  of  the  excitatory  change,  are  relatively  affected  by 
change  of  temperature. 

THE  EFFECT  OF  INJURY.  The  irritabihty  of  the  nerve  of  a  muscle- 
nerve  preparation  is  not  equal  in  all  parts  of  its  course,  but  is  greater  at  the 
upper  end,  probably  in  consequence  of  the  proximity  of  the  cross-section. 

Some  time  after  a  motor  nerve  is  divided  the  increased  irritabihty  at 
bhe  upper  end  gives  way  to  a  decreased  irritabihty,  and  this  decrease  goes  on 
till  the  nerve  is  no  longer  excitable.  The  diminution  in  excitabihty  gradually 
extends  down  the  nerve  fibre,  so  that  the  part  of  the  nerve  nearest  the  muscle 
remains  excitable  the  longest.  This  progressive  change  in  the  irritabihty 
of  a  nerve  after  section  is  spoken  of  as  the  Ritter-Valli  law.  It  is  soon 
followed  by  definite  histological  changes  in  the  nerve,  which  we  shall  describe 
later. 


SECTION  VII 


THE  NEURO-MUSCULAR  JUNCTION 

The  excitatory  process  travelling  down  a  motor  nerve  has  to  be  transmitted 
to  the  muscle  by  the  intermediation  of  the  nerve-ending  or  end-plate.  We 
have  learnt  to  regard  the  axis  cylinder  as  the  seat  of  the  propagated  ex- 
citatory process.  In  the  end-plate,  however,  the  axis  cylinder  comes  to 
an  end.  When  stained  by  methylene  blue  or  by  impregnation  with  chromate 
of  silver  or  mercury,  the  axis  cylinder,  after  passing  through  the  sarcolemma 
of  the  muscle  fibre,  is  seen  to  break  up  into  a  number 
of  branches  (in  some  cases  forming  a  typical  end- 
arborisation),  which  lie  on  or  are  embedded  in  a 
small  amount  of  imdifi'erentiated  protoplasm  con- 
taining nuclei  (the  '  sole  plate ').  A  similar  break 
in  structural  continuity  seems  to  occur  in  the  central 
nervous  system  wherever  an  impulse  is  propagated 
from  the  axon  process  of  one  nerve-cell  to  the  body 
or  dendrites  of  another  nerve-cell.  The  end-pro- 
cesses of  the  axon  come  in  contact  with  the  next 
member  in  the  chain  of  neurons,  but  no  anatomical 
continuity  is  to  be  made  out,  at  any  rate  in  the 
higher  animals.  In  the  central  nervous  system 
the  area  of  contiguity,  where  an  impulse  passes 
from  one  neuron  to  another,  is  spoken  of  as  a  synapse. 
The  presence  of  the  synapse,  or  end-plate,  between 
muscle  and  nerve  imposes  certain  new  conditions 
on  the  conduction  of  the  excitatory  impulse.     One 

of  the  most  important  of  these  hes  in  the  fact  that  the  conduction  across 
the  end-plate,  and  probably  across  the  synapse  of  the  central  nervous 
system,  is  irreciprocal.  An  excitatory  process  started  in  the  nerve  travels 
easily  across  the  end-plate  to  the  muscle.  On  the  other  hand,  an  excitatory 
process  started  in  the  muscle  does  not  extend  through  the  end- plate  to 
the  nerve  fibre.  This  fact  may  be  shown  on  the  frog's  sartorius.  If  the 
lower  tibial  end  of  the  muscle  be  spht,  as  in  Fig.  122,  a  mechanical  stimulus, 
such  as  a  snip  with  the  scissors,  apphed  to  the  lower  nerve-free  end  of  one 
of  the  limbs,  e.g.  at  A,  causes  a  contraction  of  the  corresponding  half  of 
the  muscle,  which  does  not  extend  to  the  other  half.  On  snipping  the 
muscle  a  httle  higher  up  at  b,  where  nerve-endings  are  present,  the  resulting 

275 


i'lu.  122. 


276  PHYSIOLOaY 

contraction  involves  the  whole  of  the  muscle,  owing  to  the  fact  that  the 
excitation  started  in  the  nerve- endings  spreads  in  both  directions  through 
the  branching  nerve  fibres.  It  is  possible  that  this  irreciprocity  of  conduc- 
tion may  be  of  comparatively  late  appearance  in  evolution.  So  far  as  we 
know,  an  excitatory  process  in  a  sheet  of  muscle  and  nerve  fibres,  such  as 
we  find  in  lower  invertebrata,  e.g.  in  medusa,  may  travel  with  equal  facihty 
in  all  directions.  We  are  probably  not  warranted  from  our  experiments 
on  skeletal  muscle  in  concluding  that  the  contraction  of  a  cardiac  muscle- 
cell  may  not  set  up  an  excitatory  process  in  the  surrounding  network  of 
nerve  fibres.  It  is  impossible,  however,  to  put  such  a  suggestion  to 
experimental  test,  since  in  the  heart  there  is  no  portion  of  muscle  fibre 
sufficiently  removed  from  nerves  to  allow  of  an  excitation  being  applied 
which  might  not  at  the  same  time  affect  the  nerve  fibres. 

There  is  evidence  that  the  transmission  of  the  excitatory  condition 
across  the  end-plate,  from  nerve  to  muscle,  involves  a  special  excitatory 
process  and  the  expenditure  of  energy.  Thus  there  is  a  period  of  delay 
between  the  arrival  of  an  excitatory  impulse  at  the  terminations  of  the 
motor  nerve  and  the  beginning  of  the  electrical  change  which  marks  the 
moment  of  stimulation  of  the  muscle  fibre.  If  we  compare  the  latent  period 
of  a  muscle  stimulated  directly  with  its  latent  period  when  excited  through 
the  nerve,  we  find  that  there  is  an  increased  period  of  delay  in  the  latter 
which  is  not  wholly  accounted  for  by  the  time  taken  for  the  impulse  to 
travel  from  the  stimulated  spot  down  the  nerve  fibres  to  the  muscle.  The 
extra  delay  is  due  to  the  processes  occurring  in  the  end-plate.  This  end- 
plate  delay  amounts  to  -0013  sec.  We  may  take  it  roughly  at  a  thousandth 
of  a  second.  The  end-plate  seems  to  be  the  weakest  point  in  the  neuro- 
muscular chain.  We  have  already  seen  that,  when  a  nerve  of  a  nerve- 
muscle  preparation  is  stimulated  repeatedly,  the  muscle  very  soon  shows 
signs  of  fatigue,  and  that  the  seat  of  this  fatigue  is  not  in  the  nerve,  nor 
in  the  muscle,  but  in  the  end-plate. 

It  has  been  suggested  that  the  excitation  of  muscle  through  nerve 
depends  on  an  electrical  change  or  discharge  at  the  nerve-ending.  This 
,  discharge  must  originate  in  the  terminations  of  the  axon  and  must  influence, 
in  the  first  instance,  the  substance  which  forms  the  intermediary  between 
the  axon  and  the  contractile  material  of  the  muscle.  We  have  indeed 
direct  evidence  of  the  existence  of  a  third  substance,  neither  nerve  nor 
muscle,  at  the  point  of  junction  of  these  two  tissues.  Thus,  curare  is 
generally  said  to  paralyse  the  end-plates.  Evidence  for  this  statement 
has  been  given  in  the  previous  chapter.  Kiihne  has  shown  that  when  the 
irritabihty  of  the  frog's  sartorius  is  tested  at  different  points  it  is  greater  in 
the  situation  of  the  end-plates.  This  might  be  ascribed  to  the  presence 
of  the  more  irritable  nerve-fibres  passing  into  the  muscle-fibres  at  these 
points.  The  unequal  distribution  of  irritabihty  is  not,  however,  changed 
when  the  muscle  is  fully  poisoned  with  curare,  so  as  to  block  entirely  the 
passage  of  any  impulse  from  the  nerve  to  the  muscle.  We  must  therefore 
regard  curare  as  acting,  not  on  the  axon  terminations,  but  on  the  substance 


THE  NEURO-MUSCULAR  JUNCTION  277 

intervening  between  these  terminations  and  the  contractile  substance  of 
the  muscle.  Additional  evidence  of  the  existence  of  such  a  "  receptor  " 
substance,  as  he  calls  it,  has  been  furnished  by  Langley.  Nicotine  resembles 
curare  in  blocking  the  passage  of  impulses  from  the  motor  nerve  to  skeletal 
muscle,  though  inferior  to  curare  in  this  respect.  If  4  mg.  of  nicotine  be 
injected  into  the  vein  of  an  anaesthetised  fowl,  the  hind  hmbs  become 
gradually  stiff  and  extended  in  consequence  of  a  tonic  contraction  of  all  their 
muscles.  The  effect  slowly  passes  off,  but  can  be  reinduced  by  a  second 
dose  of  nicotine.  It  is  worthy  of  note  that  the  stimulating  effect  of  nicotine 
occurs  even  when  sufficient  is  given  entirely  to  paralyse  the  motor  nerves. 
It  might  be  thought  that  the  stimulating  effect  of  nicotine  was  a  direct 
one  upon  the  muscle  fibre,  but  experiment  shows  that  curare  has  a  marked 
antagonising  action  on  the  contraction  produced  by  nicotine,  A  sufficient 
dose  of  curare  annuls  the  contraction  produced  by  a  small  amount  of  nicotine 
and  diminishes  that  caused  by  a  large  amoimt.  The  point  of  action  of  the 
nicotine  must  therefore  be  the  same  as  that  of  the  curare.  After  a  muscle 
has  been  relaxed  by  curare  it  can  be  still  made  to  contract  by  direct  stimula- 
tion. On  the  other  hand,  nicotine  will  produce  its  stimulating  effect  when 
injected  into  a  bird  in  which  degeneration  of  all  the  nerve  fibres  of  the 
muscle  has  been  produced  by  previous  section  of  the  nerve-trunks.  It  is 
evident  therefore  that  nicotine,  hke  curare,  acts,  not  on  the  axon  termina- 
tions, but  on  a  receptor  substance,  an  intermediary  substance  intervening 
between  the  axon  terminations  and  the  contractile  substance  of  the  muscle. 

Evidence  in  favour  of  such  an  intermediary  substance  has  been  brought 
by  Keith  Lucas  from  an  entirely  different  standpoint.  In  determining 
the  optimal  electrical  stimuli  or  the  '  characteristic  '  of  muscle  and  nerve 
by  the  condenser  method  {v.  p.  203),  Lucas  finds  that,  even  after  moderate 
doses  of  curare  sufficient  to  abohsh  the  possibihty  of  excitation  through 
the  nerve-trunk,  the  muscles  show  two  optimal  stimuli,  pointing  to  the 
existence  in  them  of  two  excitatory  substances,  one  of  which  is  not  paralysed 
by  moderate  doses  of  curare.  This  result  was  confirmed  when  the  tissue 
was  investigated  by  determining  the  relation  of  current  duration  to  the 
liminal  current  strength  necessary  to  excite.  In  a  normal  sartorius  he  finds 
three  substances,  each  distinguished  by  its  own  '  excitation  time,'  In  the 
pelvic  nerve-free  end  of  the  sartorius  there  is  only  one  substance  with  an 
excitation  time  of  -017  sec.  This  may  be  regarded  as  the  muscle  substance 
proper.  In  the  sciatic  nerve-trunk  there  is  a  second  substance  with  a  much 
steeper  characteristic  and  with  an  excitation  time  of  -003  sec.  On  experi- 
menting on  the  middle  region  of  the  sartorius  we  find  not  only  these  two 
substances  but  a  third  substance,  which  Lucas  calls  the  substance  [3,  with 
an  extremely  rapid  excitatory  process.  Its  excitation  time  is  •0(^'K)5  sec. 
The  presence  of  these  three  substances  in  the  middle  part  of  the  toad's 
sartorius  is  sliowu  in  the  diagrams  (Fig,  123),  which  represent  the  relation  of 
streugtli  to  duration  of  the  currents  necessary  to  evoke  a  contraction.  In 
this  cuivo  (t  represents  the  muscle  material,  y  the  nerve  material,  and  [i  the 
curve  of  the  intermediary  substance. 


278 


PHYSIOLOGY 


Similar  conditions  are  found  in  the  visceral  neuro-muscular  system. 
Here  the  nerve  fibres  leaving  the  central  nervous  system  do  not  pass  direct 
to  the  muscle  fibres,  but  end  in  arborisations  round  gangUon-cells,  which 
are  collected  to  form  the  gangha  of  the  sympathetic  chain  or  gangha  situated 
more  peripherally  and  nearer  the  reacting  tissue.  Eelays  of  fibres,  for  the 
most  part  non-meduUated,  arise  from  these  ganghon-cells  and  pass  to  the 
unstriated  muscles  of  the  blood-vessels  and  viscera,  where  they  end  in 
plexuses  or  networks  among  the  muscle  fibres,  possibly  connected  by  short 
branches  with  the  fusiform  muscle  fibres  themselves.     No  structure  is 


'V' 

;  V 

a. 

u.j-i^.1-.. 

,  1,  ,  ,  , 

Fig.  123. 

present  at  the  periphery  exactly  analogous  to  the  end-plate,  and  it  is  possible 
that  as  Elhott  suggests,  the  end-plate  is  really  homologous  with  the  whole 
of  the  sympathetic  ganghon  with  its  post-ganglionic  fibres  passing  to  the 
visceral  muscles.  At  any  rate,  the  action  of  curare  and  of  nicotine  on  these 
peripheral  gangha  is  very  similar  to  their  action  on  the  skeletal  end-plates, 
nicotine,  however,  having  a  relatively  stronger  action  than  curare.  In- 
jection of  nicotine  stimulates  and  then  paralyses  the  peripheral  nerve-cells 
of  the  visceral  system ;  curare  in  sufficiently  large  doses  paralyses  them. 
More  instructive  in  relation  to  the  presence  of  receptor  substances  is  the 
action  of  adrenahn.  This  substance,  which  is  produced  by  the  medulla 
of  the  suprarenal  glands,  has  a  specific  action  on  all  tissues  innervated  by 
the  sympathetic  system.  It  causes  almost  universal  constriction  of  the 
blood-vessels,  dilatation  of  the  pupil,  acceleration  of  the  heart,  and  inhibition 
of  the  intestinal  muscles,  with  the  exception  of  the  ileo-cohc  sphincter, 
which  causes  it  to  contract,  all  of  which  effects  can  also  be  produced  by 
stimulation  of  branches  of  the  sympathetic  nerve.  On  the  other  hand 
tissues  which  are  not  innervated  from  the  sympathetic,  such  as  the  blood- 
vessels of  the  brain,  are  unaffected  by  the  drug.  This  fact,  together  with 
the  opposite  effects  of  adrenalin  on  different  unstriated  muscles,  shows 
that  its  action  cannot  be  a  direct  one  on  muscle-fibre.  It  presents  a  marked 
contrast,  for  instance,  to  barium  salts,  which  produce  a  contraction  of 
every  unstriated  muscle-fibre  in  the  body.     On  the  other  hand,  we  cannot 


THE  NEURO-MUSCULAE  JUNCTION  279 

ascribe  this  action  to  a  stimulation  of  the  sympathetic  nerve- endings,  since 
adrenalin  is  equally  effective  if  applied  after  the  whole  of  these  nerve-endings 
have  been  made  to  degenerate  by  section  of  the  post-ganghonic  sympathetic 
nerve-trunks.  Its  action  therefore  must  he  at  the  junction  between  nerve 
and  muscle,  and  must  be  on  some  intermediate  or  receptor  substance  de- 
veloped at  the  myoneural  junction,  and  having  for  its  function  the  trans- 
ference of  the  excitatory  process  from  the  nerve  fibre  to  the  contractile 
substance  of  the  muscle  fibre.  Similar  receptor  substances  may  act  as 
intermediaries  in  every  case  of  propagation  of  an  impulse  across  a  synapse 
of  whatever  description,  and  may  by  their  properties  determine  the  peculiar 
quahties  of  the  synapse.  We  may  compare  them  to  the  fulminating  cap 
which  in  a  shell  is  used  to  transfer  the  process  of  combustion  from  the  slow- 
match  to  the  bursting  charge.  Their  existence  is  of  especial  importance 
when  we  endeavour  to  investigate  the  mode  of  action  of  drugs.  It  is  probable 
that  they  will  be  found  to  play  a  great  part  in  determining  the  differential 
action  of  drugs  on  various  tissues  in  the  body. 


SECTION  VIII 


POLARISATION  PHENOMENA  IN  NERVE 

ELECT ROTONIC  CURRENT.  If  a  constant  current  be  passed  through 
a  nerve  fibre  through  the  electrodes  x  and  y, — x  being  the  anode  and  y  the 
cathode — and  the  extrapolar  portions  of  the  nerve  ah,  cd  be  connected  with 
galvanometers,  the  needles  of  both  are  deflected,  and  the  direction  of  the 
deflection  shows  the  existence  of  a  current  in  the  extrapolar  portions  of 
the  nerve  a  to  h,  and  from  c  to  d. 

We  thus  see  that  a  passage  of  a  current  through  a  part  of  a  nerve  gives 


t     i 


y 


G'  G2 

Fig.  124.     Diagram  showing  electrotonic  currents,     p,   polarising  circuit ; 
Gi,  g2,  galvanometers. 

The  galvanometers  will  indicate,  before  the  passage  of  the  polarising  current, 
the  ordinary  demarcation  current  of  the  nerve  resulting  from  the  cross-section  at 
.  the  upper  end.  This  current  flows,  in  the  outer  circuit,  from  equator  to  cut  end, 
and  therefore  in  the  nerve  fibre  from  a  to  h,  and  from  d  to  c.  The  effect  of  closing 
the  polarising  current  will  be  to  increase  the  current  of  rest  between  a  and  6, 
and  to  diminish  that  between  c  and  d, 

rise  to  a  current  flowing  through  a  considerable  portion  of  the  nerve  fibre 
on  each  side  of  the  polarising  current  and  in  the  same  direction.  This 
current  is  called  the  electrotonic  current.  It  must  not  be  confounded  with 
the  current  of  action,  which  originates  at  one  of  the  poles,  only  at  make  or 
break  of  the  current,  and  is  transmitted  thence  in  the  form  of  a  wave  with 
a  measurable  velocity  (in  the  frog)  of  about  30  metres  per  second  The 
electrotonic  current  is  developed  instantaneously,  and  lasts  the  whole  time 
that  the  current  is  flowing  through  the  nerve.     Its  production  is  dependent 

280 


POLARISATION  PHENOMENA  IN  NERVE  281 

on  the  occurrence  of  polarisation  between  the  sheath  and  the  conducting 
part  of  the  nerve  fibre  and  may  be  exactly  reproduced  on  a  model  consisting 
of  a  core  of  zinc  or  platinum  wire  in  a  casing  of  cotton  soaked  with  ordinary 
salt  solution.  Although  thus  physical  in  origin,  its  production  is  dependent 
on  the  vitality  of  the  nerve,  and  so  is  not  to  be  confounded  with  the  simple 
spread  of  current. 

The  polarisation  phenomena  resulting  from  the  passage  of  a  constant 
current  through  a  medullated  nerve  can  be  studied  on  a  model  made  up  of 


Glass  tube 

containing  0-6/^  Na  CI. 

Pt.wire 

Fig.  125.     Apparatus   for  imitating  the   polarisation  phenomena  in   medullated 
nerve  {'  Kernleiter  '  model). 

a  glass  tube  filled  with  normal  salt  solution,  containing  a  platinum  or  zinc 
wire  stretched  through  it  (Fig.  125).  On  leading  a  current  through  a  and  b, 
and  connecting  c  and  d  with  a  galvanometer,  a  current  will  be  observed  in 
the  extrapolar  portion  of  the  model  in  the  same  direction  as  in  the  intrapolar. 
That  this  spread  of  current  is  due  to  polarisation  is  shown  by  the  fact  that, 
if  the  model  be  made  of  zinc  wire  immersed  in  saturated  zinc  sulphate  solu- 
tion, so  that  no  polarisation  can  occur,  the  spread  of  current  to  the  extra- 
polar  area  is  also  wanting.  If  we  examine  the  phenomena  taking  place  at 
the  anode,  we  see  that  a  current  passes  here  through  an  electrolyte  to  the 
conducting  core.  Every  passage  of  a  current  through  an  electrolyte  must 
be  accompanied  by  dissociation,  the  current  being  carried  by  the  ions. 
We  get  therefore  a  movement  of  negative  ions  up  into  the  electrode,  and 
a  deposition  of  electropositive  ions  on  the  core  (Fig.  127,  a).  In  the  same 
way  at  the  cathode  there 
will  be  a  deposit  of  electro 
negative  ions  on  the  core 
(Fig.  126,  d),  so  we  may 
say  that  the  core  is  posi- 
tively polarised  '^at  the 
anode  and  negatively  polar- 
ised at  the  cathode.  This  ^'7- J 26.  IMagram  to  show  polarisation  at  the  surface 
.        ,  .  .  between  conducting  core  and   electrolj-tc  sheath  in  a 

polarisation  while  opposing      '  Kovlciier.' 
the    primary    current,   will 

set  up  currents  in  the  surrounding  electrolytic  sheath,  as  shown  by  the 
arrows  in  Fig.  127,  the  current  passing  from  a  to  h  and  from  b  to  c  in  the 
electrolyte,  returning  towards  a  in  the  core.  Hence  if  we  lead  off  from 
the  sheath  in  the  neighbourhood  of  the  anode  from  a  and  c,  a  current 
will  pass  in  the  galvanometer  from  a  to  c,  that  is  along  the  core  in  the 
same  direction  as  the  intrapolar  current.  The  same  factors  will  cause  an 
extrapolar  current  in  the  cathodic  area,  the  catelectrotonic  current. 


-ill 

il,+ 

++++++ 

+ 

+  -+.♦- 

c 

b         a 

d        e 

f 

282  PHYSIOLOGY 

This  polarisation  will  not  disappear  at  once  on  breaking  the  polarising 
current.  The  nerve  or  nerve-model  will  still  be  positively  polarised  at  the 
anode  and  negatively  polarised  at  the  cathode.  On  connecting  therefore 
these  two  points  with  the  galvanometer,  we  shall  get  a  current  in  the  opposite 
direction  to  the  previous  polarising  current,  viz.  from  anode  to  cathode 
(Fig.  128).  This  is  the  so-called  negative  polarisation  of  nerve.  Similarly 
in  the  extrapolar  regions  of  the  nerve  we  shall  have  currents  in  the  same 


"^     Polarising 


*^Tf<r5c^ 


d     e     f 


"^-^  "^       -^     "^"^  ^<^       y^  Negative  polarisation. 

Fig.    127.      Diagram  to  show  polarisation  ^-^ 

currents  in  a  '  Kernleiter,'  or  in  a  medul-  FiG.  128.     Diagram  to  show  direction  of 

lated  nerve.  the  negative  polarisation  current. 

direction  as  the  previous  polarising  current,  as  shown  by  the  arrows.  So 
far  then  the  nerve  behaves  exactly  hke  the  mechanical  model.  If,  however, 
we  pass  a  very  strong  current  through  a  nerve,  and  then  quickly  switch 
the  nerve  on  to  a  galvanometer,  we  find  a  momentary  current  through  the 
galvanometer  in  the  same  direction  as  the  previous  polarising  current.  This 
is  known  as  positive  polarisation  of  nerve.  It  is  absolutely  dependent  on 
the  Hving  condition  of  the  nerve,  and  is  in  fact  an  excitatory  phenomenon 
due  to  the  strong  excitation  which  occurs  at  break  of  the  current  at  the 
anode.  Thus  in  the  diagram  (Fig.  129)  a  strong  current  is  passing  through 
through  the  nerve  from  a  to  h.  When  this  current  is  broken,  excitation 
occurs,  as  we  have  already  learnt,  at  the  anode,  and  this  excitatory  state 
may,  if  the  previous  currents  were  strong,  last  two  or  three  seconds.  An 
excited  tissue  is,  however,  always  negative  towards  adjacent  unexcited 

^K      Polarising  RiBX^^^V* 


'-/?>'         Positive  polarisation 


Fig.  129.     Diagram  to  show  direction  of  the  Fig.  130.     Diagram  of  arrange- 

positive  polarisation  current,  due  to  a  break  ment  for  showing  paradoxical 

excitation  at  the  anode.  contraction. 

tissue,  and  therefore  if  we  connect  a  to  k,  there  must  be  a  current  outside 
the  nerve  from  h  to  a,  and  in  the  nerve  from  a  to  k,  viz.  in  the  same  direction 
as  the  polarising  current.  We  see  therefore  that  negative  polarisation  is 
due  to  polarisation  occurring  between  an  electrolytic  sheath  and  a  con- 
ducting core,  whereas  positive  polarisation  is  hardly  a  polarisation  effect  at 
all,  but  is  a  current  of  action. 


POLARISATION  PHENOMENA  IN  NERVE  283 

PARADOXICAL  CONTRACTION.  If  the  sciatic  nerve  of  a  frog  be 
dissected  out,  and  one  of  the  two  branches  into  which  it  divides  be  cut, 
and  the  central  end  of  this  branch  stimulated,  the  muscles  supphed  by  the 
other  half  of  the  nerve  contract  to  each  stimulus.  Ligature  or  crushing 
of  the  nerve  x  (Fig.  130)  between  the  points  stimulated  and  the  point 
which  joins  the  main  trunk  puts  a  stop  to  this  effect,  showing  that  it  is 
not  due  to  a  mere  spread  of  current.  The  fibres  passing  down  n  are  in 
fact  stimulated  by  the  electrotonic  current  developed  in  x  during  the 
passage  of  the  exciting  current. 


SECTION  IX 

THE  NATURE  OF  THE  EXCITATORY  PROCESS 

Under  this  heading  we  have  really  two  questions  to  discuss,  namely,  (a)  the 
nature  of  the  change  excited  at  the  stimulated  spot  in  an  excitable  tissue, 
and  (b)  the  propagation  of  the  excitatory  change  away  from  the  excited  spot, 
e.g.  down  a  nerve  fibre.  That  these  two  phenomena  are  more  or  less  in- 
dependent and  may  be  dealt  with  separately  is  shown  by  the  result  of  passing 
a  constant  current  through  a  parallel-fibred  muscle,  such  as  the  sartorius. 
In  this  case,  as  we  have  seen  (p.  214),  at  make  of  the  current  an  excitatory 
change  occurs  at  the  cathode  and  is  transmitted  throughout  the  whole 
length  of  the  muscle,  giving  rise  to  a  twitch  of  the  muscle.  During  the 
passage  of  the  current  there  is  still  an  excitatory  change  at  the  cathode, 
but  limited  to  a  region  within  one  or  two  milhmetres  of  the  cathode. 

An  attempt  has  been  made  by  Boruttau  and  other  physiologists  to 
explain  the  nerve  process,  not  as  a  wave  of  electrical  change  affecting  the 
substance  of  the  axis  cylinder  itself,  but  as  a  propagated  catelectrotonic 
current.  This  observer  found  that,  by  working  with  a  '  platinum  core 
model'  {'  Kernleiter')  (Fig.  125)  of  considerable  length,  the  catelectrotonic 
current  was  developed  at  one  end  of  the  model  some  appreciable  time  after 
a  current  had  been  sent  in  at  the  other  end,  thus  resembhng  a  current  of 
action.  It  is,  however,  impossible  to  explain  all  the  electrical  phenomena 
of  nerve  as  due  simply  to  polarisation.  We  might  go  so  far  as  to  assume 
that  the  excitatory  effect  at  the  cathode  is  due  to  negative  polarisation, 
and  that  excitation  at  break,  i.e.  at  the  anode,  is  caused  by  the  sudden 
coming  into  existence  of  a  negative  polarisation  current ;  but  then  it  would 
be  difficult  to  understand  how  the  excitation,  so  produced  at  the  anode,  should 
give  rise  to  a  current  so  much  exceeding  the  current  which  produced  it  that 
it  would  appear  in  our  external  circuit  as  a  current  of  positive  polarisation. 

The  same  objection  would  hold  to  the  comparison  of  a  nerve-fibre  with 
a  submarine  cable.  An  electric  disturbance  produced  at  any  part  of  a  cable 
[i.e.  a  conducting  wire  in  an  insulating  sheath)  is  propagated  along  the 
cable  at  a  certain  finite  velocity  which  can  be  calculated  when  we  know 
the  conductivity  of  the  core,  the  capacity  of  the  cable,  and  the  di-electric 
constant  of  the  sheath.  In  all  these  cases  there  must  be  a  decrement  of 
the  change  as  it  is  transmitted  away  from  its  seat  of  origin,  a  decrement  for 
the  existence  of  which  there  is  no  evidence  in  a  nerve  fibre  or  other  excitable 
tissue.*     Moreover  the  phenomenon  of  propagation  of  an  excitatory  process 

*  It  might  be  urged,  on  the  other  hand,  that  one  would  not  expect  to  find  any 
appreciable  decrement  in  a  cable  only  1  to  3  inches  long. 

284 


THE  NATURE  OF  THE  EXCITATORY  PROCESS  285 

is  equally  well  marked  in  tissues,  such  as  muscle  and  non-medullated  nerve 
fibres,  which  show  very  httle  of  the  electrotonic  effects  described  in  the  last 
section.  The  absence  of  decrement  in  the  excitatory  process  has  been 
taken  as  an  indication  that  the  axis  cyhnder  of  the  nerve  is  the  seat  of  energy 
changes  which  may  be  let  loose  under  the  influence  of  chemical  or  electrical 
changes,  just  as  the  energy  of  a  contracting  muscle  is  set  free  by  the  exertion 
of  an  infinitesimal  force  applied  as  a  stimulus.  The  nerve  on  this  view 
does  not  simply  transmit  the  energy  which  is  imparted  to  it,  like  a  telegraph 
wire,  but  itself  furnishes  the  energy  of  the  descending  nerve-process. 

Against  this  view  might  be  urged  the  absence  of  phenomena  of  fatigue 
in  nerve,  as  showing  that  nervous  activity  is  not  accompanied  by  any  ex- 
penditure of  energy  or  using  up  of  material.  But  it  must  be  remembered 
that  this  absence  of  fatigue  holds  good  only  for  medullated  nerve  fibres  and 
is  not  found  in  non-medullated  nerves,*  and  even  in  medullated  nerves  the 
persistence  of  irritability  is  dependent  on  the  continual  supply  of  a  certain 
small  amount  of  oxygen.  It  may  therefore  possibly  be  explained  by  a 
continual  process  of  restitution  taking  place  at  the  expense  of  the  sheath. 
Fatigue  is  absent,  not  because  nothing  is  used  up,  but  because  the  assimilative 
changes  exactly  balance  and  make  good  the  dissimilation  involved  in  the 
propagation  of  a  nervous  impulse. 

There  is  thus  a  certain  amount  of  justification  in  the  comparison  of  a 
nerve  fibre  to  a  chain  of  gunpowder,  though  in  the  nerve  fibre  the  impetus 
to  disintegration,  imparted  from  each  particle  to  the  next  in  order,  consists, 
not  in  a  rise  of  temperature  at  the  point  of  ignition,  but  in  all  probability 
in  an  electrical  change ;  and  the  total  evolution  of  energy  is  so  small  that 
it  cannot  be  measured  as  heat  by  the  most  sensitive  methods  at  our  disposal. 
The  excited  condition  at  any  segment  of  a  nerve  is  associated  with  a  develop- 
ment of  electromotive  forces  at  the  junction  of  the  segment  with  the  adjacent 
resting  segments.  The  current  of  action  thereby  produced  can  pass  by  the 
sheath  of  the  nerve,  so  that  it  must  enter  the  axon  at  the  excited  spot,  and 
leave  it  at  the  adjacent  unexcited  segment.  Hermann  has  suggested  that  in 
this  way  the  current  of  action  at  any  excited  spot  may  excite  the  adjacent 
segments  or  molecules,  causing  them  to  become  negative  and  thus  setting  up 
a  current  of  action  which  in  its  turn  excites  the  succeeding  segments.  In  this 
way  the  excitatory  process  may  travel  the  whole  length  of  the  nerve.  Propa- 
gation would  thus  involve  the  successive  setting  up  of  an  excitatory  process 
all  along  the  nerve  or  excitable  tissue,  though  it  is  difiicult  to  see  why  on  this 
theory  every  excitatory  state  should  not  give  rise  to  a  propagated  change. 
We  are  as  yet  a  long  way  from  a  comprehension  of  the  changes  involved 
in  the  process  of  excitation,  though  we  are  able  to  form  some  idea  of  many  of 
the  factors  which  must  be  involved.  Any  theory  of  the  excitatory  process 
must  take  into  account  the  following  phenomena  : 

(1)  The  excitatory  state  is  attended  wdth  an  electrical  change  of  such 

*  This  statement  is  based  chiefly  on  experiments  on  the  olfactory  nerve  of  the  pike. 
Halliburton  andBrodie  foimd  no  signs  of  fatigue  in  the  non-medullated  fibres  of  the 
sympathetic  supply  to  the  spleen,  even  after  several  hours  stimulation. 


286  PHYSIOLOGY 

a  nature  that  the  excited  spot  is  negative  to  adjacent  unexcited  spots.  This 
electrical  change  rises  rapidly  to  a  maximum  and  dies  away  more  slowly, 
the  rate  of  its  rise,  and  still  more  of  its  subsidence,  varjang  largely  according 
to  the  nature  of  the  tissue  under  investigation. 

(2)  The  excitatory  change  is  aroused  only  at  the  poles  of  a  current 
passing  through  the  tissue,  i.e.  at  those  places  where  polarisation  can  occur 
in  consequence  of  the  electrical  movement  of  ions. 

(3)  Excitation  only  occurs  at  the  cathode  at  make  of  the  current, 
and  only  occurs  if  the  current  attains  a  sufficient  strength  within  a  certain 
period  of  time,  the  relation  of  strength  of  current  to  rate  of  change  varying 
in  different  tissues. 

(4)  All  hving  tissues  are  made  up  of  colloids,  divided  into  compartments 
by  membranes  of  various  permeabihties  and  permeated  with  salts  and  other 
electrolytes  in  solution. 

Disregarding  for  the  moment  all  considerations  of  structure,  it  is  possible 
to  form  a  hypothesis  of  the  nature  of  electrical  excitation  which  takes  into 
account  the  facts  just  mentioned  and  enables  us  to  give  a  quantitative  or 
mathematical  expression  to  the  factors  involved.  An  electrical  current 
passing  through  a  tissue  containing  membranes,  impermeable  to  the  dis- 
solved ions,  will  set  up  differences  of  concentrations  at  and  near  the  mem- 
branes. Nernst,  on  the  supposition  that  these  differences  of  concentrations, 
when  sufficiently  large,  would  cause  an  excitation,  arrived  at  a  formula 
connecting  the  lowest  current  required  to  excite  with  its  duration,  and 
another  formula  connecting  the  lowest  amplitude  of  an  electrical  current 
with  its  frequency.  The  mathematical  investigation  of  the  question  has  been 
continued  by  A.  V.  Hill  in  conjunction  with  Keith  Lucas.  For  this  purpose 
we  may  suppose  that  the  excitable  unit  is  represented  by  a  cyhndrical  space 

closed  at  its  two  ends  by  the  mem- 
branes A  and  B  (Fig.  131)  and 
filled  with  a  solution  of  electro- 
lytes. If  a  current  be  passed 
from  B  to  A  the  positively  charged 
ions  will  move  towards  A  and 
Fig.  131.  tend  to  accumulate  there.      The 

accumulation  of  the  ions  near  the 
membranes  will^be^Hmited  by  the  tendency  of  the  ions  to  equahse  their  con- 
centration in  all  parts  of  the  cell  by  diffusion.  If  we  suppose  that  a  necessary 
condition  for  excitation  is  that  the  concentration  of  the  ions  in  the  neigh- 
bourhood of  one  of  the  membranes  shall  reach  a  certain  definite  value,  it 
becomes  possible  to  calculate  under  what  conditions  of  strength,  duration, 
&c.,  an  electrical  current  will  just  produce  excitation.  The  rise  of  the 
excitatory  state  would  here  be  determined  by  the  rate  at  which  the  ions 
accumulate,  the  subsidence  of  the  excitatory  state  by  the  rate  of  dispersal  of 
the  ions  by  diffusion.  The  formula  arrived  at  by  these  observers  has  this 
form :  .         ^ 


THE  NATURE  OF  THE  EXCITATORY  PROCESS  287 

where  i  is  the  smallest  current  which  will  excite, 

t  is  duration  of  the  current. 
while  \,  fx,  0  are  constants  which  depend  on  : 

(1)  The  distance  between  the  membranes. 

(2)  The  distance  from  the   membrane  at  which  the   concentration 

changes  are  being  considered. 

(3)  The  diffusion  constant  of  the  ion, 

(4)  The  number  of  ions  by  which  a  given  quantity  of  electricity  is 

carried. 

(5)  A  constant  expressing  in  general  terms  the  ease  with  which  a 

propagated  disturbance  is  set  up. 
Investigation  on  these  hnes  may  give  us  in  future  sufficient  infor- 
mation to  form  a  material  conception  of  the  factors  involved  in  excitation, 
factors  which  in  the  above  formula  have  only  a  symbolic  existence.  Thus 
a  determination  of  the  distance  between  the  membranes  would  give  us  some 
clue  to  the  size  of  the  ultimate  excitatory  units  in  the  tissue  involved.*  The 
constant  fx  has  reference  only  to  the  position  relative  to  the  membranes  at 
which  the  changes  of  concentration  are  effective.  From  Lucas's  experiments 
it  would  seem  that  the  changes  of  concentration  occur  in  the  immediate 
neighbourhood  of  one  of  the  membranes.  Macdonald  has  brought  forward 
evidence  that  the  passage  of  a  current  through  a  nerve  involves  the  setting 
free  of  certain  inorganic  ions.  The  subsidence  of  the  excitatory  state 
depends  on  the  rate  of  dift'usion  of  ions.  If,  however,  we  compare  the  rates 
of  subsidence  of  the  excitatory  state  in  different  tissues  we  find  much  greater 
divergence  than  would  be  possible  on  the  assumption  that  the  diffusion  is  one 
affecting  inorganic  ions.  Thus  between  the  substance  ^  (the  intermediate 
substance)  of  the  frog's  sartorius  and  the  ventricular  muscle  fibre  of  the 
same  animal,  the  rate  of  subsidence  of  the  excitatory  state  changes  in  the 
ratio  4000  :  1.  If  the  ions  concerned  were  simple  ions,  such  as  H-,  Ca--,  Na-, 
Cr,  &c.,  it  would  be  impossible  to  account  for  this  wide  variation,  since  their 
velocities  differ  in  the  ratio  of  10  :  1  at  most.  Moreover  the  effect  of  rise  of 
temperature  on  the  rate  of  subsidence  is  greater  than  the  effect  of  a  similar 
rise  on  ionic  velocities.  It  is  evident  therefore  that  the  theory  is  one  for  use 
as  a  working  hypothesis  only.  That  excitation  is  associated  with  accumu- 
lation of  ions  in  the  region  of  the  exciting  electrode,  that  the  subsidence  of 
of  the  excitatory  state  is  due  to  disappearance  by  diffusion  or  otherwise  of 
these  ions,  there  can  be  little  doubt.  But  the  questions  as  to  the  nature  of 
these  ions,  and  their  relation  to  the  colloidal  constituents  of  the  excitatory 
tissue,  or  to  other  possible  substances,  changes  in  which  may  form  an  integral 
part  in  the  excitatory  state,  must  be  left  for  future  investigation. 

*  It  would  be  premature  at  present  to  give  any  histological  significance  to  Hill 
and  Lucas's  diagrammatic  cylinder.  As  Hardy  has  pointed  out,  the  nerve  cannot 
consist  of  a  row  of  such  cylinders,  otherwise  excitation  would  occur  throughout  the 
whole  intrapolar  region,  and  not  be  confined  to  the  cathode  at  make  and  the  anode 
at  break.  It  may  be  that  we  are  dealing  here  again  with  the  jwlarisable  sheath  of  the 
'Kenileiter.'  and  that  the  membrane  a  corresponds  to  the  surface  of  the  axis  cylinder 
or  of  its  neuro-fibrils. 


CHAPTER  VII 
THE  CENTRAL  NERVOUS  SYSTEM 

SECTION  T 

THE  EVOLUTION  AND   SIGNIFICANCE  OF  THE 
NERVOUS  SYSTEM 

Every  vital  phenomenon  maybe  regarded  as  a  reaction  conditioned  by  some 
change  in  the  environment  of  the  animal  and  adapted  to  its  preservation.  In 
the  community  of  cells  forming  the  whole  organism,  the  defence  of  any  one 
part  must  involve  the  co-operation  of  the  whole  community ;  no  change 
in  a  cell  of  the  body  can  be  regarded  as  a  matter  of  indifference  to  any  of  the 
other  cells.  For  this  subordination  of  the  activities  of  each  part  to  the 
welfare  of  the  whole,  as  for  the  co-operation  of  all  parts  in  maintaining  the 
welfare  of  each,  a  means  of  communication  is  necessary  between  the  various 
cells.  For  some  of  the  lower  functions  the  channel  of  communication  is  the 
blood,  which  serves  as  a  medium  for  carrying  food  material  from  one  part  of 
the  body  to  another,  or  for  the  transmission  of  chemical  messengers,  which, 
elaborated  by  one  set  of  cells,  may  affect  the  metabohsm  of  cells  in  distant 
parts  of  the  body.  This  method  of  correlating  different  activities  would, 
however,  be  too  slow  and  clumsy  for  the  quick  adaptation  of  the  organism 
to  sudden  changes  of  environment.  Such  a  rapid  correlation  can  be  effected 
only  by  a  propagation  of  some  molecular  change  from  the  seat  of  incidence  of 
the  stimulus  either  to  all  parts  of  the  body,  or  to  some  mechanism  controlling 
all  parts  of  the  body.  The  medium  for  the  propagation  of  a  state  of  excitation 
is  furnished  by  the  nervous  system.  We  have  seen  that  stimuh  of  various 
kinds,  involving  such  various  forces  as  thermal,  chemical,  and  electrical 
energy,  are  transformed  by  a  muscle  or  nerve  fibre  into  what  we  call  a  state 
of  excitation,  which  is  propagated  along  the  fibres,  whether  nerve  or  muscle, 
at  a  certain  definite  rate,  its  passage  in  the  case  of  the  muscle  being  followed 
by  a  wave  of  contraction. 

In  unicellular  animals,  such  as  the  amoeba  and  vorticella,  there  is  no 
difiierentiation  of  any  structure  which  can  be  regarded  as  pecuharly  nervous. 
A  stimulus  appHed  to  any  part  of  the  amoeba  may  evoke  responsive  activity 
in  all  other  parts.  A  slight  touch  applied  to  any  point  on  a  vorticella  will 
cause  an  excitation  which  is  rapidly  propagated  to  the  stalk,  causing  this  to 

288 


EVOLUTION  OF  THE  NERVOUS  SYSTEM 


289 


contract  and  so  withdraw  the  organism  from  any  possible  injury.  In  the 
lowest  metazoa,  such  as  the  sponges,  we  find  no  special  nervous  structures. 
The  cells  forming  the  sponge  may  react  to  changes  in  their  environment  by 
contraction  or  by  alteration  of  their  relative  positions.  Many  of  the  cells  can 
move  from  one  part  of  the  sponge  to  the  other  in  response  to  chemical 
changes  occurring  in  the  body  of  the  sponge.  So  far,  however,  no  cells  have 
been  distinguished  as  endowed  above  their  fellows  ^vith  the  property  of 
irritabiUty  or  the  power  of  reaction  to  stimulus.  It  is  in  the  next  class,  that 
of  the  Coelenterata,  where  we  first  find  a  definite  nervous  system.     The  object 


B 


m.c. 


Fig.  132,     Diagrammatic  representation  of  evolution  of  a  nervous  system. 

(Modified  from  Foster.) 
ec,  epithelial  cell ;    mp,  muscular  process  ;    sc,  sensory  cell ;    wp,  nerve  process 
or  fibre  ;  mc,  muscle-cell ;  sn'p,  sensory  nerve  process  ;  mwp,  motor  nerve  process ; 
cc,  central  cell. 

of  a  nervous  system  is  to  ensure  the  co-operation  of  the  whole  organism  in  any 
reaction  to  changes  in  its  surroundings.  At  its  first  appearance  therefore  we 
should  expect  a  nervous  system  to  be  developed  in  connection  with  that  layer 
of  the  animal  which  is  in  immediate  relation  to  the  environment,  namely, 
the  efiblast  or  external  layer.  In  some  species  of  hydra,  though  no  typical 
nervous  tissues  have  been  detected,  many  of  the  epithehal  cells  lying  on  the 
surface  are  prolonged  at  their  inner  ends  into  a  long  contractile  process  (Fig. 
132,  a),  so  that  stimuH  apphed  to  the  surface  and  acting  on  the  epithelial 
cells  can  cause,  as  an  immediate  response,  a  contraction  of  the  underlying 
nmscular  processes.  We  may  easily  conceive  that  in  such  an  animal,  among 
the  cells  forming  the  epiblast,  certain  cells  might  become  endowed  with  a 
special  sensitiveness  to  external  changes,  other  cells  being  developed,  like 
those  of  the  hydra  just  mentioned,  into  special  contractile  structures.  If  in 
the  course  of  development  the  protoplasmic  continuity  between  these  two 
sets  of  cells  had  not  become  interrupted  (and  we  have  no  ground  for  assuming 
that  such  an  interruption  occurs  under  normal  circumstances),  it  is  evident 
that  we  should  have  so  produced  the  simplest  form  of  a  reflex  arc  (Fig.  132,  b), 
namely,  a  sensory  cell,  which  is  stimulated  by  slight  physical  changes  in  its 
surroundings  and  is  thereby  tliro\\^i  into  a  state  of  activity  similar  to  that 
which  we  have  already  studied  in  nmscle  and  nerve.  This  state  of  activity 
would  be  propagated  by  the  protoplasmic  channels  to  the  muscular  cell  and 

10 


290 


PHYSIOLOGY 


/ 


arouse  there  the  specific  function  of  the  muscle,  namely,  contraction.  In  such 
a  simple  reactive  tissue,  Hnes  of  less  resistance  would  be  rapidly  laid  down 
through  the  protoplasmic  continuum,  and  these  hnes,  acquiring  a  specific 
structure  or  composition,  would  form  a  network  uniting  sensory  and  muscular 
cells.  Thus  a  stimulus  apphed  to  any  sensory  cell  would  spread  to  the  ad- 
jacent sensory  and  muscular  cells,  and  the  response  of  the  muscle-cells  would 
be  greatest  near  the  stimulated  spot,  gradually  djang  away  as  the  area  of  the 
excitation  widened.  A  further  step  in  the  development  of  such  a  hypotheti- 
cal elementary  nervous  system  would  occur  when  certain  of  the  sensory  cells 
(Fig.  132,  c)  developed  a  special  sensitiveness,  not  to  mechanical  changes  in 
the  environment,  but  to  the  protoplasmic  excitatory  process  arriving  at  them 
along  the  nerve  network.     These  cells  would  act  as  relays  of  force,  picking 

up  the  excitations   arriving  from 

^^- ,  the  undifferentiated  sensory  cells, 

and  sending  them  on  with  increased 
vigour  along  the  nerve  network. 
In  such  a  manner  a  stimulus 
applied  at  one  point  could  be  sent 
on  in  successive  relays  from  cell  to 
cell  throughout  the  whole  reactive 
tissue  on  the  surface  of  the  body. 
We  cannot  point  to  any  par- 
ticular animal  as  presenting  in- 
stances of  either  of  the  two  types 
of  elementary  nervous  system  just 
described.  If  such  exist,  they 
have  not  yet  been  investigated, 
or  the  undifferentiated  character 
of  their  nervous  tissues  has 
thwarted  the  efforts  of  zoologists 
to  display  their  specific  characters 
by  staining  reagents.  In  the 
lowest  definite  nervous  system 
with  which  we  are  acquainted, 
namely,  that  of  the  jelly-fish, 
all  three  1  types  of  cell,  the  sensory  cell,  the  reactive  or  central  cell,  and  the 
motor  cell,  are  already  developed  and  have  undergone  among  themselves  a 
considerable  degree  of  differentiation.  In  a  jelly-fish  or  medusa,  such  as 
aureha  or  sarsia  (Fig.  13.3),  the  reactive  tissue  of  the  body  is  confined  to  the 
under-surface  of  the  so-called  umbrella  with  the  tentacles  and  manubrium. 
A  section  through  the  umbrella  shows  a  layer  of  epithelium  containing 
differentiated  sense-cells,  below  which  is  a  plexus  or  rather  network  of  fine 
nerve  fibres  with  a  certain  number  of  nerve- cells  at  the  nodes  of  the  network. 
From  this  network  fibres  pass  more  deeply  to  end  in  a  finer  network  situated 
among  a  layer  of  muscle  fibres  formed,  hke  the  sensory  cells,  by  a  differentia- 
tion of  the  primitive  epithelium  or  epiblast  (Fig.  134).     Besides  this  diffuse 


Fig.    133.      Diagrammatic  view  of  a  jelly-fish 

(Hertwig.) 

TJ,  umbrella  ;    m,  manubrium;    t^,  T2,  tentacles 

V,  velum  ;   N,  nerve  ring  ;   r,  '  marginal  body.' 


EVOLUTION  OF  THE  NERVOUS  SYSTEM 


291 


nervous  system,  there  is  a  continuous  ring  of  nerve  fibres  round  the  margin 
of  the  umbrella,  thickened  at  intervals  by  the  accumulation  of  nerve-cells, 
which  are  in  close  relation  to  special  collections  of  sensory  cells  in  the 
'  marginal  bodies.'  These  sensory  cells  present  a  differentiation  among  them- 
selves, some  being  apparently  determined  for  the  reception  of  mechanical 


Flu.  134.  Diagram  of  subepithelial  plexus  of  nerve  fibres  and  nerve-cells,  communicat- 
ing on  the  one  side  with  the  sensory  epithelium,  and  on  the  other  side  with  the  sub- 
umbrellar  sheet  of  muscle  fibres.     (After  Bethe.  ) 

stimuli,  others  for  the  reception  of  light  stimuh,  while  others  again  are  found 
in  close  relation  with  Httle  masses  of  calcium  carbonate  crystals,  by  the  direc- 
tion of  the  weight  of  which  the  cells  are  able  to  react  to  changes  in  the  position 
of  the  animal  in  space.  In  the  jelly-fish  therefore  the  nervous  or  reactive 
system  has  already  acquired  a  considerable  degree  of  differentiation. 


I'lu.  l;}o.  Figure  of  a  ji'lly-lisli  in  wliicli  all  the  marginal  bodies  exccjit  one  have 
boon  removed,  and  wliich  lias  been  incised  in  various  directions  so  as  to  divide 
the  nerv(>  ring  and  all  the  "  long  paths,'  so  that  only  the  diffuse  nerve  network 
remains  functional.     (Romanes.) 


We  may  study  the  behaviour  of  a  more  primitive  systeni  if  wo  remove 
the  special  sense-organs  of  the  medusa  by  cutting  off  the  whole  of  the  marginal 
ring  with  its  contained  marginal  bodies  (Fig.  135).     We  have  then  a  layer 


292 


PHYSIOLOGY 


of  contractile  tissue,  innervated  by  a  nerve  network,  and  covered  by  a  layer 
of  epithelium  containing  sense-cells.  To  this  network  is  attached  the 
manubrium,  which  represents  the  mouth  and  stomach  of  the  animal.  In 
such  a  mutilated  jelly-fish  it  is  easy  to  show  that  a  stimulus  apphed  to  one 
spot  on  the  surface  travels  outwards  from  the  excited  spot  to  all  parts  of  the 
bell.  The  stimulus  is  propagated  also  to  the  manubrium,  which  in  some 
species  bends  in  the  direction  of  the  excited  spot — that  is  to  say,  in  the  direc- 
tion which  represents  the  shortest  possible  path  from  the  excited  spot  to  the 
manubrium.  This  preparation  rarely  presents  any  automatic  activity.  It 
may  react  to  a  constant  stimulus  by  a  rhythmic  series  of  contractions,  but 
remains  perfectly  motionless  in  the  absence  of  stimulus.     The  unmutilated 


Fig.  136.     Schema  showing  the  utility  of  the  multiplication  of  neurons  and  their 
grouping  in  central  ganglia.     (Cajal.) 

A,  an  ideal  invertebrate  with  only  cutaneous  '  sensory  '  neurons. 

B,  invertebrate,  such  as  a  medusa,  with  sensory  and  motor  neurons,  but 
no  central  nervous  system. 

c,  invertebrate  {e.g.  Annelid)  in  which  the  motor  neurons  are  concentrated 
in  central  ganglia. 

a,  sensory  neuron  ;   b,  muscle  ;   c,  motor  neuron. 

jelly-fish  presents  rhythmic  contractions  of  its  sub-umbrella  tissue  which  are 
inaugurated  in  any  or  all  of  the  marginal  bodies  and  serve  to  drive  the 
animal  onwards  through  the  water  in  which  it  is  immersed.  The  rhythmic 
contractions  may  be  initiated,  augmented,  or  diminished,  in  response  to 
stimuh  of  hght,  mechanical  irritation,  or  changes  in  the  position  of  the  whole 
animal  acting  on  the  marginal  bodies.  In  the  reaction  of  an  animal  to  ex- 
ternal stimuli  it  must  be  an  advantage  if  the  energies  of  the  whole  can  be 
concentrated  in  defence  of  any  one  part  and  be  evoked  by  a  stimulus  applied 
at  one  point.  Such  a  co-operation  of  the  whole  for  the  benefit  of  the  part 
involves  the  existence  of  direct  paths  from  the  stimulated  point  to  all  parts 
of  the  animal  if  the  reaction  is  to  take  place  with  any  promptitude.  In  the 
medusa  we  find  a  beginning  of  such  '  long  paths.'  The  general  direction  of 
the  fibres  of  the  network  is  radial,  and  there  is  a  concentration  of  such  fibres 
in  the  neighbourhood  of  the  marginal  bodies,  so  that  an  excitation  can  pass 
more  readily  from  a  sense-organ  to  the  menubrium  than  it  can  laterally  along 
the  circumference  of  the  animal.  Moreover,  a  stimulus  which  is  too  shght 
to  excite  a  reflex  contraction  of  the  muscular  tissue  may  travel  along  the 
nerve  tissue  to  each  of  the  marginal  ganglia  and  arouse  these  to  a  discharge  of 
motor  impulses.  We  have  therefore  in  the  medusa  sensory  cells  of  different 
sensibihties  ;  central  cells  specially  adapted  to  reacting  to  and  reinforcing  a 


EVOLUTION  OF  THE  NERVOUS  SYSTEM 


293 


nerve  stimulus  started  by  a  small  change  in  the  environment ;  a  general 
nerve  network  propagating  the  excitatory  changes  in  all  directions,  but  with 
special  ease  in  certain  directions ;  and  a  reactive  muscular  tissue  which 
carries  out  movements  at  the  end  of  the  chain  of  excitation,  all  the  elements 
forming  the  chain  being  derived  from  epiblastic  cells. 

A  further  differentiation  of  a  nervous  system,  such  as  that  just  described, 
must  in  the  first  place  involve  the  laying  down 
of  more  '  long  paths  '  and  the  collection  of  the 
special  '  central '  cells  into  closely  comiected 
masses  (gangha),  so  as  to  concentrate  the  control 
of  the  reactions  of  the  body,  and  to  permit  of  the 
ready  subordination  of  every  part  to  the  needs  of 
the  whole.  A  special  direction  is  given  to  this 
development  by  the  evolution  of  animals,  such  as 
worms  and  crustaceans,  which  are  segmented  and 
capable  of  locomotion.  The  fact  that  these  animals 
are  segmented  determines  the  collection  of  the 
central  cells  into  a  chain  of  gangha,  one  ganghou 
or  pair  of  gangha  being  provided  for  each  segment. 
In  the  act  of  locomotion  it  is  of  advantage  to  the 
animal  that  those  sense-organs  or  sensory  cells 
which  are  projicient,  i.e.  which  are  stimulated  by 
changes  in  the  environment  originating  at  a  distance 
from  the  animal,  should  be  collected  together 
near  that  part  which  goes  first,  namely,  the  head 
end.  Thus  the  projected  sensations  of  sight, 
those  which  are  excited  by  chemical  changes  in 
the  surrounding  medium  and  represent  the  sense 
of  smell,  and  those  which  are  specially  aroused 
by  vibrations  in  the  surrounding  medium  and 
correspond  to  those  which  we  call  the  sense  of 
sound,  are  in  the  majority  of  these  animals  sub- 
served by  organs  situated  near  the  head  end. 

The  wisdom  of  a  man  is  measured  by  his  fore- 


sight.    The  chances  of  an  animal  in  the  struggle 


for  existence  are  determined  by  the  degree  t-o  which 
the  reactions  of  the  animal  to  its  immediate  en- 
vironment are  held  in  check  in  response  to  stimuli 
arising  from  approaching  events.  An  animal  with- 
out power  to  see,  smell,  or  hear  its  enemy  will  re- 
ceive no  impulse  to  fly  until  it  is  already  within  its 
enemy's  jaws.  It  must  therefore  be  of  advantage  to 

segmented  animal  that  the  activities  of  the  whole  chain  of  segmented  gangha 
should  be  subservient  to  those  central  nerve-cells  which  are  in  direct  con- 
nection with  the  projicient  sense-organs  at  the  head.  The  influence  exerted 
by  the  head  ganglia  will  be  in  the  first  place  inhibitory  of  the  direct  reaction 


Fig.  137.  View  of  central 
nervous  system  of  craj-- 
fish.     (After  Yung  and 

VOGT.) 

a,  cerebral  ganglion. 

b,  commissure, 
e,  suboesophageal ganglion. 
g,  first  abdominal  ganglion. 
/,  oesophagus. 
m,  optic  nerve, 
p,  antennary  nerve. 
s,  stomato-gastric  nerve. 


294 


PHYSIOLOGY 


excited  in  each  segment  by  stimulation  of  its  surface,  and,  for  this  influence 
to  be  propagated,  long  tracks  must  be  laid  down,  joining  up  ganglion  to 
ganghon  and  propagating  impulses  from  the  head  gangha  to  the  most 
distant  part  of  the  chain.  As  a  type  of  such  a  system  we  may  refer  to  the 
crayfish. 

In  this  animal  the  central  nervous  system  (Fig.  137)  consists  of  a  chain  of  thirteen 
ganglia,  namely,  six  abdominal  ganglia,  six  thoracic  ganglia,  and  one  supraoesophageal 
or  cerebral  ganglion.  In  the  abdomen  and  thorax  the  ganglia  form  a  longitudinal 
series  situated  in  the  middle  line  of  the  ventral  aspect  of  the  body  close  to  the  integu- 


GAMGLION  -  CNA 


Fig.  1.38.     Diagram  of  nervous  system  of  a  segmented  invertebrate  (earthworm 
or  crayfish).     (From  Schafek,  after  Retzius.) 
s',  sensory  cells;     s,  afferent  nerve  fibres  ;   m,  motor  neuron  ;   i,  central 
or  intermediate  cell. 


ment.  All  give  origin  to  a  variable  number  of  nerves,  which  are  distributed  partly 
to  the  muscles,  partly  to  the  skin  and  sense-organs.  They  are  connected  by  longitu- 
dinal bands  of  nerve  fibres  or  commissures,  which  are  double,  each  ganglion  being  bilobed. 
The  most  anterior  of  the  thoracic  ganglia,  which  is  the  largest,  is  marked  at  the  side 
by  notches,  as  if  it  were  made  up  of  several  pairs  of  ganglia  fused  together.  From  this 
ganglion  two  commissures  pass  forward  round  the  gullet  to  unite  in  front  of  this  tube, 
behind  the  eyes,  with  the  transversely  elongated  mass  of  ganglion  cells  and  fibres 
called  the  supraoesophageal  ganglion.  This  ganglion  consists  of  three  fused  pairs  of 
ganglia,  which  have  been  termed  the  protocerebron,  the  deuterocerebron,  and  the  trito- 
cerebron.  The  most  anterior  gives  origin  to  the  optic  nerves,  which  run  by  the  optic 
stalks  to  the  eyes.  From  the  middle  ganglion  on  each  side  a  tegumentary  nerve  passes 
to  ramify  in  the  integument  and  from  the  inferior  surface  the  antennulary  nerves 
pass  to  the  internal  antenna?.  From  these  small  branches  are  distributed  to  the  organ 
of  hearing.  The  posterior  protuberance  of  the  brain  gives  origin  to  the  antennary 
nerves  which  pass  to  the  large  external  antennae  of  the  animal.     The  first  thoracic, 


EVOLUTION  OF  THE  NERVOUS  SYSTEM 


295 


or  suboesophageal,  ganglion  gives  origin  to  ten  pairs  of  nerves  which  are  distributed 
to  the  mandibles,  to  the  jaws  or  maxillae,  to  the  maxillipedes,  and  to  the  branchial 
appendages  of  the  latter. 

When  we  investigate  the  structural  basis  of  such  a  nervous  system  we 
find  that,  as  in  medusa,  the  starting-point  of  the  reflex  arc  is  in  certain 
neuro- epithelial  cells  (Fig.  138)  lying  on  the  surface  of  the  body.  These  cells 
are  spindle-shaped,  and  have  one  short  process  passing  to  the  surface,  and  a 
long  process  which  runs  in  a  nerve  fibre  or  collection  of  fibres  towards  the 
ganglion  of  the  segment.  Arrived  at  the  ganglion  it  divides  into  two 
branches,  which  pass  towards  the  two  ends  of  the  body  and  become  lost  in 


Fig.  139.     Diagram  of  a  reflex  arc  in  a  (ncuro- fibrillar)  invertebrate  nervous  system. 
(Bethe.)     The  efferent  paths  are  coloured  red,  the  afferent  black. 

the  granular  material  forming  the  inner  part  of  each  ganghon.  The  ganglia 
themselves  consist  internally  of  this  punctated  substance  or  granular 
material,  and  externally  of  a  capsule  of  ganglion-cells.  Each  of  the  ganglion- 
cells  sends  one  thick  process  towards  the  centre,  which  rapidly  divides, 
some  of  the  branches  passing  into  the  granular  material,  while  one  branch 
passes  outwards  in  a  nerve  to  end  in  a  network  of  fine  fibrils  within  the 
muscles  on  the  surface  of  the  body.  The  nervous  impulse  excited  in  the 
sensory  cell  on  the  periphery  travels  therefore  up  a  nerve  fibre  into  the  grami- 
lar  substance  of  the  ganglion.  From  this  granular  substance  it  is  collected 
by  the  fine  branches  of  the  ganglion-cells  and  is  transmitted  by  them  along 
the  motor  nerve  fibre  to  the  muscles.  The  central  granular  material  consists 
entirely  of  a  close  felt- work  of  fibres,  which  may  be  regarded  as  processes 
either  of  the  sensory  nerve  fibres  or  of  the  nerve-cells.  The  typical  reflex 
arc  in  this  case  therefore  is  formed  by  two  nerve-cells  with  their  processes. 
Such  a  nerve-cell  with  its  processes  is  spoken  of  as  a  neuron.  The  first  neuron 
the  recipient  neuron,  or  receptor,  is  represented  by  the  sensory  cell  with  its 


296  PHYSIOLOGY 

two  processes  in  the  granular  material.  The  second  neuron  is  formed  by  the 
ganghon-cell  with  its  finely  branched  dendritic  processes  in  the  granular 
matter  and  its  motor  axon,  which  passes  into  the  muscle  fibres.  As  to  the 
manner  in  which  the  impulse  passes  from  the  branches  of  one  cell  into  those 
of  the  other,  opinions  are  still  divided.  The  question  will  have  to  be  more 
fully  considered  when  we  come  to  deal  with  the  vertebrate  nervous  system. 
Many  beheve  that  there  is  no  anatomical  continuity  between  the  two  neurons, 
and  that  the  excitatory  change  is  transmitted  by  a  mere  contiguity,  a  change 
m  one  set  of  nerve-endings  exciting  a  corresponding  change  in  another  set  of 
nerve- endings  in  immediate  contact  with  them.  By  certain  methods,  however, 
it  is  possible  to  show  the  existence  of  an  anatomical  continuum  throughout 
the  whole  nervous  system  in  these  invertebrate  animals.  Apathy  and  Bethe 
have  demonstrated  the  presence  of  a  continuous  system  of  neurofibrils, 
much  smaller  than  an  individual  nerve  fibre,  which,  starting  in  a  sensory  cell, 
pass  into  a  network  of  fibrils  forming  the  greater  part  of  the  central  granular 
matter.  From  this  network  neurofibrils  run  along  the  dendrites  into  the 
ganghon-cells,  forming  there  a  small  network  through  the  centre  of  which  a 
neurofibril  is  continued  down  the  nerve  processes  again,  and  passes  out  along 
the  motor  nerve  to  end  in  a  network  of  fibrils  among  the  muscle  fibres.  In  a 
system  so  constituted  it  is  evident  that,  although  an  excitatory  process 
passing  along  a  given  fibril  may  find  certain  paths  easier  than  others,  and  so 
maintain  a  constant  prescribed  path  through  the  nerve  system,  yet  it  will 
be  possible,  by  sufficiently  increasing  the  strength  of  the  excitatory  process, 
to  cause  it  to  travel  in  all  directions  in  the  central  nervous  system  and  to 
evoke  in  this  way  a  general  activity  of  all  parts  of  the  body,  a  condition  in 
fact  found  to  obtain  in  the  normal  animal.  It  is  significant  that,  although 
a  great  number  of  fibrils  pass  into  the  bodies  of  the  ganghon-cells,  yet  in 
many  cases,  especially  in  crustaceans,  fibrils  are  to  be  found  sweeping  from  the 
neuropilem  or  nerve  network  of  the  granular  substance  into  a  nerve  process, 
and  thence  into  its  motor  axon  without  at  any  time  entering  the  body  of  the 
cell  (Fig.  139). 


SECTION  II 

THE   NERVOUS  SYSTEM   OF  VERTEBRATES 

In  these,  as  in  the  invertebrata,  the  central  nervous  system  is  developed 
by  an  involution  of  the  epiblast,  reveahng  thereby  its  primitive  relations 
to  the  surface  of  the  body.  At  an  early  period  in  foetal  hfe,  shortly  after  the 
formation  of  the  two  layers  of  epiblast  and  hypoblast,  a  thickening  is  ob- 
served in  the  epiblast.  This  thickening  soon  gives  place  to  a  groove,  the 
neural  groove  (Fig.  140),  and  the  walls  of  the  groove  folding  over  form  a 


Fig.  140.     Transverse  section  of  human  embryo  of  2-4  mm.  to  show  developing 

neural  canal.     (T.  H.  Bkyce.) 

»c.  neural  canal  ;    mc,  muscleplatc  ;    ;«y,  outer  wall  of  somite  ; 

sc,  sclerotome. 


canal,  the  neural  canal,  which  is  dilated  at  the  head  end  of  the  embryo  to 
form  three  enlargements  known  as  the  cerebral  vesicles. 

When  first  formed  the  canal  is  oval  in  cross-section,  its  wall  being  made 
up  of  a  layer  of  columnar  cells  between  the  outer  extremities  of  which 
are  seen  smaller  rounded  cells.  The  internal  layer  of  columnar  cells  send 
a  process  peripherally  which  branches  at  the  end  so  as  to  form  a  close 
meshwork  of  fibres.  These  fibres  branch  more  and  more  as  development 
progresses,  and  eventually  form  the  supporting  tissue  of  the  adult  central 
nervous  tissue,  known  as  the  neuroglia.  As  the  wall  of  the  canal  grows  in 
thickness,  some  of  the  cells  may  wander  outwards  and  form  neurogUa-cells 
with  numerous  radiating  branches.  In  the  adult  nervous  system  little  is 
left  of  those  colls  except  their  nuclei,  so  that  the  neuroglia  appears  as  a  close 
felt-work  of  fibres,  to  which  here  and  there  nuclei  nro  attached.     These  cells 

297  1»)  * 


298 


PHYSIOLOGY 


are  formed  from  the  most  superficial  layer  of  the  invaginated  epiblast,  and 
are  spoken  of  as  S'po7igioUasts.  The  deeper  layer  of  cells,  which  are  to  give 
rise  to  the  permanent  nerve-cells,  and  are  therefore  known  as  neuroblasts, 
rapidly  divide  and  form  a  thick  layer  surrounding  the  internal  layer  of 
spongioblasts,  through  which  pass  the  peripheral  processes  of  the  latter. 
When  first  formed  these  cells  have  no  processes.  Later  on  each  neuroblast 
acquires  a  pear  shape,  the  stalk  of  the  pear  having  a  somewhat  bulbous 
extremity  (Fig.  142).  The  stalk  continually  elongates,  and  the  elongated 
process  may  leave  the  spinal  cord  altogether  and  grow  outwards  to  any  part 

of  the  body  of  the  embryo,  or  may  pass 
to  other  parts  of  the  central  nervous  sys- 
tem. This  long  process  of  the  developing 
nerve- cell  is  known  as  the  axon.  Some 
time  after  its  formation  other  processes 
grow  out  from  the  cell,  which  soon  branch 
and  end  in  the  immediate  neighbourhood 
of  the  cell.  The  axons  of  the  cells  near  the 
ventral  part  of  the  neural  tube  grow  out 
11  1         to   the   different   muscles   of  the   body, 

■  J         1  «L       where  they  end  in  close  connection  with 

Mm.  f^         1        /"^     *^®  muscular  fibres  by  an  arborisation 

1^  I  0%        ^l      IV^K  "^^^^  forms  the  end-plate.     They  provide 

%^  \'  /      I' *  ;  an   efferent  path  for  impulses   running 

from  the  central  nervous  system  to  the 
musculature  of  the  body.  The  afferent 
channel  is  formed  in  a  somewhat  different 
manner.  Even  before  the  neural  groove 
has  closed  in,  a  thickening  of  the  epiblast 
is  seen  immediately  external  to  the 
groove  on  each  side.  This  thickening 
becomes  divided  into  a  series  of  collections  of  cells  lying  immediately  under 
the  epiblast  on  the  lateral  and  dorsal  surface  of  the  neural  canal.  The 
cells,  which  are  at  first  round  or  oval,  send  off  two  processes  in  opposite 
directions  so  that  they  become  bi-polar  (Fig.  142).  One  process  passes  into 
the  central  nervous  system,  where  it  divides,  some  of  its  branches  being 
distributed  in  the  nervous  system  at  the  same  level,  while  others  run  a  con- 
siderable distance  towards  the  head  immediately  outside  the  tube  of  nerve- 
cells.  The  other  process  grows  downwards,  along  with  the  processes  from 
the  ventral  cells  of  the  tube,  towards  the  periphery  of  the  body,  where  it  ends 
in  close  connection  with  the  surface  in  the  various  sense-organs  of  the  skin 
and  muscles.  These  collections  of  bi-polar  cells  form  the  posterior  root 
ganglia.  In  fishes  they  retain  their  primitive  character  throughout  life, 
but  in  mammals  the  bi-polar  cell  is  to  be  found  only  in  the  spiral  and  vesti- 
bular ganglia  which  give  origin  to  the  fibres  of  the  eighth  nerve.  In  all 
the  other  ganglia  the  shape  of  the  cell  becomes  modified  by  an  approxima- 
tion of  the  points  of  attachment  of  the  two  processes  until  finally  the  cell 


Fig.  141.     Neuroblasts  from  the  spinal 
cord  of  a  chick  embryo.     (CaJal.) 

A,  three  neuroblasts  stained  to  show 
neuro-fibrils  ;  a,  a  bi-polar  cell. 

B,  a  neuroblast  showing  the   '  incre- 
mental cone  '  c. 


THE  NERVOUS  SYSTEM  OF  VERTEBRATES 


299 


becomes  iini-polar,  giving  off  one  process  wliicli  divides  by  a  T-shaped 
junction  into  two,  one  of  which  runs  towards  the  spinal  cord,  while  the  other 
takes  a  peripheral  course  as  the  afferent  nerve  fibre.  The  central  nervous 
system  thus  becomes  provided  with  a  '  way  in  '  and  a  '  way  out '  for  the  chain 
of  impulses  concerned  in  a  nervous  reaction  or  reflex  action.  The  further 
development  of  the  spinal  cord  is  mainly  determined  by  the  extension  of  the 


Fig.  142.     Section  through  developing  spinal  cord  and  nerve-roots  from  chick 
embryo  of  fifth  day.     (C.ajal.) 
A,  ventral  root ;   b,  dorsal  root ;  c,  motor  nerve-cells  ;  d.  sympathetic  ganglion- 
cells  ;   E,  spinal  ganglion  cells  still  bi-polar ;   f,  mixed  nerve  ;   h,  c,  d,  motor  nerve 
fibres  to  /,  developing  spinal  muscles  ;   e,  a  sensorj'  nerve-trunk. 

axons  of  the  cells  outside  the  tube  of  cells  themselves,  and  by  the  provision 
of  the  '  long  paths  '  which  are  a  necessary  condition  of  increased  efficiency  of 
the  reacting  organ.  Some  time  after  the  outgrowth  of  the  axon  a  medullary 
sheath  is  formed,  apparently  by  the  agency  of  the  axon  itself,  so  that  each 
group  of  axons  leaving  or  entering  the  cord  forms  a  bundle  of  medullated 
nerve  fibres.  The  long  branches  of  the  posterior  or  dorsal  roots  running  up 
towards  the  head  form  a  mass  of  fibres  behind  the  tube  of  cells  known  as 
the  posterior  columns.  Fibres  starting  in  the  spinal  cord  itself  run  upwards 
and  downwards  to  end  in  other  parts  of  the  cord,  or  in  the  more  anterior 
divisions  of  the  central  nervous  system  forming  the  brain,  and  surround  the 
neural  tube  on  its  ventral  and  lateral  aspects  with  a  sheath  of  white  matter. 
To  these  white  fibres  are  added  others,  which  take  origin  in  the  brain  and  pass 
all  the  way  down  the  cord.     Meanwhile  the  cells  themselves  become  separated 


300 


PHYSIOLOGY 


by  the  ramifications  between  them  of  the  branches  of  axons  entering  the 
cord,  as  well  as  of  the  dendrites  of  the  cells  themselves.  Thus,  in  its  adult 
form,  the  spinal  cord  consists  of  a  central  mass  of  nerve-cells  and  fibres, 
known  as  the  grey  matter,  which  is  encased  in  a  sheath  of  white  matter 
formed  of  medullated  nerve  fibres.  The  cord  itself  is  cyhndrical  in  shape, 
and  is  divided  into  two  symmetrical  halves  by  the  anterior  and  posterior 
fissures.  In  each  half  of  the  cord  the  grey  matter  on  cross-section  is  cres- 
centic  in  shape,  presenting  an  anterior  or  ventral  horn  and  a  posterior  or 
dorsal  horn,  and  is  connected  with  the  corresponding  mass  in  the  other  half 
of  the  cord  by  grey  matter  known  as  the  anterior  and  posterior  grey  com- 
missures. Between  the  two  grey  commissures  is  the  central  canal,  relatively 
very  minute  when  compared  with  the  condition  in  the  f  CBtus  and  lined  by  a 
single  layer  of  columnar  cihated  epithehum,  the  cells  of  which  are  directly 
descended  from  the  neural  epithehum  lining  the  medullary  canal. 


THE  STRUCTURE  OF  NERVE-CELLS 

In  the  adult  animal  a  typical  nerve-cell,  such  as  those  forming  a  prominent 
feature  in  the  anterior  horn  of  the  spinal  cord,  is  a  large  cell  with  many 
branches.     It  has  a  large  vesicular  nucleus  with  very  little  chromatin. 


Fig.  143.  Nerve-cell  from  the  spinal  cord, 
stained  by  Nissl's  method. 
a,  axis-cylinder  process  or  axon ;  h,  proto- 
plasm of  cell,  consisting  of  c,  fibrillated 
ground  substance,  and  e,  the  granules  of 
Nissl ;   d,  nucleus.     (Lenhossek.) 


Fig.  144.  The  point  of  origin 
of  the  axon,  the  '  nerve- 
hillock,'  highly  magnified, 
to  show  absence  of  Nissl's 
granules  from  the  origin  of 
the  process.     (Held.) 


which  may  be  collected  into  one  or  two  nucleoh.  The  body  of  the  cell 
presents  dift'erent  appearances  according  to  the  manner  in  which  it  has 
been  treated  for  histological  examination.  When  separated  from  the  sur- 
rounding tissues  by  means  of  dissociating  fluids  it  may  present  traces  of 
striation,  the  individual  striae  running  from  one  process  to  another  of  the 
cell.  When  treated  fresh  with  methylene  blue,  or  hardened  by  alcohol 
or  corrosive  sublimate  and  stained  with  methylene  blue  or  toluidine  blue, 


THE  NERVOUS  SYSTEM  OF  VERTEBRATES  301 

the  protoplasm  is  seen  to  contain  angular  masses  which  are  deeply  coloured 
with  the  dye  (Fig.  143).  These  masses  are  known  as  the  Nissl  granules  or 
bodies.  By  other  methods  it  is  possible  to  demonstrate  that  the  whole 
protoplasm  of  the  cell  between  the  Nissl  bodies  is  pervaded  by  fine  fibrils, 
which  enter  the  cell  from  the  processes  and  may  run  out  of  the  cell  by  the 
axon  or  may  run  into  some  of  the  other  shorter  processes  (Fig.  146).  The 
processes  of  the  cell,  as  is  evident  from  their  development,  are  of  two  kinds. 
The  axon  which  becomes  continuous  with  the  axis  cylinder  of  the  medullated 


Figs.   145  and  146.     Nerve-cells  from  siainal  cord.     (Bethe.) 
Fig.  145,  showing  Golgi  network,  and  neurofibrils  :    d,  c,  /,  junctions  of  axons 
with  Golgi  network.     Fig.  146,.  showing  neurofibrils  and  Nissl  bodies. 

nerve  fibre  arises  from  a  part  of  the  cell  body  known  as  the  axon  hillock, 
which  is  the  only  part  of  the  cell  free  from  Nissl  bodies  (Fig.  144).  The 
other  processes,  which  may  be  very  numerous,  are  known  as  the  dendrites. 
They  are  generally  thicker  than  the  axon  at  their  origin  from  the  cell,  but 
rapidly  diminish  in  size  as  they  give  off  branches,  the  branches  apparently 
terminating  freely  in  the  grey  matter  in  the  immediate  neighbourhood  of 
the  cell.  In  specimens  stained  by  the  Golgi  method  the  dendrites  may 
sometimes  present  a  somewhat  serrated  outline.  The  Nissl  bodies  of  the 
cell  extend  some  way  into  the  dendrites. 

A  nerve  cell  with  all  its  processes,  axon,  and  dendrites  is  spoken  of  as  a 
neuron.  From  the  development  of  the  central  nervous  system  in  vertebrates, 
it  is  evident  that  the  nervous  path  of  every  reaction  must  be  made  up  of 
two  or  more  neurons.  If  we  take,  for  example,  the  simplest  possible  reaction 
which  might  be  eifected  through  a  single  segment  of  the  spinal  cord,  we  see 
that  the  afferent  impulse  might  be  started  by  some  stimulus  appUed  to  the 
ramifications  in  the  skin  of  the  distal  processes  of  the  posterior  root  ganglion- 
cell  {cf.  Fig.  132).  The  nerve  impulse  so  started  is  carried  by  the  nerve  fibre 
past  the  T-shaped  junction  in  the  posterior  root  ganghon  into  the  cord. 


302  PHYSIOLOGY. 

and  along  a  branch  of  the  entering  nerve  fibre  which  runs  right  across  the 
cord  to  terminate  in  the  neighbourhood  of  the  anterior  horn-cells.  Here 
the  impulse  must  be  transmitted  in  some  way  to  the  dendrites  or  body  of 
one  of  the  large  motor  nerve-cells  in  the  anterior  horn,  whence  it  is  carried 
along  the  axon  of  the  cell,  leaving  the  cord  by  the  anterior  root  and  passing 
down  a  peripheral  nerve  to  the  end- plate  on  a  muscle  fibre.  Here  again 
by  some  means  the  arrival  of  the  impulse  excites  the  muscle  to  contract. 
This  reaction  never  takes  place  in  the  contrary  sense,  i.e.  no  impulse  started 
in  the  motor  nerve  can  travel  back  through  the  spinal  cord  and  along  the 
sensory  nerve.  Although  an  impulse  excited  in  the  nerve  passes  easily 
to  the  muscle,  an  excitatory  process  started  in  the  muscle  itself  is  confined 
to  this  tissue  and  never  extends  to  the  nerve  fibre.  Apparently  the  same  ■ 
rule  holds  good  ^dthin  the  grey  matter  of  the  central  nervous  systein,  where 
two  neurons  come  into  relation  with  one  another.  An  impulse  passes  easily 
from  the  axon  of  one  into  the  dendrites  and  cell  of  the  other  neuron,  but, 
so  far  as  we  are  aware,  it  is  impossible  by  exciting  an  axon  to  cause  a 
retrograde  wave  of  excitation  to  pass  through  its  corresponding  cell  and 
into  t  he  terminations  of  the  axons  in  immediate  contact  with  the  cell. 
This  statement  has  been  called  by  Sherrington  the  '  Law  of  Forward 
Direction.'  It  might  be  also  spoken  of  as  the  irrecifrocal  conduction  of  the 
nerve  arc.  The  character  of  a  reaction  to  any  stimulus,  apphed  to  the 
surface  of  the  body,  is  determined  by  the  course  which  the  impulse,  excited 
in  the  afferent  nerves,  takes  on  entrance  into  the  central  nervous  system. 
This  course  is  laid  down  by  the  connections  of  the  neurons  through  which 
the  nerve  impulse  passes.  In  the  central  nervous  system  therefore,  more 
than  in  any  other  part  of  the  body,  function  is  directly  dependent  on  struc- 
ture. Theoretically  if  we  had  a  perfect  knowledge  of  the  connections  of 
the  neurons  in  the  central  nervous  system  and  knew  the  nerve  fibres  affected 
by  any  given  stimulus,  we  should  be  able  to  prophesy  exactly  the  result 
of  such  stimulus.  In  the  case  of  the  simpler  reactions  this  is  already  possible, 
but  in  the  higher  parts  of  the  nervous  system  the  enormous  complexity  of 
the  systems  of  neurons  excludes  any  possibility  of  our  forming  more  than 
a  general  idea  as  to  the  nerve  paths  traversed  in  any  given  reaction ;  and 
the  variations  which  exist  from  individual  to  individual  must  always  prevent 
in  the  intact  animal  an  absolute  prediction  of  the  results  of  any  stimulus. 


SECTION  III 

GENERAL  CHARACTERISTICS  OF  REFLEX 
ACTIONS 

There  are  certain  features  common  to  all  reactions,  carried  out  through 
the  intervention  of  the  central  nervous  system,  which  must  be  regarded 
as  determined  by  the  properties  of  the  neurons,  i.e.  the  conducting  links 
in  the  chain  of  excitatory  tissues  intervening  between  the  stimulated  spot 
on  the  exterior  and  the  reacting  tissue,  muscle  or  gland.  These  charac- 
teristics may  be  roughly  classified  as  follows  : 

(1)  LOCALISATION.  In  a  simple  system  of  neurons  a  given  stimulus 
will  nearly  always  produce  the  same  reaction.  In  a  frog  possessing  only  a 
spinal  cord,  the  upper  parts  of  the  central  nervous  system  having  been 
destroyed,  any  harmful  stimulus  applied  to  a  toe  will  cause  a  lifting  of  the 
leg.  If  the  motor  nerve  to  the  gastrocnemius  be  excited,  the  whole  muscle 
contracts.  If  one  of  the  nerve-roots  entering  into  the  formation  of  the 
sciatic  nerve  be  excited,  only  certain  fibres  of  the  gastrocnemius  contract, 
the  locahty  of  the  reacting  fibres  being  determined  by  their  connection  with 
the  excited  nerve  fibres.  In  the  same  way  the  contraction  of  certain  muscles 
of  the  leg,  in  response  to  a  stimulus  applied  to  the  skin  of  the  foot,  is  deter- 
mined by  the  fact  that  the  nerve  fibres,  which  carry  the  impulses  from  the 
toe  into  the  spinal  cord,  divide  there  and  make  connections  with  the  motor 
neurons,  whose  axons  are  distributed  to  the  several  muscles  involved  in  the 
reaction.  The  connection  of  the  sensory  with  the  motor  neuron  may  be 
direct,  but  in  most  cases  the  impulse  has  to  pass  through  intermediate  neurons 
before  arriving  at  the  motor  neurons.  The  path  of  the  impulse,  however, 
in  spite  of  its  enormous  extension,  is  as  definite  as  is  the  path  from  an  excited 
motor  nerve-root  to  a  muscle  fibre. 

(2)  DELAY.  Instead  of  one  nerve-ending  intervening  between  the 
stimulated  nerve  and  the  reacting  tissue,  there  will  be,  in  the  case  of  the 
reflex  action,  two,  three,  or  more  nerve-endings  interpolated  in  the  path  of 
the  impulse.  These  nerve-endings  are  the  fields  of  conjunction,  the  si/napses, 
between  the  axon  of  one  neuron  and  the  dendrites  and  cell  body  of  the  neuron 
next  in  the  chain. 

We  have  seen  that  there  is  a  distinct  difference  between  the  latent  period 
of  a  muscle  excited  through  its  nerve  as  compared  with  the  latent  period 
when  excited  directly,  and  we  ascribed  this  latent  period  to  a  delay  in  the 
motor  end-plate.     We  should  expect  therefore  to  find  that  the  delay  or 

303 


304  PHYSIOLOGY 

latent  period  in  the  case  of  a  reflex  action,  i.e.  the  lost  time  in  the  conversion 
of  an  afferent  into  an  efferent  impulse  in  the  central  nervous  system,  would  be 
appreciable  and  would  increase  with  the  complexity  of  the  response — that  is, 
with  the  number  of  neurons  involved  in  the  reaction.   Such  is  indeed  the  case. 

In  determining  the  actual  '  lost  time  '  in  the  central  nervous  system 
for  any  given  reflex,  it  is  necessary  to  subtract  from  the  total  delay,  inter- 
posed between  the  apphcation  of  the  stimulus  and  the  resultant  movement, 
the  time  taken  by  the  impulse  in  travelling  to  and  from  the  central  nervous 
system,  as  weU  as  the  latent  period  of  the  muscles  themselves.  The  re- 
mainder is  known  as  the  '  reduced  reflex  time.'  Wundt  found  in  the  frog, 
when  a  reflex  contraction  of  the  gastrocnemius  was  excited  by  a  stimulation 
of  a  posterior  root  of  the  same  side,  that  the  reduced  reflex  time  was  -008  sec. 
For  a  crossed  reflex  the  delay  was  increased  by  -004  sec.  If  we  assume  that 
one  additional  neuron  is  involved  in  the  crossed  reflex,  the  lost  time  at  a 
synapse  would  be  -004'  sec.  ;  if  two  cells  are  intercalated,  the  synapse  delay 
would  be  only  -002  sec.  Since  the  uncrossed  reflex  has  a  delay  of  -008  sec, 
at  least  two,  and  possibly  four,  synapses  are  involved  in  the  path  of  this 
simple  reflex. 

The  bhnking  excited  by  stimulation  of  the  eyelid  has  a  reduced  reflex 
time  of  -047  sec. 

(3)  SUMMATION.  When  contractile  tissues,  such  as  striated  or  un- 
striated  muscle,  are  excited  by  single  shocks,  a  certain  minimal  strength 
of  stimulus  is  necessary  in  order  to  produce  a  contraction.  Weaker  stimuH 
are  spoken  of  as  sub-minimal,  and  when  apphed  singly  have  apparently 
no  efiect  on  the  muscle.  In  dealing  with  the  properties  of  involuntary 
muscle  we  saw  that  a  sub-minimal  stimulus  is  not  necessarily  devoid  of 
efiect  because  it  fails  to  evoke  a  contraction,  since,  if  repeated  at  sufficiently 
frequent  intervals,  a  summation  of  stimulus  occurs,  so  that  at  the  fifth  or 
sixth  apphcation  a  stimulus,  which  was  previously  inefiective,  becomes 
effective  and  a  contraction  results.  The  muscle  will  now  continue  to  respond 
to  each  stimulus,  but,  if  the  excitations  be  discontinued  for  a  time,  reapphca- 
tion  of  a  stimulus  of  the  same  strength  becomes  once  more  inefiective.  This 
summation  of  stimulus  is  a  prominent  feature  in  all  reflex  actions,  so  much 
so  that  it  may  be  often  impossible  to  evoke  a  reaction  to  a  very  strong 
single  induction  shock,  whereas  the  application  of  a  tetanising  current  too 
weak  to  be  felt  on  the  tongue  may  produce  a  marked  reaction.  We  shall 
have  occasion  later  on  to  deal  with  special  examples  of  this  summation  of 
stimulus. 

(4)  FATIGUE.  In  the  muscle-nerve  preparation  the  weakest  point 
and  that  which  soonest  sufiers  from  fatigue  is  the  end-plate,  or  rather  the 
field  of  conjunction  of  nerve  fibre  and  muscle  fibre.  In  the  central  nervous 
system  the  synapses  of  the  different  neurons  are  equally  susceptible,  and 
since  several  of  such  synapses  are  involved  in  every  reflex  action,  we  should 
expect  to  find  that  the  central  nervous  system  would  show  signs  of  fatigue 
before  the  peripheral  structures.  If  a  given  reaction  be  repeatedly  eh  cited 
by  applying  a  stimulus  to  a  certain  area  of  the  surface,  the  reaction  becomes 


CHARACTERISTICS  OF  REFLEX  ACTIONS  305 

feebler  and  finally  disappears  altogether  long  before  any  signs  of  fatigue 
in  the  motor  apparatus  can  be  detected  by  stimulation  of  the  motor  nerve 
itself.  This  fatigue  is  produced  equally  well  if  the  reaction  be  excited  by 
stimulating  a  sensory  nerve  directly,  and  since  we  know  that  it  is  practically 
impossible  to  fatigue  nerve  fibres,  we  must  conclude  that  the  seat  of  fatigue 
is  in  the  grey  matter  of  the  spinal  cord  itself. 

(5)  '  BLOCK  '  OR  RESISTANCE.  In  the  central  nervous  system 
there  is  an  absolute  block  to  the  passage  of  an  impulse  backwards  through 
a  synapse,  i.e.  from  a  nerve-cell  or  its  dendrites  into  the  end  ramifications 
of  an  axon.  The  phenomena  of  fatigue  show  that  there  is  a  certain  degree 
of  resistance  at  the  synapse  to  the  passage  of  an  impulse  in  the  normal 
direction,  and  that  this  resistance  is  rapidly  increased  under  the  conditions 
which  produce  fatigue.  When  we  study  the  structure  of  the  central  nervous 
system  more  fully,  we  find  that  although  there  are  certain  shortest  possible 
paths,  i.e.  ones  involving  few  neurons,  for  every  impulse  arriving  at  the 
central  nervous  system,  yet  so  extensive  is  the  branching  of  the  entering 
nerve  fibres  and  so  complex  are  the  neuron  systems  with  which  they  come 
in  connection  that  an  impulse  entering  along  one  given  fibre  could  spread 
to  practically  every  neuron  in  the  spinal  cord  and  brain.  Such  a  result  is 
indeed  observed  in  animals  poisoned  by  strychnine.  In  such  animals  the 
slightest  stimulus  applied  to  any  part  of  the  skin  excites  strong  tonic  spasms 
in  the  whole  musculature  of  the  body.  Every  single  nerve  fibre,  that  is  to 
say,  can  discharge  into  every  motor  neuron  of  the  cord.  That  this  result 
does  not  ensue  on  locahsed  stimulation  in  a  normal  animal  is  dependent  on 
the  varying  resistance  to  the  passage  of  an  impulse  into  the  several  neurons 
with  which  the  entrant  fibre  comes  in  relation.  A  small  stimulus  will  dis- 
charge therefore  only  along  the  few  neurons  where  the  resistance  is  lowest. 
Increase  of  the  stimulus,  either  by  increase  of  its  strength  or  by  summation 
of  weak  stimuh,  will  enable  the  impulse  to  spread  along  more  neurons  and 
therefore  will  elicit  a  more  widespread  response.  Only  when  the  blocks 
are  entirely  removed  by  the  administration  of  strychnine,  or  when  the 
stimuli  are  abnormally  powerful  and  long  continued,  will  the  impulse  spread 
to  all  regions  of  the  central  nervous  system,  so  that  response  becomes  general 
and  inco-ordinate  instead  of  local  and  adapted  to  the  stimulus. 

(6)  FACILITATION  OR  '  BAHNUNG.'  The  passage  of  a  nervous 
impulse  across  a  synapse  or  series  of  synapses  in  the  central  nervous  system 
has  a  twofold  eft'ect.  If  the  passage  be  too  often  repeated  phenomena  of 
fatigue  are  produced,  and  there  is  an  increase  of  the  block  at  each  synapse. 
If,  however,  the  stimulus  be  not  excessive  and  the  reaction  not  too  frequently 
evoked,  the  effect  of  passage  of  an  impulse  once  is  to  diminish  the  resistance, 
so  that  a  second  application  of  the  stimulus  evokes  the  reaction  more  easily. 
The  process  of  summation  in  fact  is  chiefly  in  the  direction  of  removal  of 
block.  We  have  a  close  analogy  to  this  process  of  facilitation  in  the  '  stair- 
case phenomenon  '  observed  in  cardiac  and  unstriated  muscle.  In  these 
tissues  the  repetition  of  a  sub-minimal  stinuilus  renders  it  in  time  effective, 
and  then   repetition   of  the   now    eft'ective    stimulus    causes    a    gradually 


306  PHYSIOLOGY 

increasing  height  of  contraction,  which  depends  on  the  state  of  the  contracting 
tissue  itseK  and  cannot  be  evoked  by  changes  in  the  strength  of  the  stimulus. 
This  process  of  faciHtation  or  '  Bahnung  '  is  of  great  interest  in  connection 
with  the  development  of  '  long  paths  '  in  the  central  nervous  system,  and 
more  especially  with  the  acquirement  of  new  reactions  by  the  higher  animals. 
The  Law  of  Facihtation  is  really  the  Law  of  Habit.  When  an  impulse  has 
passed  once  through  a  certain  set  of  neurons  to  the  exclusion  of  others  it 
vnll  tend,  other  things  being  equal,  to  take  the  same  course  on  a  future 
occasion,  and  each  time  that  it  traverses  this  path  the  resistances  in  the 
path  will  be  smaller.  Education  is  the  laying  down  of  nerve- channels  in 
the  central  nervous  system,  while  still  plastic,  by  this  process  of  '  Bahnung  ' 
along  fit  paths,  combined  with  inhibition  (by  pain)  in  the  other  unfit  paths. 
Memory  itself  has  the  process  of  '  facilitation  '  as  its  neural  basis. 

(7)  INHIBITION.  The  constant  occurrence  of  a  reaction  in  response 
to  a  given  stimulus  is  obtained  only  if  care  be  taken  to  isolate  the  segment 
of  the  central  nervous  system  involved  from  the  entry  of  other  afferent 
stimuli.  As  a  rule,  if  two  stimuh  be  apphed  simultaneously  at  different 
points,  the  reaction  which  ensues  will  not  be  a  combined  one,  the  resultant 
of  the  reactions  which  would  be  normally  conditioned  by  each  single  stimulus, 
but  will  be  a  response  to  one  of  the  stimuh,  which  we  must  therefore  regard 
as  the  more  effective.  The  reaction  to  the  other  stimulus  is  either  abohshed 
altogether  or  comes  on  after  a  considerable  period  of  delay.  The  central 
nervous  system  can  apparently  attend  to  only  one  thing  at  a  time.  In 
physiological  terms  we  should  say  that  every  effective  reaction  inhibits 
every  other  reaction.  In  the  spinal  cord  of  the  frog  the  normal  withdrawal 
of  the  foot  in  response  to  stimulation  of  the  toe  of  the  same  side  can  be 
inhibited  by  strong  stimulation  of  the  other  sciatic  nerve,  by  stimulation 
of  the  spinal  cord  at  a  higher  level,  or  by  stimulation  of  the  optic  lobes. 
Immediately  after  pithing  the  brain  of  the  frog,  the  whole  animal  becomes 
flaccid  and  motionless,  and  for  the  next  few  minutes  it  is  impossible  to  eHcit 
any  reaction  by  stimulation,  however  strong,  apphed  to  the  skin  of  the 
body.  In  the  production  of  this  condition  of  '  shock  '  the  inhibition  of  all 
the  spinal  centres,  produced  by  the  strong  stimulation  of  the  injury  to  the 
brain  and  medulla,  plays  at  any  rate  an  important  part.  We  may  say  that 
the  passage  of  an  impulse  through  a  chain  of  neurons  diminishes  the  block 
for  subsequent  impulses  at  each  synapse  that  it  traverses,  but  increases 
during  its  passage  the  block  in  all  the  adjacent  synapses. 

In  dealing  with  the  special  reactions  of  the  spinal  cord  we  shall  have 
occasion  to  refer  more  fully  and  in  greater  detail  to  many  of  these  properties 
which  are  characteristic  of  all  reflexes.  Before,  however,  treating  of  the 
functions  of  the  separate  parts  of  the  central  nervous  system  in  the  higher 
mammals,  it  may  be  of  interest  to  consider  the  exact  nature  of  the  structure 
intervening  between  neuron  and  neuron  at  each  field  of  conjunction  or 
synapse,  as  well  as  the  significance  of  the  two  chief  elements  of  the  central 
nervous  system,  nerve-cell  and  nerve  fibre,  in  the  production  of  co-ordinated 
purposive  reactions. 


SECTION  IV 

NATURE  OF  THE  CONNECTION  BETWEEN 
NEURONS 

The  study  of  the  development  of  the  central  nervous  system  in  higher 
animals  has  shown  that  this  system  is  made  up  of  neurons,  the  connections 
of  which  determine  the  possible  paths  of  impulses  in  the  adult  cord.  The 
first  stage  in  the  development  of  the  neuron  is  a  single  cell  without  processes, 
and  it  is  only  by  the  growth  of  these  processes  out  from  the  cell  that  the 
spinal  cord  becomes  capable  of  serving  as  an  aggregate  of  conducting  paths. 
Moreover  the  deferred  acquisition  of  an  influence  of  one  neuron  on  the  next 
neuron  in  the  line  of  impulse,  or  at  any  rate  on  the  peripheral  tissue  which 
receives  the  end  arborisation  of  its  axon,  is  shown  by  the  fact  that  entire 
destruction  of  the  spinal  cord  in  the  embryo  at  an  early  stage  in  its  develop- 
ment does  not  prevent  in  any  way  the  development  of  the  voluntary  muscles 
(Harrison)  ;  although,  after  birth,  a  severance  of  the  connection  between 
spinal  cord  and  skeletal  muscle  leads  to  a  rapid  degeneration  and  atrophy 
of  the  latter.  In  the  nmscle-nerve  preparation  there  is  an  apparent  break 
of  structure  at  the  termination  of  the  nerve  in  the  muscle  fibre,  any  con- 
tinuity between  nerve- ending  and  contractile  substance  being  subserved 
by  undifferentiated  protoplasm.  There  is  therefore  no  difficulty  in  con- 
ceiving a  propagation  across  a  similar  nerve-ending  or  synapse,  between 
the  axon  of  one  neuron  and  the  cell  body  or  dendrites  of  another  neuron. 
If,  however,  the  conception  we  have  formed  above  of  the  evolution  of  a 
nervous  system  from  a  continuous  conducting  protoplasmic  network,  by  a 
process  of  facilitation  or  '  Bahnimg  '  attended  by  histological  differentiation, 
be  correct,  we  should  expect  to  find  in  the  fully  developed  brain  and  spinal 
cord  some  traces  at  any  rate  of  continuity  throughout  the  whole  system  of 
neurons.  The  question  as  to  the  existence  of  anatomical  continuity  from 
neuron  to  neuron  has  been  hotly  discussed  both  for  vertebrates  and  in- 
vertebrates. In  the  case  of  the  latter,  evidence  in  favour  of  the  continuity 
of  neuro-fibrillse  from  sensory  surface  to  reacting  tissue  is  very  strong. 
Many  observers,  especially  Apathy,  Bethe,  and  Held,  have  described  a 
similar  continuity  in  the  nervous  system  of  mammals.  The  last-named 
observer  regards  this  continuity  as  a  product  of  later  development  and  as  due 
to  a  process  of  concrescence  occurring  between  the  axon  terminations  and 
the  bodies  of  the  nerve-cells  with  which  they  come  in  contact.  It  is  easy 
to  show  the  existence  of  a  fibrillar  structure  both  in  the  nerve-cell  and  in  the 

307 


308 


PHYSIOLOGY 


nerve  fibre  (Fig.  147).  The  axis  cylinder  of  the  nerve  fibre  can  be  regarded 
as  made  up  of  fine  fibrillae  embedded  in  an  interfibrillar  substance.  At  the 
nodes  of  Ranvier  the  interfibrillar  substance  is  interrupted,  the  fibrillse  alone 
extending  into  the  next  internode  and  representing  the  continuous  structure 
which  determines  the  conducting  power  of  the  nerve  fibre.  In  the  nerve- 
cell  the  fibrillse  occupy  all  the  space  between  the  Nissl  bodies,  passing  from 
dendrite  to  dendrite,  and  many  of  them  from  all  the  dendrites  and  all  parts 
of  the  cell  sweeping  through  the  axon  hillock  to  form  the  fibrillse  of  the  nerve 
fibre.     The  existence  of  these  fibrillar  structures  in  nerve-cell  and  nerve 


^. 


Ax, 


.7 


A 


Fig.  147.  Part  of  an  anterior  cornual 
cell  from  the  calf's  spinal  cord, 
stained  to  show  neuro  fibrils. 
(Bethe.) 

Ax,  axon;   a,  b,  c,  dendrites. 


Fig.  148.  Arborisation  of 
collaterals  from  the  pos- 
terior root-fibres  round 
the  cells  of  the  posterior 
horn.   (Ram()]s-  y  Cajal.) 


fibre  is  accepted  by  most  histologists.  The  question,  however,  of  the  con- 
nection between  the  fibrillee  of  one  axon  and  those  of  the  next  neuron,  i.e. 
the  histology  of  the  synapse,  presents  much  greater  difficulties  and  has 
excited  much  difference  of  opinion.  If  we  examine  a  nerve-cell  such  as  a 
cell  of  Purkinje  of  the  cerebellum,  or  a  cell  of  Clarke's  column  in  the  cord, 
we  find  that  it  is  surrounded  by  a  thick  basket-work  of  fibres  which  are  the 
arborisations  or  end  terminations  of  the  axons  which  pass  to  the  cell  to 
enter  into  functional  relationships  with  it  (Figs.  148  and  149).  This  peri- 
cellular network  is  of  great  extent  and  may  equal  in  total  diameter  the 
diameter  of  the  cell  itself.     Whether  the  basket-work  is  really  a  network, 


NATURE  OF  CONNECTION  BETWEEN  NEURONS 


309 


or  merely  a  felt-work  in  which  the  fine  fibres  intertwine  among  each  other 
without  becoming  actually  continuous  at  any  points,  is  difficult  to  make 
out.  On  the  periphery  of  the  cell  itself  another  network  has  been  described 
and  is  known  as  the  Golgi  network  (Fig.  150).  This  has  been  displayed 
both  by  the  process  of  impregnation  with  silver  chromate  (Golgi  method), 
as  well  as  by  staining  with  methylene  blue.  Some  authors  have  regarded 
this  network  as  an  artefact  due  to  precipitation  of  albuminous  fluids  on  the 
surface  of  the  cell.  According  to  Bethe,  however,  the  Golgi  network  on  the 
one  hand  receives  fibres  from  the  encircling  pericellular  basket-work  of  axons, 


Fig.  14!).  Baskot-vvorkof^fibrcs 
around  two  cells  of  Purkinjc. 
(Cajal.) 

a,  axis-cylindoi'  or  ncrve-fibro 
process  of  one  of  the  cor])uscles 
of  Purkinje;  h,  fibres  jirolonged 
over  the  beginning  of  the  axis- 
cylinder  process  ;  c,  branches  of 
the  nerve-fibre  processes  of  cells 
of  the  molecular  layer,  felted 
together  around  the  bodies  of 
the  coi'puscles  of  Purkinje. 


Fig.  1.50.     Superficial    network    of    Golgi    surrounding 
two  cells  from  the  cerebral  cortex  of  the  cat ;   Erlieh's 
method.     (Cajal.) 
A,  large  cell ;   b,  small  cell ;   a,  a,  folds  in  the  network; 

1),  a  ring-like  condensation  of  the  network  at  the  poles 

of   the    larger    cell ;     c,    spinous    projections    from    the 

surface. 


and  on  the  other  hand  gives  off  towards  the  interior  of  the  cell  fine  fibrils, 
which  are  continuous  witli  the  neurofibrillar  of  the  cell  and  pass  out  in  its 
axon.  The  diagrammatic  course  of  a  nerve  impulse  according  to  Bethe  is 
represented  in  the  accompanying  diagram  (Fig.  151).  An  impulse  starting 
from  the  periphery  of  the  body  travels  up  the  distal  process  of  the  posterior 
root  ganglion-cell,  passes  either  through  the  cell  or  directly  to  the  central 
process,  and  travels  along  this  to  the  terminations  of  the  posterior  root 
fibres  round  a  posterior  horn-cell.  Here  it  passes  into  the  peri-cellular 
basket-work  or  axon  network,  thence  into  the  Golgi  network  and  along 
the  fibrillar  of  the  cell  out  by  the  fibrillse  of  the  axon  and  so  to  a  fresh  synapse 
with  a  cell  of  the  anterior  horn. 

There  are  certain  physiological  difficulties  in  the  acceptance  of  this 


310 


PHYSIOLOGY 


doctrine  of  continuity  through  the  central  nervous  system.  Even  if  it  be 
true,  it  would  not  in  any  way  upset  the  importance  of  the  neuron  theory. 
Every  plant  or  animal  individual  must  be  regarded  as  a  protoplasmic  con- 
tinuum. With  growth  of  the  hving  matter,  its  metaboHc  functions  demand 
the  dispersion  of  nuclear  material  through  the  protoplasm,  and  this  is 
effected  by  division  of  the  nucleus.  Considerations  of  strength  and  rigidity 
demand  the  division  of  the  protoplasm  into  compartments  or  cells,  which, 
at  j&rst  at  any  rate,  remain  in  protoplasmic  continuity.  This  division  has 
probably  a  further  advantage  in  that  lesions  of  parts  of  the  individual  entail 
merely  the  death  of  the  cells  immediately  affected  and  do  not  necessarily 


Fig.  151.     Schema  of  the  neurofibrillar  continuum,  involved  in  an  ordinary  reflex 
act,  in  a  vertebrate  nervous  system.     (Bbthe.) 

spread  to  the  whole  organism.  Thus  in  the  central  nervous  system  injury 
to  one  axon  causes  degeneration  of  the  axon  below  the  point  of  section,  but 
the  degeneration  stops  short  at  the  end  arborisation  and  does  not  spread 
into  the  next  neuron.  If  we  assume  that,  in  consequence  of  the  straitness 
of  the  path,  the  propagation  through  the  fibrillse  is  especially  difficult  in  the 
synapse,  most  of  the  phenomena  described  above  as  characteristic  of  the 
reactions  which  take  place  in  the  central  nervous  system  can  be  easily  ex- 
plained on  the  theory  of  continuity  of  the  fibrillse.  The  serious  difficulty 
in  the  acceptance  of  this  theory  is,  however,  the  '  Law  of  Forward  Direction,' 
i.e.  the  fact  that  an  impulse  will  pass  from  an  axon  to  the  next  neuron,  but 
will  not  pass  backwards  across  the  synapse  from  the  cell  body  to  the  con- 
tiguous axon.  Bethe  suggests  that  this  rule  of  Forward  Direction,  which 
is  possibly  present  only  in  the  more  highly  developed  nervous  systems,  may 
be  due  to  a  species  of  "  polarity  "  of  the  nerve-fibril,  of  such  a  nature  that 
an  impulse  is  strengthened  and  so  assisted  on  its  passage  in  the  normal 
direction,  but  is  diminished  and  finally  abolished  when  it  passes  in  the 
opposite  direction.  Such  an  explanation  is  unsatisfactory,  since  there  is 
absolutely  no  experimental  evidence  of  the  existence  of  such  polarity  in  a 


NATURE  OF  CONNECTION  BETWEEN  NEURONS  311 

nerve  fibre  ;  all  the  evidence  that  we  have  at  present  points  to  a  nerve  fibre 
having  the  power  of  propagating  equally  well  in  either  direction.  It  is 
certainly  more  useful  to  regard  a  synapse  as  of  the  nature  of  a  motor  nerve- 
ending,  in  which  an  impulse  arriving  along  the  branches  of  an  axon  excites 
a  fresh  impulse  in  the  excitable  tissue,  i.e.  the  nerve-cell,  with  which  the 
branches  of  the  axon  come  in  contact.  Moreover  the  neurons  are  formed 
without  any  structural  connection  with  the  future  destination  of  their  axons. 
These  grow  out  as  processes  with  thickened  amoeboid  extremities.  Harrison 
has  shown  that  the  growth  of  the  axo]i  from  the  cell  may  be  observed  under 
the  microscope  in  a  neuroblast  separated  altogether  from  the  body,  and 
kept  on  a  warm  stage  in  a  thin  layer  of  coagulated  lymph.  It  is  possible 
that  we  may  have  to  distinguish  two  types  of  nervous  system,  viz.  : 

(a)  A  neurofibrillar  type,  peculiar  to  invertebrata,  with  conduction  in 
all  directions. 

(6)  A  synaptic  type,  in  which  the  Law  of  Forward  Direction  holds,  of 
later  evolution,  and  forming  the  greater  part  of  the  nervous  system  of 
vertebrata. 


SECTION  V 
FUNCTIONS  OF  THE  NERVE-CELL 

When  a  unicellular  organism,  containing  a  single  nucleus,  is  cut  into  two 
parts,  both  continue  to  live  for  some  time,  each  performing  active  move- 
ments and  evincing  all  the  phenomena  which  we  associate  with  activity 
and  therefore  with  destructive  katabolism.  For  the  continued  existence 
of  a  cell  the  processes  of  constructive  metabolism,  or  anabolism,  must  take 
place  pari  passu  with  those  of  disintegration,  and  for  this  the  presence  of 
the  nucleus  is  necessary.  Hence,  in  a  few  days,  the  half  cell  with  the  nucleus 
has  repaired  its  loss  and  become  once  again  a  normal  individual,  whereas 
the  half  without  a  nucleus  undergoes  degeneration  and  death.  The  axon 
of  a  nerve- cell  can  be  regarded  as  analogous  to  a  long  pseudopodium  of  an 
amoeba.  Like  this,  if  cut  away  from  that  part  of  the  cell  containing  the 
nucleus,  though  capable  for  a  time  of  discharging  its  active  function  of 
propagation  of  excitatory  impulses,  yet  it  finally  dies,  death  of  the  nerve 
fibre  occurring  in  the  mammal  within  three  to  five  days  after  separation 
of  the  axon  from  the  cell.  Every  nerve-cell  therefore  may  be  looked  upon 
as  a  trophic  centre  of  the  nerve  fibre  proceeding  from  it  as  well  as  of  the 
medullary  sheath,  which  is  practically  a  product  or  secretion  of  the  axis 
cylinder.  But  has  the  nerve-cell  any  more  important  functions  to  dis- 
charge ?  It  has  long  been  customary  to  endow  the  nerve-cell  with  all 
the  properties  which  are  distinctive  of  a  nervous  system,  and  to  ascribe 
to  it  the  active  part  in  the  origination  of  automatic  actions,  in  the  reflection 
of  afferent  impulses,  and  in  the  supply  of  energy  to  all  nervous  processes. 
That  the  passage  of  impulses  through  the  nerve-centres  requires  the  ex- 
penditure of  energy  by  these  centres  can  be  proved  in  various  ways.  In 
the  first  place,  we  have  the  fact  that  in  all  nervous  systems,  at  any  rate  of 
the  higher  animals,  arrangements  are  made  for  their  free  supply  with  oxygen 
Very  short  deprivation  of  oxygen  causes  a  complete  block  throughout  the 
system,  in  many  cases  preceded  by  a  short  period  of  increased  excitability 
or  ease  of  transmission.  If,  in  the  rabbit,  the  thoracic  aorta  be  clamped 
for  a  few  minutes,  the  hind  limbs  become  paralysed,  and  if  the  obstruction 
be  continued  for  half  an  hour,  there  is  widespread  degeneration  and  death 
of  the  cells  with  their  fibres  in  the  grey  matter  of  the  lumbar  and  sacral 
cord.  In  the  second  place,  the  ready  production  of  fatigue  of  the  nervous 
system  points  to  a  considerable  using  up  of  material  as  a  condition  of  the 
passage  of  nerve  impulses.  In  many  instances,  moreover,  an  infinitesimal 
stinmlus  travelling  up  a  few  nerve  fibres  may  excite  widespread  activity 
of  the  whole  central  neivous  system  with  the  discharge  of  impulses  along 

.312 


FUNCTIONS  OF  THE  NERVE-CELL  313 

practically  every  nerve  of  the  body.  Thus  the  presence  of  a  crumb  on  the 
larynx  will  excite  impulses  travelling  up  the  superior  laryngeal  nerve,  which 
in  themselves  can  involve  but  httle  expenditure  of  energy.  The  result, 
however,  of  their  arrival  at  the  central  nervous  system  is  the  discharge  of 
impulses  along  the  motor  nerves  causing  spasmodic  contractions  of  almost 
every  muscle  in  the  body.  It  seems  beyond  doubt  then  that  energy  is 
evolved  in  the  central  nervous  system  as  a  result  of  metabolic  changes,  and 
that  energy  may  be  added  to  impulses  passing  through  the  central  nervous 


^W^^' "t^^-  '^"' 


r.lob^"^  j 


XvW/ 


Fig.  152.  Diagrammatic  representation  of  the  brain  of  Cacrinus  to  show  the  parts 
involved  in  Bethe's  experiment.  The  dotted  line  x  shows  the  incision  employed 
to  isolate  the  neuropilem  of  the  ganglion  of  the  second  tentacle. 

system,  which  therefore  acts  as  a  relay  of  force.  But  this  activity  does  not 
necessarily  require  the  presence  or  co-operation  of  nucleated  cells.  In 
dealing  with  the  nature  of  a  nerve  impulse  we  had  reason  to  conclude  that 
there  may  be  an  actual,  though  minimal,  liberation  of  energy  in  the  axis 
cylinder  with  the  passage  of  each  nerve  impulse.  The  non-nucleated  parts 
of  a  cell,  whether  the  axon  or  the  cell  body,  are  equally  capable  of  this 
evolution  of  energy,  and  we  might  conceive  therefore  of  a  nervous  system 
which,  existing  for  a  few  days,  might  act  as  a  normal  reflex  centre  in  the 
entire  absence  of  the  nucleated  cell  bodies. 

This  conception  has  been  realised  by  Bethe  in  an  experiment  on  the  crab  (Carcinus 
menas).  In  this  animal  the  reflex  movements  of  the  tentacle  are  carried  out  by  a  gang- 
lion situated  at  its  base.  As  in  the  other  Crustacea,  the  cell  bodies  in  this  ganglion  lie 
outside  the  mass  of  neuro-fibrils  in  the  centre,  forming  a  sort  of  capsule  (Fig.  152). 
Bethe  was  able,  under  the  dissecting  microscope,  to  remove  the  cell  bodies  without 
interfering  with  the  nerves  entering  or  leaving  the  central  mass  of  fibrils.  All 
the  nerve  processes  with  their  connections  were  therefore  left  intact.  In  animals, 
operated  in  this  way,  Bethe  found  that  for  two  or  three  days  the  tentacle  reacted 
normally  to  stimuli  applied  to  its  surface.  The  reflex  functions  of  the  ganglion  were 
not  in  any  way  affected  by  the  removal  of  the  nucleated  bodies  of  the  cells.     A  similar 


314  PHYSIOLOGY 

experiment  would  be  impossible  in  the  central  nervous  system  of  vertebrates,  since 
impulses  must  of  necessity  pass  through  the  cell  body  on  their  way  from  the  termination 
of  one  axon  to  the  begimiing  of  the  next.  In  the  spinal  root  ganglion,  however,  most 
of  the  cells  lie  on  the  surface.  In  the  rabbit  Steinach  exposed  a  posterior  root  ganglion, 
separating  it  from  all  its  vascular  supply,  but  leaving  its  nervous  attachments  intact. 
The  wound  was  opened  every  day  for  the  next  few  days  and  an  instrument  passed 
under  the  ganglion  so  as  to  divide  any  newly  forming  vessels.  As  a  result  of  the 
deprivation  of  blood-supply  the  ganglion-cells  died.  But  Steinach  found  that  nerve 
impulses  were  still  conducted  perfectly  well  through  the  ganglion  at  a  time  when 
microscopic  examination  showed  a  complete  atrophy  of  all  cells.  It  is  therefore  only 
in  virtue  of  the  fact  that  the  nerve-cell  is  the  seat  of  the  nucleus,  and  therefore  of  the 
assimilative  functions  of  the  neuron,  that  any  pre-eminent  importance  can  be  ascribed 
to  it  in  the  building  up  of  a  reactive  nervous  system. 

Prominent  among  the  functions  with  which  the  nerve-cell  has  been 
endowed  is  that  of  automaticity  of  actiofi  in  the  absence  of  stimulus  other 
than  that  supplied  by  its  own  metabohsm  or  by  the  fluids  which  bathe  it. 
A  priori  there  is  no  reason  to  deny  to  the  neuron  a  property  which  is  pos- 
sessed by  other  cells  of  the  body,  such  as  the  muscular  cells  of  the  heart,  and 
is  a  fundamental  quahty  of  undifferentiated  protoplasm.  The  purpose, 
however,  for  which  these  cells  have  been  evolved  and  differentiated  is 
that  of  reaction,  of  adapting  the  organism  to  changes  in  its  environment, 
and  it  is  doubtful  whether,  in  this  differentiation,  it  has  retained  any  auto- 
matic properties  whatsoever.  In  the  absence  of  any  afferent  impulse  the 
whole  central  nervous  system  would  probably  be  inert.  In  a  frog  retaining 
only  the  spinal  cord  Hering  divided  all  the  posterior  roots.  The  frog  re- 
mained flaccid  and  motionless.  Injection  of  strychnine  was  powerless 
to  evoke  the  usual  tetanic  spasms.  In  such  a  strychninised  frog,  however, 
it  was  only  necessary  to  open  the  wound  and  touch  one  of  the  divided 
posterior  roots  to  throw  the  whole  bod}^  into  convulsions.  As  shown  by 
Sherrington  and  Mott,  division  of  all  the  afferent  nerves  coming  from  the 
upper  limb  in  monkey  or  man  entirely  abohshes  all  such  contractions  of  the 
limb,  as  are  usually  affected  through  the  intermediation  of  the  cerebral 
cortex.  Cutting  off  the  major  portion  of  the  afferent  impulses  to  the  respira- 
tory centre  does  not,  it  is  true,  abohsh  all  respiratory  discharges,  but  converts 
the  rhythmic  respirations  into  a  series  of  inspiratory  spasms  which  are 
repeated  at  long  intervals  and  are  entirely  inadequate  for  the  proper  aeration 
of  the  blood.  According  to  Sherrington  a  repetition  on  the  mammal  of 
Hering's  experiment  does  not  lead  to  the  same  results,  since  a  spasmodic 
discharge  is  produced  from  the  isolated  spinal  cord  as  a  result  of  asphyxia. 
But  it  is  doubtful  whether  in  this  case  there  was  not  some  continuous  excita- 
tion of  the  cord  going  on,  as  a  result  of  the  closure  of  the  demarcation  current 
in  the  cut  ends  of  the  posterior  roots  by  the  body  fluids.  It  is  possible  that 
the  neurons  possess  some  automatic  power,  i.e.  some  power  of  initiating 
nervous  processes,  as  a  result  of  changes  in  the  fluids  surrounding  them. 
This  automaticity,  however,  is  not  a  prominent  feature  of  the  nervous  system, 
which  has  been  evolved  as  a  purely  reactive  mechanism  to  the  afferent 
impulses  resulting  from  the  material  changes  continually  taking  place  in  the 
environment  of  the  animal. 


SECTION  VI 


STRUCTURE   OF  THE   SPINAL   CORD 

In  the  higher  representatives  of  the  invertebrate  class  the  central  nervous 
system  consists,  as  we  have  seen,  of  a  chain  of  gangha,  each  ganglion  or  pair 
of  ganglia  presiding  over  the  reactions  of  its  own  segment,  but  connected  by 
long  paths  with  the  other  ganglia  and  with  the  head  ganglia.  The  latter,  being 
especially  developed  in  connection  with  the  organs  of  special  sense  which  are 
projicient  in  function,  acquire  a  control  over  the  rest  of  the  ganglia  (Fig.  153). 
The  vertebrate  spinal  cord  may  be  looked  upon  as  a  chain  of  ganglia  which 

DORSAL 

Spinal    caual  'Neui-en.teric  canal 


/n/undifculuTa  VENTRAL 


DORSAL 


a^opKaja.  VENTRAL 

(T-  Co.n. 

Fio.  153.  Vertebrate  central  nervous  system  compared  with  that  of  tlie  arthrojiocl. 
(Gaskell.)  (Note  that  according  to  Gaskell  the  ventricles  of  the  hrain  and  the  primitive 
neural  canal  corres])ond  to  the  invertebrate  stoTnach  ami  intestine.) 

have  become  fused  concurrently  with  a  dimiinition  in  the  importance  of  the 
local  segmental  reactions  and  with  a  growth  in  the  solidarity  of  the  whole 
system  ;  so  that  in  the  higher  vertebrates,  at  any  rate,  little  trace  of  the 
primitive  segmental  arrangement  is  evident  in  the  internal  structure  of  the 
cord.  Some  remains  of  this  arrangement  still  persist,  however,  in  the  origin 
from  the  cord  of  nerve  roots,  which  are  distributed  roughly  within  the  area  of 
the  corresponding  segment  of  the  body. 

In  man  the  spinal  cord  is  an  elongated  cylindrical  structure  slightly 
flattened  from  before  backwards  and  about  eighteen  inches  long.  It 
gives  ol^  a  series  of  nerve-roots,  which  are  ananged  in  thirty-one  pairs 
and  are  distributed  symmetrically  to  the  two  sides  of  the  body.     Each 

315 


316  •  PHYSIOLOGY 

nerve  arises  by  two  roots,  an  anterior  and  a  posterior,  the  anterior  being 
composed  of  a  series  of  rootlets  spread  over  a  considerable  area  of  the  cord, 
while  the  posterior  roots  arise  as  a  compact  bundle  from  a  groove  on  the 
postero-lateral  aspect  of  the  cord.  The  posterior  nerve-roots  pass  through  a 
gangHon  and  join  the  anterior  roots  in  the  intervertebral  foramina  to  form  the 
mixed  nerve.  On  section  the  cord  is  seen  to  consist  of  a  core  of  grey  matter 
surrounded  on  all  sides  by  white  matter.  The  white  matter  is  made  up  of 
meduUated  nerve  fibres  which  are  devoid  of  a  neurilemma,  and  run  within 
tunnels  or  tubes  in  the  supporting  neurogha.  The  grey  matter  has  roughly 
the  form  of  a  letter  H,  and  consists,  in  cross-section,  of  a  comma-shaped 
mass  on  each  side  of  the  cord,  joined  across  the  middle  hne  by  a  band  of  grey 
matter.  On  the  anterior  aspect  of  the  cord  is  a  furrow,  the  anterior  fissure, 
which  contains  a  process  of  the  enveloping  membrane  of  the  cord,  the  pia 
mater,  and  is  hmited  at  its  bottom  by  a  band  of  white  matter,  the  anterior 
white  commissure,  which  unites  the  anterior  columns  of  white  matter. 

On  the  hinder  aspect  of  the  cord  is  another  fissure,  the  posterior  fissure, 
which  is  very  narrow  and  is  built  up  chiefly  by  neuroglia.  A  third  fissure  at 
the  point  of  origin  of  the  posterior  nerve-roots  serves  to  divide  the  white 
matter  of  the  cord  into  an  antero-lateral  column  and  a  posterior  column,  and 
the  former  is  imperfectly  separated  by  the  spread-out  anterior  rootlets 
into  anterior  and  lateral  columns.  The  cord  in  cross-section  (Fig.  154) 
is  circular  in  the  dorsal  region  and  oval  in  the  cervical  and  lumbar  regions. 
It  presents  two  marked  enlargements,  namely,  the  cervical  enlargement, 
corresponding  to  the  outflow  of  the  nerves  going  to  the  upper  hmb,  and 
the  lumbo-sacral  enlargement,  which  gives  off  the  nerves  to  the  lower  limb. 
In  the  sacral  region  it  rapidly  tapers  off  to  a  blunt  point.  In  the  centre  of 
the  band  of  grey  matter,  connecting  the  two  masses  on  each  side  of  the  middle 
Hne,  is  the  central  canal  of  the  cord,  the  remains  of  the  primitive  neural  canal 
of  the  embryo.  The  grey  matter  in  front  of  it  is  called  the  anterior  grey 
commissure,  that  behind  the  posterior  grey  commissure.  The  comma- 
shaped  mass  of  grey  matter  on  each  side  of  the  cord  presents  in  front  the 
broad  anterior  comu,  and  behind  the  narrower  posterior  cornu,  which 
extends  up  to  the  postero-lateral  groove  in  the  Hne  of  emergence  of  the 
posterior  roots.  In  the  dorsal  region  of  the  cord  the  grey  matter  projects 
into  the  lateral  column  of  white  matter  to  form  the  lateral  horn.  The  grey 
matter  consists  of  a  supporting  tissue  of  neuroglia  in  which  are  embedded 
nerve-cells  and  their  processes  and  the  endings  of  nerve  fibres.  The  neurogha 
is  formed  of  a  thick  felt- work  of  fibres  with  here  and  there  nuclei  applied  to 
the  fibres.  Occasionally  we  may  meet  cells  provided  with  a  very  large 
number  of  branches  and  representing  the  cells  from  which  all  the  fibres  of  the 
neurogha  have  been  derived.  The  neurogha  is  present  in  specially  large 
amount  in  two  situations,  namely,  immediately  around  the  central  canal 
and  as  a  capsule  to  the  enlargement  of  the  posterior  cornu,  known  as  the 
head  or  cafut  cornu  posterioris.  In  this  latter  situation  the  neurogha  con- 
tains a  large  number  of  small  richly  branched  nerve-cells  and  is  spoken  of  as 
the   substantia  gelatinosa  of   Rolando.     The   nerve-cells   are   arranged   in 


STRUCT UEE  OF  THE  SPINAL  CORD 


317 


distinct  groups.  In  the  anterior  horn  we  may  distinguish  three  groups,  a 
median  group  of  cells  near  the  middle  line,  many  of  which  send  their  processes 
across  to  the  other  side  in  the  anterior  white  commissure,  and  an  external 


Cervical. 


Dorsal. 


Lumbar. 


i'lt;.   Ip4.     Sections  of  human  .spinal  cor.l  from]thc  lower  cervical,  mid-clor.^^al.  and 

mid-Iurabar  regions,  showing  the  principaf  groups  of  nerve-cells,  and  on  the 

right  side  of  each  section  the  conducting  tracts  as  they  occur  in  the  several 

regions  (magnified  about  7  diameters).     (E.  A.  Schafer.) 

a,  b,  c,  groups  of  cells  of  the  anterior  horn  ;  d,  cells  of  the  lateral  horn  ;  e.  middle 

group  of  cells  ;  /,  cells  of  Clarke's  column  ;    g.  cells  of  posterior  horn  ;    cc,  central 

canal ;  ac,  anterior  commi.ssure. 


318 


PHYSIOLOGY 


group  often  subdivided  into  a  postero- external  and  an  antero-external.  The 
latter  group  is  especially  developed  in  the  regions  of  the  cervical  and  lumbar 
enlargements  and  consists  of  very  large  multipolar  cells  with  many  dendrites 
which  send  their  axons  into  the  anterior  roots  and  by  these  to  the  muscles  of 
the  Kmbs.  Another  group  of  rather  smaller  cells  is  found  in  the  lateral 
horn,  in  that  region  of  the  cord  where  this  is  marked.  A  very  definite  group 
of  cells  may  be  seen  in  the  dorsal  region  of  the  cord  in  the  inner  aspect  of 
the  root  of  the  posterior  horn.  This,  which  is  known  as  Clarke's  column, 
is  formed  by  large  cells  elongated  in  the  longitudinal  direction  of  the  cord. 
Besides  these  definite  columns  a  number  of  nerve-cells  are  distributed  irregu- 
larly through  the  grey  matter,  especially  of  the  posterior  horn. 


Direct pyraniicH^^^ 


Ant.  lot. J 

asc.  tract. 


Posterior  Soots, 
with  coUakrcds. 


Fig.  155.  Spinal  cord.  (After  Lbnhossek.)  On  left  side  of  figure  are  shown 
the  nerve-cells  with  their  axis-cylinder  processes.  On  the  right  side  the  dis- 
tribution of  the  chief  collaterals. 

1,  motor  cells ;    2,  cells  of  the  columns  ;    2a,  cells  of  Clarke's  column,  sending 
processes  across  into  direct  cerebellar  tract ;   3,  4,  and  5,  commissural  cells. 

According  to  the  destiny  of  their  axons  these  nerve-cells  may  be  divided  into  four 
groups  (Fig.  155). 

(1)  THE  MOTOR  CELLS,  the  largest  of  all,  which  send  their  axons  into  the  anterior 
roots,  where  they  run  to  supply  skeletal  muscle  fibres.  A  i  a  sub-group  of  these  cells  we 
may  class  the  somewhat  smaller  cells  of  the  lateral  horn,  which  in  all  probability  send 
their  axons  by  the  anterior  roots  to  supply  visceral  muscles.  Their  axons  can  be 
distinguished  from  the  motor  axons  by  the  smaller  diameter  of  the  nerve  fibres  they 
form.  They  pass  later  from  the  mixed  nerve  along  a  white  ramus  communicans  into 
the  sympathetic  system,  in  the  ganglia  of  which  they  end. 

(2)  CELLS  OF  THE  COLUMNS.  As  typical  of  these  cells  we  may  take  those 
which  form  Clarke's  column.  Their  axons  do  not  leave  the  central  nervous  system, 
but  pass  out  into  the  white  matter  to  some  other  part  of  the  central  nervous  system, 
contributing  thus  to  form  the  white  columns  of  the  cord. 

(.3)  COMMISSURAL  CELLS.  These  cells  send  their  axon  across  the  middle 
line  to  the  op])ositc  side  of  the  cord,  making  up  a  great  part  of  the  anterior  white  com- 
missure. 

(4)  CELLS  OF  GOLGI.  These  cells  are  found  chiefly  in  the  posterior  horn.  They 
are  multi-polar  and  are  distinguished  from  all  the  other  cells  by  the  fact  that  their 


STRUCTURE  OF  THE  SPINAL  CORD 


319 


axon  does  not  pass  far  from  the  cell,  but  rapidly  breaks  up  into  a  number  of  branches 
which  terminate  in  the  near  neighbourhood  of  the  cell  giving  off  the  axon.  They  may 
be  regarded  as  association  cells,  i.e.  as  serving  to  establish  a  functional  connection 
between  many  different  cells  at  any  given  level  of  the  grey  matter. 

The  white  matter  of  the  cord  is  divided  by  the  fissures  already  described 
into  anterior,  lateral,  and  posterior  columns.  The  nerve  fibres  of  which 
it  is  composed  are  all  of  them  axons  of  nerve-cells  situated  at  different  levels 
of  the  central  nervous  system  or  outside  the  cord.  Since  the  whole  object  of 
the  study  of  the  anatomy  of  the  cord  is  the  tracing  out  of  the  systems  of 
neurons  of  which  it  is  made  up,  and  therefore  of  the  possible  paths  of  any 
reflexes  or  nerve  impulses  through  the  cord,  a  mere  anatomical  differentiation 
of  different  columns  is  quite  useless  unless  we  can  determine  in  each  column 
the  origin  and  destination  of  the  fibres  of  which  it  is  composed. 

For  tracing  out  the  course  of  the  different  axon  systems  in  the  central  nervous 
system  several  methods  are  available. 

(a)  HISTOLOGICAL.  Two  methods  may  be  employed  for  staining  a  nerve-cell 
with  all  its  processes,  namely,  the  intravitam  staining  with  methylene  blue  and  the 
impregnation  method  invented  by  Golgi.  In  the  latter  method,  of  which  there  are 
many  modifications,  the  nervous  tissue  is  hardened  in  some  chromate  or  biclu-omate, 
and  is  then  soaked  in  a  solution  of  silver  nitrate  or  mercuric  chloride.  In  this  waj^ 
a  precipitate  of  silver  or  mercuric  chromate  is  formed  within  the  nerve-cells  and  their 
processes  ;  but  for  some  unexplained  reason  the  impregnation  is  not  general,  and  is 
confined  to  a  small  jjercentage  of  the  neurons.  If 
the  precipitate  were  diffuse,  even  a  thin  section 
would  be  absolutely  opaque  ;  since  it  is  partial, 
thick  sections  may  be  cut  and,  after  clearing,  allow 
the  tracing  of  the  processes  of  the  few  impregnated 
nerve-cells  through  the  whole  thickness  of  the  section. 
We  may  in  this  way  get  sections  0-1  mm.  thick  at 
the  point  of  entrance  of  a  posterior  nerve-root  and 
trace  out  the  course  and  ending  of  a  large  number  of 
the  fibres  composing  the  nerve-root,  or  we  may  in  a 
section  involving  the  anterior  nerve-root  trace  the 
course  of  an  axon  of  an  anterior  cornual  cell  out  of 
the  cord  into  the  root.  This  method  is  of  no  use  in 
tracing  any  given  nerve  fibre  through  the  whole 
length  of  the  cord.  For  this  purpose,  however, 
several  methods  are  availal)le. 

(&)  MYELINATION  METHOD  OF  FLECHSIG. 
Nerve  fibres  at  their  first  formation  as  axons  of  a 
nerve-cell  are  non-medullated,  the  medullary  sheatli 
being  formed  later  with  the  beginning  of  function  of 
the  nerve.  It  has  been  shown  by  Flechsig  that  the 
myelination  does  not  occur  simultaneously  through 
all  parts  of  the  central  nervous  system,  but  that  it 
is  later  in  proportion  as  the  nerve  fibre  is  more 
recent  in  the  phylogcnetic  history  of  the  animal. 
The  cord  in  its  most  primitive  form  can  be  regarded  fibres, 
as  a  series   of  ganglia   ])residing   over  the  different 

segments  of  the  body.  The  most  primitive  fibres  therefore  would  be  those  wliii-Ii  run 
from  the  perii)hery  of  tiie  body  to  each  segment  and  from  each  segment  out  to  the 
muscles,  and  so  a  medullary  sheath  is  first  formed  in  a  number  of  the  fibres  entering 
and  leaving  the  cord  in  the  nerve-roots.     Next   in   order  of  myelination  are  those 


rA— 


Fig.  15(5.  Section  through  the  vw- 
vioal  s])inal  cord  of  a  new-born 
cliild.  stained  by  Weigert"s 
method,  to  show  absence  of 
mcdullation  in  pyramidal  tract, 
crt,  anterior  commissure ;  Fp. 
crossed  pyramidal  tract ;  /■'< .  ilin-rt 
cerebellar  tract  ;  Zip,  jiostorior 
root  zone ;  rp'.  iwsterior  root- 
(Bechterew.) 


320 


PHYSIOLOGY 


fibres  which  connect  different  segments  of  the  cord,  the  internuncial  or  intra-spinal 
fibres.  Next  come  those  fibres  which  connect  the  spinal  cord  with  the  cerebellum. 
Last  of  all  to  receive  a  medullary  sheath  are  the  fibres  which  take  a  direct  course  from 
the  cerebral  cortex  to  the  spinal  cord.  These  are  called  the  pyramidal  tracts,  and  in 
man  are  not  medullated  until  the  first  month  after  birth  (Fig.  156). 

(c)  THE  WALLERIAN  METHOD.  A  nerve  fibre,  when  cut  off  from  the  nerve- 
cell  of  which  it  is  a  process,  degenerates.  This  degeneration  is  marked  by  a  breaking 
up  of  the  medullary  sheath  and  a  conversion  of  the  phosphorised  fat,  myelin,  of  which 
it  is  composed,  into  ordinary  fat.  Later  on  the  fat  is  absorbed  and  the  nerve  becomes 
replaced  by  a  strand  of  fibrous  tissue  in  the  case  of  peripheral  nerves,  of  neuroglia 
in  the  central  nervous  system.  If  the  white  matter  of  one  half  of  the  spinal  cord  be 
divided  in  the  dorsal  region,  and  the  animal  be  killed  about  three  weeks  after  the  opera- 
tion, sections  of  the  cord  both  above  and  below  the  lesion  will  show  the  presence  of 
degenerated  fibres.  In  order  to  display  these  fibres  pieces  of  the  cord  are  hardened 
in  a  solution  containing  bichromates  and  are  then  immersed  in  a  mixture  of  osmic 


Fig.  157.     Cells  from  the  oculo-motor  nuclei  thirteen  days  after  section  of  the 

nerve  on  one  side. 
a,  cell  from  healthy  side  ;   h,  cell  from  side  on  which  nerve  was 
divided.     (  Flatatj.  ) 


acid  and  bichromate.  By  this  method  ordinary  fat  is  stained,  but  myelin  is  left  un- 
stained (Marchi's  method).  Degenerated  fibres  are  therefore  stained  black  in  virtue 
of  their  content  in  fat.  The  black  staining  has  different  distribution  according  as  we 
take  a  section  of  the  cord  above  or  below  the  lesion.  The  existence  of  the  degeneration 
shows  that  those  fibres  which  are  degenerated  in  the  cervical  region  are  axons  of  nerve 
cells  situated  below  the  lesion,  while  the  fibres  in  the  lumbar  cord  which  are  degenerated 
must  have  their  nerve-cells  in  some  part  of  the  nervous  system  which  is  above  the 
lesion.  If  the  animal  be  kept  alive  for  a  considerable  time,  six  months  or  more,  before 
being  killed,  the  occurrence  of  degeneration  in  any  given  area  of  the  cord  will  be  shown 
by  the  absence  of  normal  nerve  fibres  in  this  area.  In  such  a  case  some  method  of 
staining  the  medullary  sheath,  such  as  that  of  Weigert  or  Heller,  is  employed,  when  the 
degenerated  area  will  be  evident  owing  to  its  inability  to  take  the  stain.  This  method, 
however,  is  not  so  satisfactory  as  the  Marchi  method,  since  it  is  impossible  in  this  way 
to  detect  in  a  section  the  presence  of  one  or  two  degenerated  nerve  fibres,  whereas 
by  the  use  of  the  Marchi  method  they  would  appear  as  black  dots  in  the  unstained 
section  {cp.  Fig.  164). 

{d)  METHOD  OF  RETROGRADE  DEGENERATION.  When  a  nerve  fibre  is 
divided  there  is  no  degeneration  as  a  rule  in  the  part  of  the  nerve  fibre  central  to  the 
lesion.  The  nerve-cell  is,  however,  affected,  and  the  extent  to  which  this  occurs  is 
more  pronounced  according  as  the  lesion  is  nearer  to  the  cell  (Fig.  157).     V,  for  instance 


STRUCTURE  OF  THE  SPINAL  CORD  321 

an  anterior  root  be  divided  and  three  weeks  later  the  animal  be  killed  and  sections  made 
of  the  corresponding  segment  of  the  cord  and  stained  with  toluidine  blue  or  methylene 
blue,  a  striking  difference  will  be  observed  between  the  cells  of  the  anterior  horn  of 
the  two  sides  of  the  cord.  On  the  side  of  the  lesion  the  nucleus  of  the  cells  will  be 
somewhat  swollen,  and  may  be  displaced  towards  the  perijjhery  of  the  cell.  The  Xissl 
granules  are  no  longer  distinct,  but  the  whole  cell  is  diffusely  stained  blue.  In  some 
cases  this  change  may  go  on  to  complete  atrophy  of  the  cell  and  consequent  degenera- 
tion of  the  whole  of  its  axon.  Generally,  however,  the  cell  gradually  recovers,  so  that 
six  months  after  the  lesion  no  difference  will  be  observable  between  the  cells  on  the 
two  sides  of  the  cord.  This  method  must  be  used  with  some  caution  as  a  means  of 
tracing  out  the  connections  of  any  given  neurons  in  the  central  nervous  sy.stem,  since 
it  has  been  shown  by  Warrington  that  somewhat  similar  changes  may  be  produced 
in  the  anterior  horn-cells  by  division  of  the  posterior  roots,  thus  cutting  off  those  im- 
pulses by  which  their  activity  is  normally  excited.  Here  we  have  a  lesion  applied  to 
one  neuron  exciting  a  histological  change  in  the  cell  body  of  another  neuron  which 
is  next  in  the  chain  of  the  nervous  arc. 

The  structure  of  the  cord  is  closely  connected  with  and  determines  its  two- 
fold function,  namely,  as  a  series  of  reflex  centres  for  the  different  segments 
of  the  body,  and  as  a  means  of  communication  between  the  trunk  and  limbs 
and  the  higher  parts  of  the  central  nervous  system.  An  examination  of  the 
relative  area  of  the  white  matter  at  different  levels  of  the  cord  shows  a 
steady  increase  from  the  lower  to  the  upper  end.  The  increase  is  not,  how- 
ever, proportional  to  the  number  of  fibres  which  enter  or  leave  the  cord  in  the 
various  spinal  nerve-roots.  Of  these  fibres  therefore  a  certain  proportion  are 
destined  to  serve  merely  the  local  segmental  reflexes,  while  others  are  con- 
tinued directly  upwards  to  the  brain  or  are  connected  with  cells  which  them- 
selves send  their  axons  up  to  the  brain  (cells  of  the  columns).  All  the  motor 
fibres  in  the  nerve  roots  arise  from  cells  in  the  spinal  cord  near  the  point  of 
origin  of  the  root.  Any  direct  influence  of  the  brain  on  the  motor  mechan- 
isms of  the  body  is  therefore  effected  through  the  intermediation  of  the 
segmental  neural  mechanisms  of  the  grey  matter  of  the  cord.  We  will 
consider  the  function  and  related  structure  of  the  cord  in  these  two  aspects  : 
first,  as  a  reflex  centre,  and,  secondly,  as  a  conductor  of  impulses  to  the 
higher  parts  of  the  central  nervous  system. 


11 


SECTION  VII 
THE  SPINAL  CORD  AS  A  REFLEX  CENTRE 

Iisr  the  evolution  of  the  cord  the  primitive  segmental  arrangement  has  been 
especially  interfered  with  by  the  development  of  the  four  limbs.  Since 
the  reactions  of  the  hmbs  transcend  in  importance  and  complexity  those  of 
the  rest  of  the  body,  a  great  enlargement  of  the  cord  has  occurred  in  the  region 
of  the  nerve-roots  which  supply  the  limbs.  Each  limb  must  be  considered 
as  produced  by  the  fusion  of  a  number  of  body  segments,  in  which  the 
morphological  segmental  arrangement  has  entirely  given  place  to  a  physio- 
logical one.  Thus  no  single  muscle  of  the  limbs  is  innervated  from  one 
nerve-root,  every  muscle  being  formed  from  elements  belonging  to  several 
segments  and  innervated  from  several  nerve-roots.  The  segmental  arrange- 
ment of  the  cord  is  hidden  moreover  by  the  increasing  complexity  of  the  spinal 
reflexes  and  the  consequent  involvement  of  many  segments  in  even  the 
simplest  reactions.  As  we  shall  see  later,  practically  no  reflex  can  be 
evoked,  even  by  stimulation  of  one  nerve  fibre  or  nerve-root  in  any  of  the 
vertebra ta,  which  does  not  involve  in  its  response  elements  belonging  to  many 
segments. 

Since  the  reactions,  which  can  be  carried  out  by  any  part  of  the  nervous 
system,  depend  on  the  neurons  of  which  the  part  is  composed,  it  is  necessary, 
before  treating  of  the  reactions  of  the  spinal  animal,  to  consider  the  "  way  in  " 
to  and  the  "  way  out  "  of  the  centre,  as  well  as  the  connections  between  the 
entering  and  issuing  paths.  Each  segment  of  the  cord  gives  off  a  pair  of 
nerve-roots,  subdivided  into  an  anterior  and  a  posterior  root  (Fig.  158).  In 
mammals  it  is  easy  to  show  that  the  posterior  root  is  exclusively  afferent  in 
function.  Section  of  the  root,  either  distal  or  proximal  to  the  ganghon,  pro- 
duces no  paralysis  of  any  description.  It  may  cause  diminished  sensation  in 
the  area  supplied  by  it,  and  if  two  or  three  adjacent  posterior  roots  be  divided, 
complete  anaesthesia  results  in  the  central  part  of  the  skin  area  supphed  from 
these  roots.  Stimulation  of  the  central  end  of  a  divided  posterior  root 
evokes  in  a  conscious  animal  signs  of  pain.  In  an  animal  possessing  only 
spinal  cord  and  bulb,  reflex  effects  are  produced,  i.e.  movements  of  skeletal 
muscles  as  well  as  effects  on  visceral  muscles,  such  as  constriction  of  blood- 
vessels, relaxation  of  intestinal  muscle,  and  so  on.  On  the  other  hand, 
section  of  an  anterior  root  causes  paralysis  of  muscles  or  parts  of  muscles. 
Section  of  all  the  anterior  roots  going  to  a  limb  will  produce  complete 
motor  paralysis  of  the  hmb.     Stimulation  of  the  central  end  of  a  divided 

322 


THE  SPINAL  CORD  AS  A  REFLEX  CENTRE  323 

anterior  root  has  no  effect.  Stimulation  of  the  peripheral  end  evokes  con- 
traction of  muscles,  and  if  the  root  experimented  on  be  in  the  upper  dorsal 
region  of  the  cord,  certain  visceral  effects,  e.(j.  dilatation  of  the  pupil  or 
augmentation  of  the  heart  beat,  may  result. 

To  this  general  law,  the  law  of  Bell  and  Magendie,  which  affirms  the  purely  afferent 
function  of  the  posterior  roots  and  the  purely  efferent  function  of  the  anterior  roots, 
certain  exceptions  must  be  noted.  In  the  first  place,  in  the  lower  vertebrata  the 
separation  of  afferent  from  efferent  fibres  seems  to  be  not  so  complete  as  in  the  higher 
vertebrates.  Thus  in  the  chick  Cajal  and  others  have  described  fibres  given  off  as 
axons  from  the  cells  of  the  grey  matter  and  leaving  the  cord  by  the  posterior  root. 
The  function  of  these  fibres  is  unknowTi.     In  the  frog  Steinach  has  stated  that  visceral 


Fig.  158.     Figures  (from  Yeo)  to  illustrate  the  degree  and  direction  of  degenera- 
tion as  a  result  of  section  of  the  spinal  roots. 
I,    division   of  whole  nerve   below   ganglion.       II.   division  of    anterior  root. 
Ill,  division  of  posterior  root  above  ganglion.     IV,  division  of  posterior  root  above 
and  below  ganglion. 

effects  may  ensue  on  stimulation  of  the  lower  posterior  roots.  This  statement  is 
controverted  by  Horton-Smith,  who,  however,  has  noticed  contractions  of  fibres  of 
voluntary  muscles  as  the  result  of  stimulating  these  roots. 

In  a  class  by  themselves  we  must  place  the  vasodilator  effects  observed  bj'  Strieker, 
Dastre  and  Morat,  and  Bayliss  to  follow  excitation  of  the  peripheral  ends  of  the  posterior 
roots.  Bayliss  has  shown  that  the  fibres,  through  which  the  vasodilatation  is  produced, 
must  have  their  cell-station  in  the  posterior  root  ganglia.  It  seems  therefore  that 
the  same  fibres  provide  for  carrying  both  afferent  impulses  from  skin  to  cord,  and  vaso- 
dilator impulses  from  the  cord  to  the  vessels  of  the  skin.  Bayliss  has  designated  the 
impulses  which  effect  the  vasodilatation  as  antidromic,  since  they  are  opposed  in  direc- 
tion to  the  normal  impulses  of  the  nerve  fibre.  Of  the  same  nature  are  the  curious 
trophic  impulses  which  extend  along  the  posterior  roots  and  which  must  come  into  play 
when  eruptions  of  erythema  or  herpes  occur  as  the  result  of  inflammation  or  haemorrhages 
in  the  substance  of  the  posterior  loot  ganglia.  Both  these  phenomena  are  at  present 
but  imperfectly  understood  ;  and  their  anomalous  character  is  only  intensified  hy  the 
further  fact  elicited  by  Bayliss,  viz.  that  it  is  possible,  by  stimulation  of  afferent  nerves, 
to  excite  reflexly  vasodilatation  through  ihe  intermediation  of  the  posterior  roots. 
Unless  this  reflex  dilatation  is  simply  an  example  of  an  '  axon  reflex  '  {v.  p.  275)  it 
would  fiu-nish  an  exception  to  the  otherwise  universal  law  of  forward  direction  in  the 
mammalian  nervous  sj'stem. 

A  third  exception  to  the  law  of  Bell  and  Magendie  is  only  apparent.  It  is  sometimes 
found  that  excitation  of  the  peripheral  end  of  a  divided  anterior  root  gives  rise  to  mani- 
festations of  pain  or  to  reflex  movement.  This  1  as  been  shown  by  Schiff  to  be  due 
to  the  presence,  in  the  sheaths  cf  the  anterior  roots,  of  fine  fibres  derived  from  the 
posterior  roots  and  taking  a  recmrent  course  to  end  probably  in  the  membranes  of  the 
cord.  This  recurrent  sensibility  is  at  once  abolished  by  section  of  two  or  three  adjacent 
posterior  roots. 


324 


PHYSIOLOGY 


THE  WAY  IN 
We  may  now  consider  the  possible  ways  open  to  a  nerve  impulse  entering 
the  cord.     Each  posterior  root  on  entering  the  cord  divides  into  two  bundles. 
The  smaller  bundle  passes  to  the  outer  side  of  the  tip  of  the  posterior  horn, 

where  its  fibres  bifurcate  (Fig.  159),  giving 
rise  to  fibres  which  pass  up  and  down  the 
cord  in  a  small  longitudinal  band  of  fibres 
known  as  Lissauer's  tract.  The  fibres  run  only 
a  short  distance  before  turning  into  the  grey 
matter,  and  terminate  in  arborisations 
round  the  cells  of  the  substantia  gelatinosa 
in  the  head  of  the  posterior  horn.  By  far 
the  greater  number  of  the  posterior  root- 
fibres  pass  to  the  inner  side  of  the  posterior 
horn  into  Burdach's  or  the  postero- external 
column.  Here  they  also  divide  into  two 
main  branches,  one  running  up  and  the 
other  down  in  the  white  matter.  The 
descending  branch  passes  through  two  or 
three  segments  before  turning  into  the  grey 
matter  of  the  posterior  horn  of  a  lower 
segment.  Of  the  ascending  branches,  some 
end  at  different  levels  of  the  cord,  but  a  cer- 
tain proportion  of  the  fibres  from  every 
root  traverse  the  whole  length  of  the  cord 
in  the  posterior  columns  to  terminate  in  the 
posterior  column  nuclei  (nuclei  graciUs  and 
cuneatus)  in  the  medulla  oblongata.  As  we 
proceed  up  the  cord  the  entering  posterior 
root  fibres  displace  the  long  fibres  of  those 
below  towards  the  middle  line,  so  that  in  a 
section  through  the  cord  in  the  upper  cervical 
region  the  posterior  median  column,  or 
column  of  Goll,  is  made  up  almost  exclu- 
sively of  fibres  from  the  hind  limb,  while 
the  postero- external  column  consists  of  fibres 
from  the  fore  limb. 

Besides  these  distant  connections,  every 

entering  nerve  fibre  makes  connection  with 

all  parts  of  the  grey  matter  in  and  about  its  level  of  entrance  by  means 

of  collaterals  (Fig.  160).     Five  groups  of  these  collateral  branches  can  be 

distinguished,  i.e., 

( 1 )  Fibres  which  arborise  round  cells  in  the  posterior  horn  of  the  same  side. 

(2)  Fibres  which  pass  through  the  dorsal  grey  commissure  to  the  grey 
matter  of  the  opposite  side  of  the  cord. 


Fig.  159.  Longitudinal  section 
of  spinal  cord  of  chick,  showing 
bifurcation  of  dorsal  root- 
fibres,  and  the  passage  of  their 
collaterals  into  the  grey  matter. 
Three  cells  of  the  dorsal  horn 
are  also  seen  sending  their 
axons  into  the  dorsal  columns. 
(Cajal.) 


THE  SPINAL  CORD  AS  A  REFLEX  CENTRE 


325 


(3)  Fibres  terminating  round  the  median  group  of  cells  of  the  anterior 
horn. 

(4)  Fibres  which  end  in  a  rich  basket-work  round  the  cells  of  Clarke's 
column. 

(5)  The  sensori-motor  bundle,  which  passes  forwards  through  the 
grey  matter  to  end  round  the  cells  in  the  anterior  horn  of  the  same  side 
of  the  cord. 

Each  entering  posterior  root  fibre,  besides  these  collaterals  in  the  neighbour- 
hood of  its  entrance,  gives  but  few 
to  higher  segments  of  the  cord 
before  it  terminates  in  the  pos- 
terior column  nuclei.  Sherrington 
suggests  that  the  cells  of  Clarke's 
column  receive  fibres  mainly  from 
the  ascending  branches  of  the  nerve 
roots  from  the  posterior  limb,  a 
corresponding  station  for  the  nerve 
fibres  of  the  anterior  limb  being 
represented  by  the  cells  of  the 
nucleus  cuneatus. 

That  several  different  systems 
of  fibres  are  included  in  these 
roots  is  shown  by  the  different 
periods  at  which  they  acquire 
their  myelin  sheath.  Among  the 
earliest  to  acquire  a  sheath  are 
the  fibres  which  end  in  the  pos- 
terior horn  and  those  which  pass 
to  the  anterior  horn,  while  the 
long  fibres  in  the  dorsal  columns 
do  not  become  medullated  until 
much  later  in  foetal  life.  Since 
the  nerve  fibres  of  the  central 
nervous  system  do  not  become 
functional  until  they  have 
acquired  a  medullary  sheath, 
we  must  conclude  that  the  reflex 

responses  affecting  the  segment  in  which  the  fibres  enter  are  developed 
earher  than  those  which  involve  also  the  activity  of  the  cerebellum  and 
medulla. 

The  primitive  segmental  character  of  the  central  nervous  system  is 
retained  in  its  pure  form  only  in  the  segmentation  of  the  dorsal  spinal  root 
ganglia.  Each  of  these  ganglia  or  afferent  roots  consists  of  the  fibres  from 
the  sense-organs  in  a  segmental  area  of  the  body  surface  as  well  as  from 
the  nuiscular  and  visceral  apparatus  in  the  same  segment.  Section  of  one 
dorsal  posterior  nerve-root  will  cause  a  diminution  of  sensibility  over  a 
band-like  area  corresponding  to  the  distribution  of  the  fibres  of  the  root, 
though  to  produce  complete  insensibility  the  two  adjacent  nerve-roots  must 


jitt 


FiG.    160.     Chief  collaterals    of    dorsal   column 
fibres  from  new-born  mouse.     (C'aJal.) 
A,    intermediate    nueleus ;     B,    anterior    (ven- 
tral)   cornu ;     c,    dorsal    or    posterior    cornu ; 
c,  substance  of  Rolando. 


326 


PHYSIOLOGY 


be  divided,  in  consequence  of  the  overlap  of  fibres  at  the  periphery.     In  the 
hmbs  the  segmental  distribution  of  the  sensory  fibres  is  made  out  with  more 


Fig.  161.  Transverse  section  of  spinal  cord,  showing  collaterals  terminating  in  a 
rich  arborisation  round  the  cells  of  Clarke's  column  (a,  b),  as  well  as  others 
passing  to  the  anterior  cornua,  and  through  the  commissures.     (CaJal.) 

difficulty.     Each  hmb  must  be  regarded  as  made  up  from  a  series  of  fused 
segments,  from  five  to  seven  in  number.  The  accompanying  diagram  (Fig.  162) 


Tcdl 


aboysaZ  or  verutj-aL  me/lvan.  lUit-  oftrvunkj 


(jf*  tJve.  kJT£^^ 


B.e£xxl 


Fig.  162. 


from  Sheriington  shows  the  manner  in  which  the  skin  fields  of  these  segments 
are  combined  to  make  up  the  total  skin  area  in  the  hind  Hmb  of  the  monkey. 


THE  SPINAL  CORD  AS  A  REFLEX  CENTRE 


327 


THE  WAY  OUT 

Primitively  the  motor  nerves  also  represent  fibres  passing  from  a  col- 
lection of  ganglion-cells  to  the  muscles  of  the  corresponding  body  segment. 
In  the  dorsal  region  this  segmental  arrangement  of  motor  nerve  fibres  is 
still  traceable  in  the  adult  animal.  In  all  other  parts  the  morphological 
has  become  subservient  to  a  physiological  arrangement.  Every  muscle  of 
the  hmbs  contains  elements  from  several  segments,  and  is  innervated  there- 
fore from  several  anterior  spinal  roots.  Hence  it  follows  that  stimulation 
of  one  anterior  root  produces  no  definite  movement  of  a  group  of  muscles, 
but  partial  contraction  of  a  number  of  muscles  which  do  not  normally  con- 
tract simultaneously.  Thus  stimulation  of  a  sensory  nerve  may  evoke 
either  flexion  or  extension  of  a  hmb,  but  not  both  simultaneously.  Stimula- 
tion of  the  motor  roots  will  cause  simultaneous  contraction  of  both  flexor  and 
extensor  muscles.  It  is  this  subordination  of  morphological  to  physiological 
arrangement  in  the  hmbs  which  has  necessitated  the  formation  of  limb 
plexuses.  The  nerve-root  is  a  mor- 
phological collection  of  fibres  ;  the 
nerve  issuing  from  a  limb  plexus 
and  passing  to  a  group  of  muscles  is 
a  physiological  collection.  When  it 
is  stimulated  it  evokes  a  contrac- 
tion of  a  group  of  muscles  which 
are  normally  synergic,  i.e.  co- 
operate in  various  movements. 

The  fibres  passing  to  the  skeletal 
muscles  are  large,  about  14  yu  to  19  /x 
in  diameter,  and  their  axis  cylinders 
represent  the  axons  of  large  nerve- 
cells  in  the  anterior  horn.  In  the 
dorsal  region  of  the  cord  in  man, 
from  the  second  dorsal  to  the  second 
lumbar  nerve-roots,  the  anterior 
roots  contain,  besides  these  coarse 
fibres,  a  number  of  fine  fibres  about  1-8  ^t  to  3-6  /u  in  diameter  (Fig.  163). 
These  fine  fibres  were  shown  by  Gaskell  to  leave  the  nerve  shortly  after  the 
junction  of  the  two  roots,  to  pass  as  a  white  ramus  commimicans  to  the  sym- 
pathetic. Excitation  of  the  white  rami  evokes  various  visceral  eftects,  such 
as  dilatation  of  the  }3upils,  augmentation  of  the  heart,  contraction  of  blood- 
vessels, inhibition  of  the  gut,  erection  of  hairs,  &c.  Gaskell  pointed  out  that 
the  outflow  of  these  fine  fibres  coincided  with  the  existence  of  a  prominent 
lateral  horn  in  the  grey  matter,  and  suggested  that  cells  of  the  lateral  horn 
might  be  regarded  as  the  origin  of  the  visceral  nerve  fibres.  This  suggestion 
has  been  confirmed  by  Anderson,  who  has  shown  that  section  of  the  white 
rami  communicantes  brings  about  an  alteration  in  the  cells  of  the  lateral  horn 
as  a  result  of  retrocrrade  degeneration. 


Fig.  163.  Section  across  the  second  thoracic 
ventral  nerve-root  of  the  dog  (stained  with 
osmic  acid)  to  show  varying  sizes  of  the  con- 
stituent fibres.     (Gaskell.) 


328 


PHYSIOLOGY 


CENTRAL  PATHS  OF  SPINAL   REFLEXES 

The  impulse  entering  the  cord  is  thus  able  to  affect  immediately  a  number 
of  systems  of  neurons,  namely,  cells  in  the  anterior  horn,  in  the  posterior 
horn,  in  Clarke's  column,  in  the  substantia  gelatinosa,  in  the  lateral  column  of 
the  same  side  of  the  cord,  and  the  corresponding  groups  of  cells  on  the  oppo- 
site side  of  the  cord  either  directly  by  crossing  collaterals  or  indirectly  through 

III.T. 


ILL. 


V.S, 


Fig.  164.  Cross-sections  of  spinal  cord  of  a  dog,  showing  the  descending  nerve- 
tracts  originating  in  the  first  three  thoracic  segments  (method  of  '  successive 
degeneration ').  The  eighth  cervical  segment  had  been  excised  and  568  days 
later  a  cross-cut  was  macle  at  level  of  the  third  thoracic  nerve.  The  extent  of  the 
lesion  is  shown  in  the  first  figure  (III.  T).  The  other  sections  show  the  degenera- 
tions as  revealed  three  weeks  later  by  Marchi's  method.     (Shebrington.) 


cells  which  send  their  axons  across  the  middle  line.  Through  the  ascending 
and  descending  fibres  of  the  posterior  columns  it  can  also  set  into  action  the 
reflex  mechanisms  of  adjacent  segments  of  the  cord.  In  addition  to  this 
direct  spread  of  afferent  impulses  up  and  down  the  cord  there  is  an  anatomical 
basis  for  a  co-ordination  between  the  grey  matter  of  different  levels.  This 
co-ordination  is  effected  through  the  intermediation  of  the  internuncial  or 
intra-spinal  fibres  which  pass  up  and  down  the  cord  from  segment  to  segment. 
The  course  of  the  descending  fibres  may  be  studied  by  carrying  out  a  total 
transection  of  the  spinal  cord  at  the  sixth  cervical  vertebra,  and  six  months 
later,  when  all  the  fibres  degenerating  as  a  result  of  the  section  have  disap- 
peared, carrying  out  a  further  transection  or  hemisection  a  few  segments 
below  the  first  transection.  If  the  animal  be  killed  two  or  three  weeks  after 
the  second  operation  it  will  be  found  that  a  number  of  fibres  in  the  white 
matter  are  degenerated  below  the  second  section  (Fig.  164).     These  fibres 


THE  SPINAL  CORD  AS  A  REFLEX  CENTRE  329 

therefore  must  be  derived  from  cells  of  the  grey  matter  situated  between  the 
levels  of  the  first  and  second  sections,  and  they  can  be  traced  down  the  cord 
through  a  large  number  of  segments.  Analogous  methods  may  be  used  for 
tracing  the  course  of  the  ascending  intra-spinal  fibres.  These  intra-spiual 
fibres  occur  in  the  following  situations  : 

(1)  In  the  lateral  columns  immediately  outside  the  grey  matter,  in  the 
bay  between  the  anterior  and  posterior  horns. 

(2)  Close  to  the  grey  matter  in  the  anterior  basis  bundle. 

(3)  In  the  posterior  columns,  united  with  the  descending  branches  of  the 
entering  posterior  roots  in  the  comma  tract,  and  also  in  the  immediate 
periphery  of  the  cord  and  abutting  on  the  posterior  fissure  in  the  septo- 
marginal tract. 

(4)  Mingled  with  the  fibres  of  the  pyramidal  tract. 

All  these  tracts  are  mixed,  i.e.  contain  both  ascending  and  descending 
fibres.  As  a  rule,  the  longer  the  course  of  a  fibre  the  more  peripherallv  does 
it  he  in  the  cord.  The  shortest  of  the  fibres  may  onlv  unite  segment  to 
segment,  while  the  longest  fibres  may  run  through  the  greater  part  of  the 
cord. 

THE  SPINAL   ANIMAL 

An  animal  possessing  only  a  spinal  cord  contains  a  reflex  neural  apparatus 
which  can  be  excited  to  activity  by  impulses  of  various  qualities  and  from  any 
part  of  the  skin.  Thus  the  afferent  impulse  may  correspond  to  what  in 
ourselves  we  call  tactile  and  be  provoked  by  mechanical  stimulation,  or  may 
result  from  changes  of  temperature  and  correspond  to  those  producing 
sensations  of  heat  and  cold.  Strong  stimuli  of  any  kind  may  give  rise  also  to 
afferent  impulses  which  in  the  intact  animal  would  have  the  quahty  of  pain. 
Since  these  stimuli  are  such  as  to  produce  injury  if  continued,  they  mav  be 
named,  when  applied  to  the  spinal  animal,  pathic  or  nocuous.  The  spatial 
distribution  of  the  stimulus  \\\\\  determine  the  situation  and  number  of  nerve 
fibres  set  into  action,  so  that  there  will  be  a  great  variation  in  the  distribution 
of  the  excited  neurons  of  the  central  grey  matter  according  to  the  quahty, 
distribution,  and  intensity  of  the  stimulus.  The  efferent  part  of  the  reflex 
is  provided  for  by  the  connection  of  the  anterior  cornual  cells  to  the  whole 
skeletal  musculature  of  the  body,  as  well  as  by  the  distribution  of  the  axons 
of  the  lateral  horn-cells  to  the  sympathetic  system  and  through  this  to  the 
viscera.  On  the  other  hand,  if  the  spinal  cord  be  separated  from  the  medulla 
oblongata  and  higher  parts  of  the  brain,  it  is  deprived  of  all  connection  with 
the  most  highly  elabai-ated  sense-organs  of  smell,  sight,  hearing,  and  equili- 
bration, and  also  of  the  important  afferent  and  efferent  impulses  which  pass 
between  brain  and  viscera  through  the  vagus  nerves.  In  studving  the 
reaction  of  the  isolated  spinal  cord  we  are  studying  a  nervous  system  cut  off 
from  its  most  complex  components,  but  at  the  same  time  deprived  of  the 
initiation  and  guidance  which  it  must  normally  be  continuallv  receiving  from 
the  higher  sense-organs  through  the  brain.  A  study  of  the  spinal  animal 
will  therefore  be  instructive  as  a  study  of  the  mammalian  nervous  svstem  in 
its  simplest  possible  aspect.     It  will,  however,  in  all  cases  be  the  study  of 

11  * 


330  PHYSIOLOGY 

an  incomplete  and  maimed  system,  the  incompleteness  increasing  as  we 
ascend  the  scale  of  animals  in  our  experimentation,  owing  to  the  increasing 
subordination  of  the  lower  to  the  higher  centres,  and  of  the  immediate 
reflexes  to  the  educated  reactions  of  the  anterior  part  of  the  brain. 

SPINAL  SHOCK 

If  the  spinal  cord  of  the  frog  be  divided  just  below  the  medulla,  for  some 
minutes  after  the  section  all  four  hmbs  are  perfectly  flaccid,  and  it  is  impos- 
sible to  evoke  any  reaction  by  the  apphcation  of  the  strongest  stimuh. 
If  the  animal  be  left  to  itself  for  half  an  hour  there  is  a  gradual  return  of 
reflex  tone ;  the  animal  draws  up  its  legs  and  assumes  a  position  not  far 
removed  from  that  of  the  normal  frog,  the  head  being  lower  than  under 
normal  conditions.  We  may  say  that  the  phenomena  of  shock  in  the  frog 
last  only  a  short  time.  With  increasing  complexity  of  the  nervous  system 
the  phenomena  of  shock  become  more  lasting,  so  that  among  laboratory 
animals  it  is  in  the  monkey  that  spinal  shock  is  most  apparent.  It  is  in- 
teresting to  note,  as  pointed  out  by  Sherrington,  that  shock  appears  to  take 
effect  only  in  the  aboral  direction.  Thus,  even  in  the  monkey,  section 
through  the  lower  cervical  region,  though  causing  profound  paralysis  of  the 
lower  hmbs  and  part  of  the  trunk,  apparently  has  no  influence  at  all  on 
the  reactions  of  the  nervous  system  above  the  section.  "  The  animal  imme- 
diately after  the  section  will  contentedly  direct  its  gaze  to  sights  seen  through 
the  window,  or,  if  the  section  have  been  below  the  brachial  region,  may 
amuse  itself  by  catching  flies  on  the  pane.  This  is  the  more  remarkable  since 
the  profound  depression  of  the  nerve-centres  below  the  point  of  section 
extends  also  to  the  blood-vessels  and  viscera,  so  that  there  is  a  great  fall  of 
blood  pressure  and  diminished  production  with  increased  loss  of  heat.  The 
sphincters  are  flaccid  or  patulous,  the  skeletal  muscles  are  toneless,  and  no 
reaction  is  evoked  by  the  strongest  stimulus  to  the  skin  or  to  a  sensory 
nerve." 

Much  discussion  has  arisen  as  to  the  duration  of  shock.  Goltz  and  others 
imagined  that  the  phenomena  of  shock  may  persist  for  months  or  even  years. 
According  to  Sherrington,  in  the  higher  animals  the  phenomena  of  shock  are 
comphcated  by  the  onset  of  an  "  isolation  dystrophy  "  which  may  occur 
before  the  condition  of  shock  has  entirely  disappeared.  In  order  therefore  to 
examine  the  capabihties  of  the  isolated  spinal  cord  at  their  best,  a  time  must 
be  chosen  when  the  sum  of  shock  and  isolation  dystrophy  together  is  at  its 
minimum. 

The  occurrence  of  shock  after  complete  transection  of  the  cord  in  the 
cervical  region  cannot  be  ascribed  to  the  fall  of  blood  pressure  which  ensues 
as  a  result  of  the  severance  of  the  efferent  vaso- motor  tracts  from  the 
vaso-motor  centre  in  the  medulla.  The  centres  above  as  well  as  those  below 
the  transection  are  equally  exposed  to  the  effects  of  the  lowered  blood  pres- 
sure, but  it  is  only  those  below  the  section  which  show  signs  of  shock.  Nor 
can  it  be  regarded  as  operative  shock  due  to  the  severity  of  the  lesion  ;  such 
an  operative  shock  would  be  effective  in  either  direction,  and  we  do  not 


THE  SPINAL  CORD  AS  A  REFLEX  CENTRE  331 

find  that  the  method  of  transection,  whether  by  tearing  across  the  cord  or 
cutting  it  with  a  minimum  disturbance,  alters  appreciably  the  amount  of 
shock  displayed  by  the  segment  of  the  cord  situated  below  the  lesion.  On 
the  other  hand,  if  in  a  dog,  which  has  undergone  transection  of  the  cord  in  the 
lower  cervical  region  and  has  been  allowed  sufficient  time  to  recover  from  the 
shock,  a  second  transection  be  carried  out  two  or  three  segments  below  the 
site  of  the  first  operation,  the  influence  of  the  second  section  is  hardly  notice- 
able on  the  lower  segment  of  the  cord.  Apparently  then  the  chief  factor  in 
determining  shock  in  all  those  centres  situated  aborally  of  the  lesion  is  the 
cutting  off  of  the  impulses  which  are  continually  streaming  down  from  the 
higher  centres  and  from  the  great  sense-organs  connected  with  the  anterior 
portions  of  the  nervous  system.  With  every  rise  in  the  animal  scale  the  im- 
pressions received  by  the  special  senses  take  an  increasing  part  in  the  deter- 
mining of  all  the  reactions  of  the  body,  so  that  we  might  expect  the  effect  of 
cutting  off  the  impulses  from  the  higher  centres  to  be  greater,  the  higher  in  the 
scale  of  animal  hfe  is  the  animal  on  which  the  experiment  is  carried  out. 

The  state  of  profound  shock  produced  in  the  spinal  cord  by  the  operation 
passes  off  gradually.  The  blood  pressure,  which  may  have  fallen  to  40  or 
50  mm.  Hg.,  rises  -within  two  or  three  days  to  its  normal  height,  i.e.  90  to 
110  mm.  Hg.  The  sphincter  muscles  of  the  anus  gradually  recover  their 
tone,  and  within  a  short  time  the  reflex  evacuation  of  the  bladder  and  rectum 
may  occur  as  in  a  normal  animal.  The  skeletal  muscles  recover  their  tone 
within  a  few  days,  and  after  a  short  time  co-ordinated  movements  can  be 
brought  about  in  the  trunk  and  limbs  by  appropriate  stimulation  of  sensory 
surfaces.  At  first  the  reactions  thus  produced  are  feeble  and  the  reflex  is 
rapidly  fatigued.  Of  these  reflexes  those  excited  by  nocuous  or  painful  stimuli 
are  the  first  to  make  their  appearance  ;  a  little  later  are  seen  those  due  to 
stimuli  affecting  the  tactile  organs  in  the  skin,  or  the  sense-organs  of  deep 
sensibihty  situated  round  the  bones  and  joints  and  excited  by  deep  pressure 
or  changes  in  posture  of  the  limbs. 

In  a  dog  which  has  undergone  complete  cervical  transection  two  or  three 
months  previously,  the  tone  of  the  muscles  is  somewhat  increased.  Although 
the  dog  is  unable  to  walk,  if  it  be  raised  and  given  a  little  push  forward,  so 
as  to  stretch  the  extensor  muscles  of  its  hind  limbs,  it  may  take  two  or  three 
steps  forward  before  its  legs  collapse.  Although  the  locomotor  apparatus 
is  present,  the  nexus  is  lacking  which  determines  the  regulation  of  these  move- 
ments through  the  organs  of  static  sense,  so  that  the  spinal  movements  are 
insufficient  to  maintain  the  animal  in  such  a  position  that  a  line  drawn  verti- 
cally from  its  centre  of  gravity  shall  fall  between  its  points  of  support.  On 
the  other  hand,  swimming  movements  may  be  carried  out  regularly.  The 
frog  deprived  of  its  brain  can  swim  like  a  normal  animal,  but  in  consequence 
of  the  depression  of  its  head  tends  to  swim  ever  deeper  in  the  water.  If  a 
'  spinal '  dog  be  held  up  by  the  fore  limbs,  the  hind  limbs  nearly  always  enter 
into  alternating  movements  of  flexion  and  extension  ('  mark  time  '  move- 
ments), the  two  limbs  acting  alternately  as  in  normal  progression.  The 
stimuli  in  this  case  seem  to  be  started  by  the  stretching  of  the  skin  and  other 


332 


PHYSIOLOGY 


THE   SIMPLE   REFLEX 


stnictures   at  the  front  of  the  thighs.     In   such   animals   three  reflexes, 

amongst  others,  can  be  excited  almost  invariably,  viz.  : 

(1)  Scratch  reflex.     Gentle  stimulation,  mechanical  or  electrical,  of  any 

point  over  a  saddle-shaped  area  on  the  dorsum  behind  the  shoulders  (Fig. 

165)  causes  rhythmic  movements  of  flexion  and  extension  of  the  hind  limb  of 

the  same  side,  the  effect  of 
which  would  be  to  scratch 
away  the  irritant  object. 
These  movements  are  re- 
peated at  the  rate  of 
about  four  per  second. 

[2)  Flexor  reflex. 
Nocuous  stimuli,  such  as 
the  prick  of  a  needle 
appHed  to  any  part  of  the 
foot,  causes  flexion  of  the 
leg  and  thigh,  often  accom- 
panied by  extension  of 
the  opposite  hind  limb. 

(3)  Extensor  or  '  stej)- 
ping'  reflex.  Gentle  pres- 
sure appHed  to  the 
plantar  surface  of  the 
hind  foot,  especially  if  the 
limb  is  somewhat  flexed, 
causes  a  movement  of  ex- 


FiG.    165.      A.    The  receptive  field,    whence  the   scratch   tension  of  the  hmb  accom 

reflex  of  the  left  hind  limb  can  be  evoked. 

B.  Diagram  of  spinal  arcs  involved.      L,  afferent  path 
from  left  foot ;  b,  afferent  j)ath  from  right  foot;  Ka,  e/3, 
receptive  paths  from  hairs  on  'scratch  area';    fc,  final    },•    j  ]•     ] 
common  path  (motor  neuron);     pa,  p/3,  proprio-spinal  neu-    JHHCl  umo 
rons.     (Sheeringto^t.) 


panied   sometimes   by    a 
flexion    of    the    opposite 


In  such  an  animal  the 
carrying  out  of  the  vis- 
ceral reflexes  may  be  very  efficient.  The  blood  pressure  has  attained  its 
normal  height  and  may  be  altered  reflexly  in  very  much  the  same  way  as 
in  a  normal  animal,  although  the  medullary  vaso-motor  centre  can  no 
longer  be  concerned.  Thus  in  the  diagram  (Fig.  166)  is  represented  the 
effect  on  the  blood  pressure  of  exciting  the  central  end  of  the  digital  nerve 
in  a  spinal  dog.  The  pressure  rises  from  90  to  208  mm.  Hg. — a  pressor 
effect  as  great  as  any  which  can  be  obtained  in  an  animal  still  possessing  all 
the  connections  of  the  vascular  system  with  the  vaso-motor  centre.  The 
height  of  the  rise  shows  that  as  regards  the  influence  on  the  blood  pressure 
the  spinal  cord  must  be  acting  as  a  whole.  No  effect  on  the  blood-vessels 
confined  to  the  segment,  or  segments,  adjacent  to  that  of  the  nerve 
stimulated  would  suffice  to  cause  a  rise  of  more  than  a  few  mm.  Hg. 

The  reflex  apparatus  for  other  visceral  functions  seems  to  be  equally 
perfect.     The  urinary  bladder,  when  sufficient  urine  is  accumulated,  con- 


THE  SPINAL  CORD  AS  A  EEFLEX  CENTRE  333 

tracts  forcibly,  the  contraction  being  accompanied  by  relaxation  of  the 
sphincter  and  followed  by  rhythmic  contractions  of  the  urethral  muscles  ; 
accumulation  of  faeces  in  the  rectum  leads  to  their  normal  evacuation.  With 
a  httle  assistance  impregnation  may  be  effected  in  or  by  such  a  maimed 


aoo  mm    Hg. 


150  mm.  Hg. 


100  mm.  HS 
b.  p. 


Signal 
Time  in   2" 

Fig.   166.     Blood  pressure  tracing   from   a   spinal   dog.     The   signal  indicates   the 
time  during  which  the  afferent  nerve  was  .stimulated.     (Sherrington.) 

animal,  and  in  the  female  may  terminate  at  full  term  in  normal  parturition. 
Pregnancy  is  accompanied  by  hypertrophy  of  the  mammary  glands  and  is 
followed  by  secretion  of  milk,  so  that  the  young  may  be  suckled  as  in  a 
normal  animal.  Similar  phenomena  have  been  observed  in  the  human  sub- 
ject. 

Such  an  animal  furnishes  us  with  an  opportunity  of  analysing  the  factors 
which  are  involved  in  the  maintenance  of  muscle  tone,  as  well  as  in  the  carry- 
ing out  of  the  simplest  reflexes  involving  contractions  of  the  skeletal 
muscles. 

MUSCULAR  TONE 

Every  muscle  in  the  body  is  in  a  condition  of  shghtly  continued  contrac- 
tion which  keeps  it  tense,  so  that  when  it  contracts  in  response  to  a  stimulus 
there  is,  so  to  speak,  no  '  slack  "  to  be  taken  up  before  the  muscle  begins  to 
pull  on  its  attachments.  This  tone  is  seen  in  the  retraction  undergone  by 
muscles  or  tendons  when  they  are  divided  in  the  living  animal. 

If  a  frog  possessing  only  spinal  cord  be  hung  up  by  its  jaw,  the  limbs  will 
be  observed  to  occupy  a  position  which  is  short  of  complete  extension.  The 
tone  of  the  muscles  which  is  concerned  in  the  maintenance  of  this  attitude  is  at 
once  abolished  by  the  destruction  of  the  spinal  cord.  It  may  be  abolished  on 
one  side  by  section  either  of  the  anterior  roots  going  to  the  muscles,  or  of  the 
posterior  roots  coming  from  the  nuiscles  (Fig.  1()7).  In  the  intact  animal 
muscle  tone  is  diminished  by  disease  and  may  be  abolished  during  profound 
anaesthesia,  as  it  is  indeed  in  the  condition  of  shock. 

Much  light  has  been  thrown  on  the  factors  which  determine  muscular 
tone  by  a  study  of  the  '  tendon  phenomena  '  of  which  the  knee-jerk  is  the 


334 


PHYSIOLOGY 


most  familiar  example.     If  the  leg  is  allowed  to  hang  loosely  in  a  jpositioil 
of  slight  flexion  at  hip  and  knee  and  the  patellar  tendon  be  struck,  the  ex- 
tensor muscles  of  the  thigh  contract  and  raise  the  leg.     This  phenomenon 
is  known  as  the  knee-jerk.      Similar  '  tendon  reflexes  '  can  be  obtained  in 
other  muscles,  such  as  the  tendo  Achillis,  the  triceps,  and  the  extensor 
muscles  of  the  wrist,  but  with  not  so  great  ease  as  is  the  case  with  the  knee. 
The  knee-jerk  is  not  altered  by  rendering  the  tendon  anaesthetic  by  section 
.,-._..,     ,        of   all  its   nerves.      The   essential   feature   is   a   slight 
passive  increase  of  the  tension  to  which  the  muscle  is 
already  subjected.     Since  the  jerk  is  abolished  by  sever- 
ance at  any  point  of  the  reflex  are,  viz.  muscle  spindle, 
cord,  muscle,  it  was  thought  at  first  to  be  of  the  nature 
of  a  reflex  action.     The  interval,  however,  which  elapses 
between  the  moment  at  which  the  tendon  is  struck  and 
the  response  of  the  muscle  is  generally  considered  to  be  too 
short  to  allow  of  an  impulse  to  travel  from  the  tendon, 
or  muscle,  up  to  the  cord  and  back  again  to  the  muscle. 
The  interval  was  found  by  Gotch  to  be  about  -005  sec, 
whereas  the  latent  period  of  contraction  which  ensues 
upon  direct   stimulation  of  the  vastus  internus  is  also 
•005  sec.     On  the  other  hand,  the  latent  period  when 
the  nerve  to  the  muscle  was  stimulated  was  '01  sec. 
The  lost  time  of  the  knee-jerk  is  less  than  one-quarter  of 
that  of  the  briefest  reflex  time.     The  contraction  has 
therefore  been  thought  to  be  due  to  the  direct  stimula- 
tion of  the  muscle  by  the  sudden  stretching  produced 
on  striking  its  tendon.     Mere  tension  of  the  muscle  is 
not,  however,  the  only  factor.     The  tone  which  is  reflexly 
maintained  in  the  muscle  is  necessary  for  this  response  to 
direct  stimulation  to  take  place,  and  it  seems  to  keep 
the  muscles  in  a  state  of  wakefulness  ready  to  respond 
]W.^  Tlfe  posterior  ^^   *^^   shghtest   local    stimulation.     The   knee-jerk  is 
roots  of  the  nerves  therefore  of  special  importance  as  an  index  to  the  tonic 
limb   \ave     been  condition  of  the  muscles    concerned,  being  brisk   and 
divided.  easily  elicited  when  the  tonus  is  pronounced,  and  shght 

KEw.)  ^^  absent  when  the  tone  of  the  muscle  is  depressed. 
Especially  interesting  is  the  relation  shown  by  Sherrington  to  exist 
between  the  tonic  condition  of  antagonistic  muscles,  e.g.  between  the  ham- 
strings and  the  vastus  internus  of  the  quadriceps  extensor  muscle.  Section 
of  the  hamstring  muscles  (so  as  to  relax  them)  or  even  section  of  their  nerve 
causes  at  once  great  increase  in  the  jerk  elicited  by  tapping  the  patellar 
tendon.  On  the  other  hand,  the  knee-jerk  is  abolished  by  stretching  the  ham- 
string muscles,  or  by  weak  stimulation  of  the  central  end  of  the  cut  nerve  to 
the  hamstrings  (Fig.  168). 

In  this  way  a  voluntary  flexion  of  the  knee  by  contraction  of  the  ham- 
strings automatically  abolishes  the  resistance  which  would  be  offered  by 


Fig.  167.     Hind  part 
of     a     spinal   frog, 


THE  SPINAL  CORD  AS  A  REFLEX  CENTRE 


335 


L.3 


the  tonic  contraction  of  the  extensor  muscles.  In  the  absence  of  such  an 
arrangement  every  movement  of  a  joint,  by  stretching  the  antagonistic 
muscles,  would  automatically  increase  their  tone,  and  thus  set  up  a  resistance 
to  itself.     The  subject  would  thus  be  muscle-bound. 

Very  great  exaggeration  of  the  tendon  phenomenon  is  observed  in  cases 
where  the  pyramidal  tracts  are  degenerated,  and  indicates  a  heightened 
reflex  excitability  of  the  lower  spinal  centres,  perhaps  reinforced  by  impulses 
from  the  cerebellum.  The  importance  of  the  latter  impulses  in  determining 
the  myotatic  irritabihty  of  the  muscles  is  especially  marked  in  man,  where 
total  transverse  lesion  of  the 
upper  part  of  the  spinal  cord 
often  abolishes  permanently  the 
tone  of  the  muscles  innervated 
from  the  lower  portion  of  the 
cord,  and  especially  the  knee- 
jerk.  How  far  this  absence  of 
tone  is  due  to  collateral  changes 
in  the  cord  has  not  yet  been 
determined.  In  animals  com- 
plete transverse  section  of  the 
cord  of  the  cervical  region  is 
followed  by  increase  of  the  knee- 
jerk,  which  in  the  rabbit  may  be 
ehcited  within  a  quarter  of  an 
hour  after  the  section  has  been 
carried  out.  In  the  increased 
myotatic  irritabihty  observed 
after  .  removal  of  the  cerebral 
cortex,  or  after  degeneration  of 
the    pyramidal    tracts    coming 

from  the  motor  cortex,  a  single  tap  on  the  patellar  tendon  may  evoke  a 
series  of  contractions  of  the  extensor  nmscles  of  the  thigh,  giving  rise  to 
what  is  known  as  knee  clonus.  In  the  same  way  forcible  flexion  of  the 
ankle  causes  a  series  of  rhythmic  contractions  of  the  calf  muscles  (ankle 
clonus),  varying  in  rhythm  from  six  to  ten  per  second.  The  heightened 
tone  of  the  muscles  under  these  conditions,  and  the  ease  with  which 
any  shght  increase  in  their  tension  gives  rise  to  clonic  contractions,  cause 
such  patients  to  liave  a  peculiar  dancing  gait,  characteristic  of  p}Ta- 
midal  degeneration,  and  known  as  the  '  spastic '  gait ;  it  is  generally  associ- 
ated with  a  certain  loss  of  voluntary  control  of  the  movements  of  the  Hmbs, 
so  that  the  whole  complex  of  symptoms  is  called  '  spastic  paraplegia." 

The  value  of  the  tendon  phenomena  as  a  means  of  diagnosis  has  tended 
to  obscure  their  great  importance  in  the  normal  individual.  Every  joint 
is  protected  by  inextensible  ligaments  and  by  muscles.  A  sudden  strain  on  a 
ligament  either  will  have  no  effect,  or  will  rupture  some  of  its  fibres  and  per- 
haps injure  the  adjacent  joint  surfaces.     An  ordinary  reflex  contraction 


Fig.    168.     Diagram   to   show  muscles  and  nerves 
concerned   in   Sherrington's    experiment    on    the 
reciprocal  innervation  of  antagonistic  muscles. 
l3,  l4,  l5,  third,  fourth,  and  fifth  Uimbar  roots ; 

si,  s2,  first  and  second  sacral  roots. 


336  .         PHYSIOLOGY 

would  be  powerless  to  prevent  this,  since  the  mischief  would  be  done  before 
the  reaction  could  take  place.  But  the  central  nervous  system  confines 
itself  to  keeping  the  muscles  awake,  so  that  they  themselves  may  react  to  any 
sudden  increase  in  their  tension  by  an  equally  sudden  contraction,  which 
saves  the  joint  before  the  central  nervous  system  has  even  become  aware 
of  the  strain. 

The  tone  of  the  muscles,  as  well  as  the  consequent  tendon  phenomena, 
is  dependent  on  the  integrity  of  the  reflex  arc  governing  the  muscles  in 
question.  It  has  been  shown  by  Sherrington  that  the  afferent  part  of  the 
arc  is  represented  by  the  afferent  nerves  from  the  muscle  itself,  and  that  these 
nerves  receive  their  sense  impressions  from  the  special  nerve-endings  charac- 
teristic of  muscle — the  '  muscle-spindles.'  Even  in  the  purely  muscular 
nerves  a  large  proportion  of  the  fibres  are  afferent  in  function,  and,  after 
section  of  the  appropriate  posterior  roots  distal  to  the  ganglia,  as  many  as 
40  per  cent,  of  the  fibres  going  to  a  muscle  may  be  found  degenerated. 
Though  most  of  these  have  the  muscle-spindles  as  their  destination,  a  certain 
number  pass  to  the  tendon  and  aponeuroses  connected  with  the  muscle,  where 
they  end  in  the  end- organs  known  as  the  organs  of  Golgi  and  the  organs  of 
Rufl&ni.  After  section  of  the  motor  nerves  the  muscle  fibres  degenerate, 
with  the  exception  of  the  modified  fibres,  which,  enclosed  in  a  connected  tissue 
sheath,  are  concerned  in  the  formation  of  the  muscle-spindles.  Muscle  tone 
and  tendon  phenomena  may  therefore  be  abolished  by  lesions  of  afferent 
nerves,  which  leave  a  considerable  part  of  the  cutaneous  sensibility  of  the 
limb  intact.  In  man  the  spinal  reflex  mechanism  connected  with  the  knee- 
jerk  is  situated  in  the  third  and  fourth  lumbar  segments.  The  jerk  may  be 
abolished  by  section  of  the  third  and  fourth  posterior  nerve-roots,  although 
to  render  the  whole  hind  limb  anaesthetic  it  would  be  necessary  to  divide  all 
the  roots  from  the  second  lumbar  to  the  fourth  sacral  inclusive. 

Recent  researches  by  Snyder  and  by  Jolly  indicate  that  the  reflex  nature  of  the 
knee-jerk  cannot  be  entirely  excluded.  Jolly,  using  the  string  galvanometer,  has  taken 
the  current  of  action  in  the  vastus  internus  muscle  as  an  index  of  the  commencing 
contraction  of  this  muscle  in  the  knee-jerk.  He  has  also  by  the  same  method,  by 
leading  off  the  afferent  and  efferent  nerves  respectively,  measured  the  lost  time  in  the 
sense-organs  and  in  the  motor  end-plates  of  the  muscle.  In  the  spinal  cord  he  obtained 
the  following  electrical  latencies  in  one  case  : 

Latency  of  knee-jerk  .....  5-3o-* 

Afferent  endings  .....         04o- 

Nerve  conduction         .  .  .  .  .1-4 

Motor  endings  and  action  current  .  .         l-S 

3-1 

Synapse  time  ....  2-2o- 

In  this  case  the  shortest  latency  determined  for  nerve-endings  has  been  deducted 
from  the  shortest  latent  period  obtained  from  the  knee-jerk  in  the  spinal  cat.  On 
the  other  hand,  some  decapitated  preparations  have  been  found  to  present  considerably 
longer  latent  periods,  e.g.  11  and  12a.  This  variation  in  the  latent  period  supports 
the  view  that  the  knee-jerk  is  a  reflex  of  which  the  synapse  time  is  very  short,  about  2(r, 

*  o-  =  -001  sec. 


THE  SPINAL  CORD  AS  A  REFLEX  CENTRE  337 

and  that  in  certain  cases  there  maybe  increased  delay  in  the  spinal  cord.  When  the 
latencies  of  the  knee-jerk  and  the  homonymous  flexor  reflex  are  compared  by  the 
electrical  method,  it  is  fomad  that  the  latter  is  roughly  double  the  former,  the  average 
latency  of  the  knee-jerk  in  the  spinal  cat  being  6-6cr,  and  of  the  homonymous  flexor 
reflex  13-2o-.  Jolly  suggests  that  this  difference  may  be  due  to  the  fact  that  the  knee- 
jerk  mechanism  involves  only  one  spinal  synapse  or  set  of  synapses,  while  the  flexor 
reflex  may  invoh^e  two.  In  these  estimates  the  rate  of  conduction  in  mammalian  nerve 
has  been  taken  at  120  metres  per  second. 


SECTION  VIII 

THE   MECHANISM   OF   CO-ORDINATED 
MOVEMENTS 

The  detailed  study  of  the  chief  reflexes  obtainable  from  a  spinal  animal  has, 
in  Sherrington's  hands,  yielded  much  information  as  to  the  linking  of  the 
various  events  which  are  concerned  in  the  carrying  out  of  every  co-ordinated 
movement,  and  as  to  the  conditions  which  determine  the  sequence  and 
extent  of  the  activities  involved. 

We  may  take,  as  the  type  of  such  a  reflex,  the  flexion  of  the  leg  and 
thigh  which  ensues  on  the  application  of  a  painful  stimulus  to  the  ball 
of  the  foot,  such  as  pricking  with  a  needle,  or  the  application  of  the  faradic 
current.  Of  course,  in  the  spinal  animal  no  pain  can  result  from  stimulation 
of  any  part  below  the  level  of  section  of  the  cord,  and  it  is  better  therefore 
under  such  circumstances  to  speak  of  nocuous  or  pathic  stimuli,  since  all 
stimuli  which  cause  pain  are  such  that,  if  their  operation  continued,  they 
would  result  in  damage  to  the  material  structure  of  the  animal.  This  flexor 
reflex  is  also  easily  obtainable  in  the  frog  as  a  result  of  stimulating  one  of  its 
toes  by  mechanical  or  chemical  stimuli,  but  it  is  easier  to  analyse  the  diflerent 
events  involved  in  the  reaction  in  the  case  of  the  larger  animal. 

The  effect  varies  with  the  strength  of  the  stimulus.  The  minimal  effec- 
tive stimulus  causes  simply  movement  of  the  foot.  As  its  strength  is  in- 
creased this  movement  is  attended  by  flexion  of  the  leg  on  the  thigh,  and 
finally  by  flexion  of  the  thigh  on  the  body.  With  still  further  increase  there  is 
a  spread  to  the  opposite  hind  limb,  which,  however,  performs  the  opposite 
movement  of  extension.  Increase  in  the  strength  of  stimulus  causes  not 
only  an  increase  in  the  strength  of  contraction  of  the  reacting  muscles,  but 
also  an  extension  of  the  reaction  to  more  and  more  muscles,  or  groups  of 
muscles.  The  spread  occurs  always  in  definite  order.  The  stimulus  when 
represented  by  the  prick  of  a  needle  can  affect  only  one  or  two  nerve  fibres. 
The  impulse  carried  along  these  fibres  through  a  posterior  root  to  the  cord 
spreads  in  the  cord,  affects  the  motor  neurons  of  the  anterior  horns,  and 
causes  these  to  discharge.  The  first  discharge  is  as  a  rule  Hmited  to  those  in 
the  immediate  proximity  of  the  entering  impulses,  but  even  when  minimal, 
involves  the  simultaneous  action  of  more  than  one  anterior  root.  We  may 
say  that  the  motor  response  is  determined  to  a  certain  extent  by  the  spatial 
proximity  of  the  afferent  to  the  efferent  tracts,  but  that  it  is  always  pluri- 

338 


THE  MECHANISM  OF  CO-ORDINATED  MOVEMENTS       339 

segmental,  the  most  important  determining  factor  being  the  adaptation  of 
the  movement  to  the  stimukis  which  is  apphed. 

The  gradual  spread  of  the  response  with  increasing  strength  of  stimulus 
is  spoken  of  as  '  irradiation.'  The  nature  of  the  response  is  determined  by 
the  locus  or  place  of  application  of  the  stimulus  and  by  the  quahty  of  the 
latter.  While  a  painful  stimulus  causes  flexion  of  the  leg,  deep  pressure  on 
the  plantar  surface  of  the  paw  causes  extension — the  '  stepping '  reflex. 
However  extensive  the  irradiation,  the  muscles  which  are  set  into  action  are 
always  such  that  their  actions  co-operate  towards  a  given  end.  Thus, 
when  the  impulse  spreads  to  the  opposite  hmb  and  produces  an  extension, 
the  reaction  is  such  as  would  ensue  when  the  dog  steps  on  a  sharp  point  and 
immediately  retracts  the  irritated  limb  away  from  the  injurious  agent  while 
it  extends  the  other  limb  in  the  first  act  of  progression  or  movement  away 
from  the  dangerous  spot. 

A  superficial  study  of  this  reflex  would  therefore  lead  us  to  the  conclu- 
sion that,  by  the  varying  resistance  in  the  different  synapses  on  the  course 
of  the  connections  of  the  stimulated  aft'erent  nerves,  the  impulses  are  directed 
so  as  to  affect  solely  and  exclusively  the  muscles  whose  activity  will  co- 
operate and  aid  the  primary  reflex.  Such  a  description  would,  however,  only 
represent  one  half  of  the  process.  Every  muscle  in  the  body  is  in  a  state  of 
tone  varying  with  its  extension.  If  this  tone  is  not  to  interfere  with  the 
carrying  out  of  a  reflex  movement,  there  must  be  some  means  by  which  it 
can  be  inhibited.  Such  an  inhibition  we  have  seen  occur  as  the  result  of  con- 
traction of  antagonistic  muscles  ;  but  the  remarkable  fact  has  been  brought 
out  by  Sherrington  that  the  impulses,  which  start  on  the  surface  of  the 
body  and  set  loose  a  chain  of  motor  impulses  resulting  in  the  co-ordinated 
contraction  of  certain  muscles,  spread  at  the  same  time  to  the  motor 
mechanisms  governing  the  muscles  antagonistic  to  the  movement,  and  exer- 
cise on  these  an  inhibitory  effect. 

This  inhibition  can  be  easily  shown  in  a  spinal  animal  in  the  following 
way.  The  anterior  thigh  muscles  are  cut  away  from  their  attachments  to 
the  tibia  and  the  patellar  tendon  is  connected  by  a  thread  with  a  recording 
lever.  On  then  exciting  the  flexor  reflex  by  nocuous  stimulation  of  the  foot, 
the  lever  attached  to  the  patellar  tendon  falls  (Fig.  169b),  showing  that  the 
extensor  muscles  have  undergone  actual  elongation.  The  same  eftect  is 
observed  even  when  the  hamstrings,  the  flexors  of  the  knee,  have  been  divided. 
The  inhibition  of  the  extensor  tone  is  thus  not  only  determined  by  the  in- 
creased tension  of  the  flexors,  but  is  a  direct  result  of  the  primary  cutaneous 
stimulus. 

From  a  broad  standpoint  the  function  of  the  nervous  system  is  the 
co-ordination  of  all  the  activities  of  the  body  so  that  these  may  be  com- 
bined to  one  common  end,  viz.  the  preservation  of  the  organism.  For 
this  purpose  there  must  be  no  clashing  between  opposing  activities 
of  different  parts.  If  one  part  is  engaged  in  any  action  this  action 
must  be  the  policy  of  the  body  as  a  whole.  Yet  the  surface  of  the  body  is 
being  continually  played  upon  by  ever-changing  stimuli,  tending  to  excite 


340 


PHYSIOLOGY 


first  one  reflex  and  then  another,  and  the  activities  so  excited  would  pro- 
duce confusion  in  the  conduct  of  the  animal,  if  there  were  not  some  means  by 
which  at  any  one  time  only  one  reaction  should  be  in  the  act  of  being  carried 
out.     The  imperative  stimulus  should  dominate  the  actions  of  the  body  as  a 


Fig.  169,  a  and  b.  (Sherrington.) 
The  flexion  reflex  observed  as  reflex  contraction  (excitation)  of  the  flexor  muscles 
of  the  knee  (a),  and  as  reflex  relaxation  (inhibition)  of  the  extensor  muscle  (b). 
The  stimulus  was  a  series  of  weak  break  induction  shocks  applied  to  a  twig  of  the 
internal  saphenous  nerve  below  the  knee.  Observation  B  was  made  four  minutes 
after  A.  Note  the  summation  of  stimuli,  in  each  case  six  stimuli  being  required  before 
the  reaction  was  evoked. 


whole.  Just  as,  in  the  mental  world,  attention  must  be  undivided  if  we 
are  to  avoid  confusion  of  judgment,  so  in  the  lower  nervous  activities  there 
must  always  be  concentration  on  one  act  or  another.  There  may  be  a 
struggle  of  different  stimuU,  but  one  must  finally  be  prepotent  and  annul 
altogether  the  influence  of  the  others.  The  study  of  the  spinal  animal 
shows  that  this  concentration  of  energy  is  obtained  by  the  process  of  inhibi- 


THE  MECHANISM  OF  CO-ORDINATED  MOVEMENTS       341 


tion.  Every  successful  reflex,  i.e.  one  which  actually  occurs,  inhibits  all 
other  reflexes  which  are  not  co-operative  with  the  one  which  is  taking  place. 
We  may,  for  instance,  stimulate  the  area  of  skin  which  gives  rise  to  the 
scratch  reflex,  and  at  the  same  time  apply  a  painful  stimulus  to  the  foot. 
The  result  is  not  a  movement  compounded  of  the  two  reflexes,  but,  as  a  rule, 
the  flexor  reflex  preponderates.  If,  for  instance,  the  scratch  reflex  be 
proceeding  and  then  the  foot  be  pricked,  the  scratch  reflex  immediately 
comes  to  an  end,  and  the  flexor  reflex  occurs. 
When  this  in  its  turn  has  come  to  an  end, 
the  scratch  reflex  may  be  once  more  re- 
sumed (Fig.  170). 

One  stimulus  may  reinforce  another  if 
the  reactions  ensuing  on  the  two  stimuli 
are  allied — i.e.  tend  to  co-operate  one  with 
another.  In  every  other  case,  however,  an 
afferent  impulse  entering  the  cord  and 
spreading  to  a  motor  mechanism,  so  as 
to  produce  a  co-ordinate  contraction  of 
various  muscles,  causes  at  the  same  time 
inhibition  of  the  muscles  antagonistic  to  the 
movement,  and  a  block,  or  inhibition,  in  all 
other  reflex  arcs  of  the  cord. 

The  anatomical  basis  of  the  various 
events  involved  in  the  carrying  out  of  such 
a  reflex  as  that  just  studied  is  shown  in  the 
diagram  (Fig.  171).  In  this  diagram  the 
nerve-fibre  a  represents  the  pain- receiving 
or  nociceptive  nerve  from  the  skin  of  the 
foot.  This  passes  by  a  posterior  root  into 
the  spinal  cord,  where  it  divides  and  gives 
off  a  number  of  collaterals.  These  collaterals, 
as  we  have  already  seen,  pass  in  various 
directions ;  some  to  the  neighbouring 
grey  matter,  some  to  the  centres  in 
the  higher  parts  of  the  nervous  system. 
Neglecting  the  latter  and  any  intermediate 
neuron  which  may  be  intercalated  between 

the  aft'erent  fibre  and  the  motor  cell,  we  see  that  those  collaterals  which 
affect  the  motor  cells  of  the  muscles  of  the  two  hind  limbs  can  be 
divided  iifto  two  sets,  one  of  which  always  produces  during  activity  excitation 
in  certain  efferent  neurons,  whilst  the  other  produces  inhibition  of  the 
efferent  neurons  of  the  antagonistic  muscles.  The  single  afferent  nerve  fibre 
is  therefore,  with  regard  to  one  set  of  its  central  terminal  branches,  specifically 
excitor,  and,  in  regard  to  another  set  of  its  central  endings,  specifically 
inhibitor.  In  the  case  in  point  the  central  terminal  branches  of  the 
nerve  a  are  excitor  for  the   flexor  muscles  of  the  same  side  and  inhibtor 


Fig.   170.     Scrateli  lefle.K  tempo- 
rarily inhibited    In-  application 
of  a  pathic  .stimulus  to  foot. 
Signal  A,  stimulation  of  scratch 
area.     Signal  n.  stimulation  of  paw 
by  strong  induction  shock. 


342  PHYSIOLOGY 

for  the  extensor  muscles  of  the  same  side  and  for  the  flexor  muscles  of  the 
opposite  side. 

The  ascending  branches  of  the  nerve  fibre  in  the  same  way  will  have 
endings  w^hich,  while  inhibitor  for  the  greater  number  of  other  possible 
reflex  changes,  will  be  excitor  in  a  shght  degree  for  certain  efferent 
neurons  whose  action  is  allied  to  that  of  the  primary  reflex.  The  diagram 
shows  also  that  the  contraction  of  the  flexor  muscle,  set  up  as  the  result 


Fig  171  Diagram  indicating  connections  and  actions  of  two  afferent  spinal 
root-cells  a  and  a',  in  regard  to  their  reflex  influence  on  the  extensor  and  flexor 
muscles  of  the  two  knees.  The  sign  +  indicates  an  excitatory  effect,  the 
sign  —  an  inhibitory  effect.     (Sherrington.) 

of  stimulating  a,  itself  initiates  a  secondary  reflex  process  from  muscle  up 
the  nerve  fibre  a  and  back  again  to  the  muscle  by  the  efferent  neuron.  This 
muscular  afferent  nerve  also  has  central  terminations  of  two  signs — excitor 
to  itself  and  inhibitor  to  the  antagonistic  muscles.  For  the  sake  of  clearness 
the  diagram  omits  a  number  of  other  channels  coming  from  other  regions  of 
the  cord,  or  from  other  efferent  nerves,  the  sign  of  which  would  be  negative, 
i.e.  which  would  tend  to  inhibit  the  activity  of  the  whole  reflex  arc. 

We  see  therefore  that  from  every  sensitive  point  on  the  surface  of  the  body 
impulses  can  be  initiated  which  will  set  into  action  whole  chains  of  neurons, 
and  will  have  a  widespread  influence  throughout  the  central  nervous  system. 
It  is  important  to  note  that  the  efferent  path  innervating,  say,  the  flexor 
muscles  of  one  side  is  common  to  many  reflexes.  It  is  used,  for  instance,  by 
mutually  antagonistic  reflexes  such  as  the  scratch  reflex  and  the  flexor  or 


THE  MECHANISM  OF  CO-ORDINATED  MOVEMENTS        343 

pain  reflex.  We  must  assume  therefore  that  the  mutual  inhibition  of  differ- 
ent reflexes  occurs,  not  in  the  '  final  common  path  ' — i.e.  in  the  motor  neurons, 
which  must  always  remain  open — but  further  back  in  the  arc,  probably  near 
its  afferent  side. 

We  have  reason  to  believe  that  the  propagation  of  impulses  through  the 
central  nervous  system  involves  expenditure  of  energy,  and  that  the  seat  of 
this  expenditure  may  be  located  in  all  probability  at  the  synapses.  It  follows 
that  the  result  of  any  particular  sensory  stimulation  will  not  be  absolutely 
invariable,  but  that  the  spread  of  the  nerve  process  in  the  nervous  system, 


Fic 


.172.  ■  Mark-time  '  reflex  in  spinal  dog,  inhibited  by  slight  stimulation  of 
the  tail  (duration  of  stimulation  shown  by  signal).  Note  the  augmentation  of 
the  mark-time  reflex  following  the  inhibition  (successive  spinal  induction). 
(Shekrington.) 


and  the  degree  of  block  presented  by  the  various  synapses  and  determining 
the  potency  of  any  given  reaction,  will  depend  on  the  condition  of  the 
various  synapses  at  the  time  of  the  stimulation. 

This  condition  may  be  altered  in  various  ways.  Repeated  excitation 
causes  in  the  synapses,  just  as  in  the  nerve-endings  of  the  skeletal  muscle,  a 
condition  of  fatigue.  Stimulation  confined  to  a  single  point  in  the  "  scratch 
area  '  of  the  spinal  dog  excites  a  scratch  reflex  which  rapidly  dies  away.  On 
shifting  the  exciting  electrodes  a  little  to  one  side  the  reflex  act  begins  again, 
often  with  greater  force  than  at  first,  and  a  very  prolonged  reaction  can  be 
induced  by  gradually  moving  the  electrodes  along  the  surface  of  the  skin.  A 
reflex  arc  therefore  rapidly  shows  signs  of  fatigue,  and  the  minute  change 
in  locus  of  stimulus  which  is  required  to  reinduce  a  practically  identical 
action  shows  that  the  seat  of  fatigue  must  lie  chiefly  on  the  afferent  side  of 
the  arc  ;  perhaps  in  the  first  synapses  through  which  the  impulse  has  to 
pass.  This  easy  incidence  of  fatigue  tends  to  cut  short  any  given  reaction 
and  to  render  it  easier  for  other  reactions  to  take  its  place. 


344  PHYSIOLOGY 

Just  as  excitation  causes  fatigue  and  therefore  furnishes  a  hindrance  to 
repetition  of  the  same  act,  so  the  reverse  process  of  inhibition,  which  is  a 
large  component  of  every  reaction,  is  followed  by  a  condition  of  increased 
excitabihty,  or  diminished  resistance  to  the  passage  of  impulses.  In  each 
case  there  is  a  tendency  for  a  '  swing-back  '  to  take  place  from  inexcitability, 
to  over- excitability,  from  excitation  to  inexcitability.  This  '  successive 
spinal  induction,'  as  it  has  been  termed,  may  be  seen  on  inhibiting  some 
moveinent  by  the  excitation  of  an  independent  reflex.  Thus  the  scratch 
reflex  is  excited,  and  then  while  the  excitation  is  still  continued  the  reaction 
is  inhibited  by  excitation  of  the  extensor  or  stepping  reflex.  As  soon  as  the 
'  stepping  '  reflex  has  passed  off,  the  scratch  reflex  returns  with  an  intensity 
greater  than  before.  This  successive  spinal  induction  explains  the  tendency 
which  exists  in  the  spinal  cord  to  an  alternation  of  response  ;  every  act  tend- 
ing to  come  to  an  end  by  fatigue  and,  as  a  result  of  negative  spinal  induction, 
inducing  the  opposed  or  antagonistic  act.  Thus  if  a  spinal  dog  be  held  up  in 
the  vertical  position,  so  that  the  hind  limbs  hang  freely,  these  latter  execute 
a  series  of  alternate  movements  of  flexion  and  extension.  The  starting-point 
of  these  is  the  stretching  of  the  anterior  thigh  muscles.  Once  started 
they  continue  of  themselves,  each  act  exciting  the  alternating  antagonistic 
act. 

A  reflex  act  has  often  been  distinguished  from  other  reactions,  described 
as  conscious  or  purposive,  by  its  fatality — i.e.  by  the  invariability  with 
which  it  results  on  a  given  stimulus,  whether  the  reaction  be  for  the  good  of 
the  animal  as  a  whole  or  not.  Thus  a  decapitated  eel  will  wind  itself  with 
ecjual  readiness  around  a  stick  or  a  hot  poker.  All  reactions  are,  however, 
purposive.  The  machinery  for  them  has  been  evolved  and  the  paths  laid 
down  in  the  spinal  cord  under  the  action  of  natural  selection,  so  that  they 
must  act,  at  any  rate  in  the  average  of  cases,  towards  the  well-being  of  the 
animal  as  a  whole.  Since  the  nerve  path  involved  in  any  reaction  includes  a 
number  of  synapses,  each  of  which  may  be  influenced  from  other  parts  of  the 
body  in  a  positive  or  negative  direction,  an  absolute  uniformity  of  response 
cannot  be  predicated  for  any  one  reaction.  There  will  be  changes  in  the 
facility  with  which  it  is  evoked  and  changes  in  its  extent,  and  these  will 
become  the  more  operative  the  greater  the  complexity  of  the  arc,  and  the 
larger  the  number  of  other  impulses  to  which  it  may  be  subject.  The 
fatality  of  response  is  therefore  only  shown  at  its  best  in  the  very  simplest 
of  reflexes,  or  the  most  lowly  organised  nervous  systems. 

The  purposive  character  of  the  reflexes  obtained  from  the  spinal  frog  has  some- 
times led  writers,  especially  in  pre-Darwinian  days,  to  endow  the  spinal  cord  with  a 
guiding  intelligence.  At  the  present  time  we  recognise  that  every  reaction  of  a  living 
being  must  be  purposive,  in  the  sense  of  being  adapted  to  the  preservation  of  the  species, 
if  the  latter  is  to  survive  in  the  struggle  for  existence.  The  question  as  to  whether 
we  are  justified  in  predicating  the  existence  of  even  a  germ  of  consciousness  or  volition 
in  the  spinal  animal  must  be  decided  in  the  negative.  "  Associative  memory  would 
seem  to  be  a  postulate  for  the  very  existence  of  perception.  Where  even  simplest 
ideas  are  not,  there  cannot  be  consciousness.  Animal  movements  that  are  appropriate 
not  only  for  an  immediate  but  also  for  a  remote  end  indicate  associative  memory. 


THE  MECHANISM  OF  CO-ORDINATED  MOVEMENTS        345 

The  approach  of  a  dog  in  answer  to  the  calling  of  its  name,  the  return  of  an  animal 
when  hungry  to  the  place  where  it  has  been  wont  to  receive  food,  such  movements 
may  be  taken  as  indicative  of  consciousness  since  they  indicate  the  working  of  associative 
memory.  Examined  by  this  criterion  all  purelj^  spinal  reactions  fail  to  evince  features 
of  consciousness  "  (Sherrington). 

THE  PART  PLAYED  BY  AFFERENT  IMPRESSIONS  IN  THE  CO- 
ORDINATION OF  MUSCULAR  MOVEMENTS.  Every  reflex  act  is  initiated 
in  the  first  place  by  some  form  of  sensory  stimulus.  In  the  carrpng  out  of 
the  muscular  contractions  and  the  resultant  movements  of  the  hmbs,  other 
impulses  are  set  up  in  the  structures  which  subserve  deep  sensibility,  in- 
cluding those  of  muscles,  which  in  their  turn  aftect  the  excitability  and  the 
activity  of  the  motor  neurons.  These  secondary  afferent  impulses  are  im- 
portant whether  the  movements  be  aroused  by  immediate  sensory  stimulation 
of  the  surface  of  the  body,  or  through  the  higher  parts  of  the  brain,  as  in 
volitional  movements. 

Their  significance  is  shown  by  the  marked  disorders  of  movement  pro- 
duced in  a  limb  by  section  of  some  or  all  of  its  afterent  nerves.  Thus  if 
all  the  posterior  roots  supplying  one  hind  limb  of  the  frog  be  divided  the 
posture  of  the  desensitised  limb  is  abnormal,  whether  the  frog  be  suspended 
or  be  in  a  sitting  posture.  Such  a  frog  generally  swims  with  the  desensitised 
hmb  in  permanent  extension.  The  complete  absence  of  muscular  tone  under 
these  circumstances  has  already  been  mentioned.  When  a  contraction  of 
the  cjuadriceps  extensor  is  induced  b}^  a  single  shock  applied  to  the  intact 
motor  nerve,  the  curve  obtained  shows  a  relaxation  Hne  much  slower  and 
more  prolonged  than  when  the  cut  nerve  is  similarly  excited.  In  the  latter 
case,  or  when  the  posterior  roots  alone  are  divided,  the  lever  at  the  end  of  re- 
laxation dips  below  the  base  hne  with  an  inertia  fling,  which  is  never  present 
while  the  nerve  is  intact.  The  contraction  of  the  muscle,  when  its  afterent 
path  is  intact,  seems  to  develop  reflexly  in  the  muscle  itself  a  condition  of 
tone  which  damps  the  inertia  swing  of  the  contraction.  In  the  dog,  after 
section  of  the  afferent  nerves  of  one  hind  hmb,  this  limb  is  not  at  first  used 
for  walking  ;  it  is  kept  more  or  less  flexed  at  hip  and  knee,  and  later,  when 
it  is  employed  in  walking,  it  is  lifted  too  high  with  each  step.  After  divasion 
of  the  afferent  fibres  of  both  limbs  these  appear  as  if  they  were  affected 
with  motor  paralysis.  At  first,  during  walking,  the  fore  limbs  simply  drag 
the  hind  limbs  after  them,  though  later,  as  the  hind  limbs  are  drawn  along, 
they  make  alternate  movements  and  may  ultimately  afford  a  certain  amount 
of  support  to  the  body. 

Still  more  striking  effects  are  observed  in  complete  apa?sthesia  of  the  fore 
limb  in  monkey  or  man.  The  Hmb  is  permanently  paralysed  ;  it  is  never  used 
in  climbing,  or  in  the  taking  of  food.  That  the  peripheral  motor  mechanism 
is  intact  is  shown  by  the  fact  that  stimulation  of  the  appropriate  area  of  the 
cerebral  cortex  in  such  animals  elicits  at  once  a  perfectly  normal  movement 
of  the  hand  or  limb.  It  seems,  however,  impossible  for  the  cortex  to  initiate 
such  movements  in  the  absence  of  all  aff"erent  impulses  arriving  from  the  limb. 
Similar  paralysis  was  observed  by  Chas.  Bell  in  the  upper  lip  of  the  ass  after 


346  PHYSIOLOGY 

section  of  the  corresponding  branches  of  both  fifth  nerves,  and  was  interpreted 
by  him  as  indicating  a  possible  motor  function  for  these  nerves. 

In  these  phenomena  of  sensory  paralysis  we  are  deahng  with  the  effects 
produced  by  the  deprivation  of  two  distinct  classes  of  afferent  impressions, 
viz.  those  from  the  skin,  and  those  from  the  deep  structures  and  muscles. 
The  phenomena  due  to  these  two  factors  may  be  studied  separately  If  in  the 
monkey  all  the  afferent  brachial  roots  except  the  last  cervical,  which  supplies 
cutaneous  sensations  to  the  whole  hand,  be  divided,  the  monkey  uses  the 
arm  and  hand  both  in  chmbing  and  in  taking  food.  A  marked  ataxy  of  the 
movement  is,  however,  observed.  Whereas  the  normal  monkey,  in  taking 
grains  of  rice  out  of  the  observer's  hand,  exhibits  perfect  precision  of  move- 
ment so  that  he  rarely  touches  the  hand  on  which  the  grains  are  lying, 
the  monkey  with  only  cutaneous  sensibility  remaining  grasps  clumsily  with 
the  whole  hand,  and  the  arm  sways  as  it  is  put  out,  often  missing  the  object 
aimed  at  altogether.  Cutaneous  insensibihty  of  the  hind  limb  causes  very 
httle  disturbance  of  locomotion,  the  alternate  movements  of  which  seem  to  be 
started  by  the  stretching  of  the  structures  at  the  front  of  the  thigh.  On  the 
other  hand,  a  patient  affected  with  such  a  loss  may  be  the  subject  of  '  static 
ataxy,'  i.e.  he  is  unable  to  stand  with  his  feet  together  and  his  eyes  shut. 
The  afferent  impressions  from  the  skin  of  the  feet  appear  therefore  to  be  neces- 
sary for  the  maintenance  of  static  equiUbrium. 

In  the  carrying  out  of  co-ordinated  movements,  such  as  those  of  loco- 
motion, the  impressions  from  the  muscles  play  a  more  important  part. 
Division  of  the  afferent  nerves  from  the  muscles  gives  rise  to  a  condition  of 
tonelessness,  and  the  passive  mobihty  of  the  joints  is  greater  than  usual,  so 
that  the  hip  with  the  Hmb  extended  at  the  knee  may  be  flexed  to  an 
abnormal  extent.  The  effect  of  this  loss  of  tone  is  more  apparent  in  the  case 
of  certain  muscles.  The  disturbance  of  co-ordination  resulting  from  the 
cutting  off  of  afferent  muscular  impressions  is  well  seen  in  cases  of  tabes 
dorsahs,  or  locomotor  ataxy,  in  man,  and  to  a  slighter  extent  in  cases  of 
peripheral  neuritis  affecting  chiefly  the  sensory  nerves  of  muscles.  The 
ataxic  gait  of  such  patient  is  characteristic.  There  is  no  loss  of  power  in 
the  muscles,  but  there  is  loss  of  control.  The  patient  is  unaware  of  the 
position  of  his  Hmbs  and  has  to  guide  his  walk  by  visual  impressions  ;  even 
then  the  movements  are  inco-ordinated.  The  contraction  of  every  muscle 
is  exaggerated,  so  that  in  walking  the  leg  is  first  raised  too  high  and  then  is 
brought  down  on  to  the  ground  with  a  stamp.  As  the  disease  progresses  the 
loss  of  control  becomes  more  and  more  pronounced,  so  that  attempts  to  walk 
simply  give  rise  to  a  profusion  of  disordered  movements,  the  legs  being  thrown 
in  all  directions  with  the  patient's  efforts,  but  with  no  effective  result.  The 
centres  are  no  longer  informed  of  the  degree  to  which  each  muscle  is  con- 
tracted, and  the  impressions  are  wanting  which  should  cut  short  the  con- 
traction of  a  muscle  when  it  has  attained  its  optimum,  and  which  should 
inhibit  the  antagonists  during  the  contraction  and  induce  activity  of  the 
antagonists  in  successive  alternation  to  those  of  the  other  muscles.  In  such 
a  patient  therefore  walking  finally  becomes  impossible,   and,  with  well- 


THE  MECHANISM  OF  CO-ORDINATED  MOVEMENTS       347 

nourished  muscles  and  a  motor  path  which  is  intact,  he  is  condemned  to  pass 
the  rest  of  his  days  in  bed. 

THE  EFFECT  OF  POISONS  ON  THE  SPINAL  CORD 
The  reflex  functions  of  the  spinal  cord  may  be  abolished  by  the  same 
drugs,  such  as  ether,  chloral,    &c.,  which  abolish  conductivity  in  a  nerve 
fibre.    The  central  effect  of  these  drugs  is  obtained  with  much  smaller  con- 

BODY     , 

prostnotonic 

NECK  . 
-    turning 


BODY.    ^ 

opisthof-onic 


NECK 

retraction 


FACE  \ 


Fig.  173.     Diagram  by  Sherrington  to  show  influence  of  tetanus  toxin  on  the 
response  to  excitation  of  the  motor  area  of  the  cortex  in  the  monkey. 
A,  normal  animal.     B,  after  poisoning  with  tetanus,     f  and/  =  flexion  of  leg 
and  arm  respectively,     e  and  e  signify  extension.      <  signifies  opening  of  mouth  ; 
=  signifies  closing  of  mouth. 


centrations  than  is  the  case  with  the  peripheral  nerves  and  is  the  cause  of 
their  anaesthetic  effect. 

More  interesting  from  the  point  of  view  of  the  physiologist  is  the  action 
of  such  a  drug  as  strychnine,  or  the  somewhat  similar  action  of  the  toxin 
formed  by  the  tetanus  bacillus.  If  a  small  dose  of  strychnine  be  injected 
into  a  spinal  frog,  after  a  short  period  of  heightened  irritability  the  slightest 
stimulus  applied  to  the  surface  will  cause  spasms,  which  may  affect  every 


348  PHYSIOLOGY 

muscle  iu  the  body.  Pinching  the  foot,  instead  of  causing  it  to  be  drawn  up 
now  causes  the  legs,  arms  and  back  to  be  rigidly  extended.  The  extension 
is  not  a  co-ordinated  act,  but  is  associated  with  strong  contraction  of  the 
flexors,  the  final  position  of  the  limbs  being  determined  by  the  preponderating 
strength  of  the  extensor  muscles.  The  real  meaning  of  this  condition  is  seen 
if,  in  a  spinal  mammal,  the  extensor  muscles  be  connected  with  a  lever  and 
the  flexor  muscles  cut.  On  exciting  the  flexor  reflex  by  pricking  the  foot, 
there  is  instantaneous  relaxation  of  the  extensor  muscles.  A  small  dose  of 
strychnine  is  now  given,  insufficient  to  cause  general  convulsions.  It  is  now 
fomid  that  on  pricking  the  foot  the  extensor  muscles  respond,  not  with 
inhibition,  but  with  a  contraction.  Strychnine  acts  by  abolishing  the  in- 
hibitory side  of  every  co-ordinated  act  and  converting  the  process  of 
inhibition  into  one  of  excitation.  Co-ordination  therefore  becomes  an  im- 
possibility, and  stimulation  of  any  spot  excites  contractions  not  only  of  the 
appropriate  muscles  but  also  of  the  antagonists  of  these  muscles,  the  direction 
of  the  resulting  movement  being  determined  simply  by  the  relative  strength 
of  the  two  sets  of  muscles. 

The  same  effect  is  produced  by  tetanus  toxin,  and,  since  the  action  of  this 
toxin  may  be  conflned  in  its  early  stages  to  one  limb,  it  is  possible  to  show 
the  abolition  of  the  inhibitor  side  of  the  reflexes  in  this  one  limb  while  the 
limb  of  the  other  side  reacts  normally  to  the  stimulus.  The  same  abolition  of 
inhibition  is  found  whether  the  response  be  excited  by  stimulation  of  the 
skin  or  by  voluntary  excitation  from  the  cortex  of  the  brain.  Thus  in  the 
monkey,  on  stimulating  the  cortex,  opening  of  the  mouth  may  be  excited 
from  all  the  spots  marked  "  <C  "  in  the  diagram,  closure  being  only  obtained 
from  those  spots  marked  "  =  "  (Fig.  173).  Under  the  influence  of  the 
tetanus  toxin  excitation  of  every  one  of  the  spots,  whether  "  <C  "  or  "  =," 
causes  closure  of  the  jaw.  It  is  impossible  for  a  patient  under  these  circum- 
stances to  open  his  mouth,  because  every  willed  impulse  for  opening  in- 
nervates at  the  same  time  the  stronger  masseter  muscles  and  effectively 
closes  the  mouth. 


SECTION  IX 

TROPHIC   FUNCTIONS   OF   THE   CORD 

The  reflexes  which  are  excited  by  painful  or  nocuous  stimuli  must  be 
regarded  as  prepotent  in  that  their  inhibitory  eft'ect  on  other  reflexes  is 
more  marked  than  that  produced  by  any  other  quality  of  stimulus.  In  the 
struggle  for  existence  the  reaction  to  nocuous  stiniuh  must  predominate  over 
those  due  to  any  other  kind,  since  it  is  essential  for  the  survival  of  the  animal 
that  the  stimulus  should  be  removed  or  avoided,  so  that  the  animal  should 
escape  from  its  injurious  effects. 

It  is  natural  therefore  that  after  complete  section  of  the  afferent  nerves 
from  any  part  of  the  surface  of  the  body  there  should  be  a  tendency  to 
trophic  disturbances,  such  as  the  formation  of  ulcers,  &c.  Such  ulceration  is 
frequently  observed  in  patients  suffering  from  spinal  disease.  After  section 
of  the  first  division  of  the  fifth  nerve  ulceration  of  the  cornea  is  often  produced. 
These  effects  are,  however,  merely  due  to  the  absence  of  the  normal  protective 
reactions  of  the  part,  and  can  be  prevented  by  scrupulous  cleanhness  and 
protection  of  the  apsesthetic  part  from  all  possible  injuries.  There  are  other 
trophic  effects  caused  by  nerve  lesions  which  cannot  be  ascribed  to  the  mere 
absence  of  protective  reflexes.  Thus  inflammation  of  the  posterior  root 
ganglia  often  sets  up  herpes  zoster,  or  '  shingles,'  in  the  region  of  cutaneous 
distribution  of  the  corresponding  sensory  nerve.  Changes  in  the  skin  ('  glossy 
skin  ')  nails  and  hair  are  often  seen  after  irritative  injuries  of  nerves  to  the 
part.  Section  of  a  motor  nerve  causes  rapid  changes  in  the  skeletal  muscles 
supplied,  which  become  smaller  and  after  months  or  years  may  disappear 
altogether,  being  replaced  by  connective  tissue.  The  changes  in  the  excita- 
bility of  the  muscles  produced  under  these  circumstances  have  already  been 
described. 

It  seems  that  the  nutrition  of  a  tissue  is  determined  by  its  activity,  and 
this  in  turn  is  under  the  control  of  some  nerve  path.  Section  of  the  nerve 
path,  by  cutting  away  the  impulses  which  normally  maintain  the  activity  of 
the  part,  must  at  the  same  time  seriously  affect  its  nutrition.  Thus  the 
muscles  which,  though  striated,  are  not  so  immediately  under  the  control 
of  the  central  nervous  system,  such  as  the  sphincter  ani,  do  not  undergo 
degeneration  after  section  of  their  nerves,  or  after  extirpation  of  the  lower 
part  of  the  spinal  cord. 

On  the  other  hand,  it  is  only  during  post-foetal  life  that  the  activity  of 
the  skeletal  nuiscles  is  determined  by  the  motor  nerves  of  the  cord.     Thus 

349 


350  PHYSIOLOGY 

they  may  be  developed  normally  even  in  the  complete  absence  of  a  central 
nervous  system.  Whether  we  are  justified  in  assuming  the  existence  of 
trophic  nerves  exercising  an  influence  on  the  nutrition  of  the  part  they  supply, 
apart  from  any  influence  on  its  other  functions,  the  experimental  evidence 
before  us  is  not  sufiicient  to  decide  ;  nor  can  we  as  yet  give  a  physiological 
analysis  of  the  changes  in  nutrition  which  may  be  brought  about  in  hysterical 
patients  under  the  influence  of  emotion. 


SECTION  X 

THE   SPINAL  CORD    AS   A  CONDUCTOR 

The  nervous  system  is  built  up  of  chains  of  neurons  which  subserve  reactions 
of  varying  complexity.  The  complexity  increases  with  the  interference  of 
the  higher  parts  of  the  brain  in  the  reactions  and  becomes,  therefore,  more 
and  more  marked  as  we  ascend  the  animal  scale.  Whatever  the  course  taken 
by  the  impulses  in  the  central  nervous  system  they  must  all  finally  make  use 
of  the  motor  common  path,  represented  by  the  anterior  spinal  roots  and  by 
the  motor  roots  of  the  cranial  nerves. 

The  co-operation  in  any  co-ordinated  movement  of  widely  separated 
portions  of  the  central  nervous  system  necessitates  the  existence  of  long 
paths,  i.e.  the  axons  of  certain  nerve-cells  must  extend  through  a  considerable 
distance  in  the  central  nervous  system  before  they  arrive  at  the  next  relay 
in  the  chain  of  which  they  form  part.  During  this  course  the  axons  run  in 
the  white  matter  of  the  central  nervous  system,  and  are  smTounded  by 
medullary  sheaths.  The  white  matter  of  the  cord  consists  almost  exclusively 
of  medullated  nerve  fibres  running  for  the  most  part  longitudinally.  These 
are  of  various  sizes,  some  of  the  smaller  fibres  being  collaterals,  which  have 
been  given  off  from  the  larger  ones  and  which  will  shortly  turn  into  the  grey 
matter.  In  section  they  resemble  closely  the  fibres  of  an  ordinary  peripheral 
nerve,  but  differ  from  these  in  that  they  have  no  primitive  sheath  or  neuri- 
lemma. Each  consists  of  an  axis  cyHnder  surrounded  by  a  thick  sheath  of 
myelin,  the  whole  embedded  in  a  tube  formed  by  the  neuroglia. 

Of  these  fibres  part  belong  to  the  spinal  cord,  the  proprio-spinal  or 
internuncial  fibres,  which  we  have  studied  previously.  The  greater  number 
serve  to  establish  connection  between  the  grey  matter  of  the  cord  or  the 
afferent  roots  entering  the  cord,  and  the  dift'erent  levels  of  the  brain,  and  these 
fibres  may  carry  impulses  either  up  towards  the  brain  or  down  towards  the 
spinal  cord  ;  they  may  be  ascending  or  afferent,  so  far  as  the  brain  is  con- 
cerned, or  descending  and  eft'erent.  No  fibre  takes  an  isolated  course  on  its 
way  through  the  cord  ;  practically  every  one  sends  off  fine  branches  or 
collaterals,  which  run  into  the  grey  matter  at  various  levels,  there  making 
connection  or  having  synapses  with  the  local  reflex  mechanisms  contained  in 
each  segment. 

On  inspection  the  white  matter  is  seen  to  be  divided  by  the  anterior 
and  posterior  fissures  of  the  cord  into  two  symmetrical  halves,  and  the 
nerve-roots  divide  each  half  into  anterior  or  ventral,  lateral,  and  posterior 

351 


352  PHYSIOLOGY 

or  dorsal  columns.  On  account  of  the  scattered  distribution  of  the  anterior 
root  fibres  over  a  considerable  area  of  the  surface  of  the  cord,  the  division 
between  the  anterior  and  the  lateral  columns  is  ill  defined,  and  the  whole 
region  is  often  defined  as  the  antero-lateral  column.  In  the  cervical  and 
upper  dorsal  region  of  the  cord  slight  grooves  on  the  surface  of  the  cord 
indicate  a  division  of  the  anterior  column  into  the  antero-median  and  antero- 
lateral columns,  and  of  the  posterior  column  into  the  postero-median  and 
postero-lateral  columns.  These  two  posterior  columns  are  often  designated 
as  the  columns  of  Goll  and  Burdach.  In  order  to  determine  the  origin, 
course,  and  destination  of  the  fibres  which  make  up  these  white  columns  we 
must  have  recourse  to  the  indirect  methods  of  development  and  of  degenera- 
tion which  were  described  on  p.  319.  By  these  means  we  may  divide 
the  white  matter  into  ascending  and  descending  tracts.  An  '  ascending ' 
tract  means,  not  that  the  direction  of  conduction  of  the  impulse  is  necessarily 
in  the  upward  direction,  i.e.  from  spinal  cord  to  brain,  but  that  the  nerve-cell 
which  gives  off  the  fibres  sends  its  axons  towards  the  brain,  while  a  descending 
fibre  in  the  cord  is  the  axon  of  a  nerve- cell  situated  in  the  upper  part  of  the 
cord,  or  in  some  part  of  the  brain.  If  the  assumption  which  we  have  made 
as  to  the  normal  direction  of  conduction  in  axons  and  dendrites  be  correct, 
an  ascending  fibre  will  also  conduct  impulses  in  an  ascending  direction. 
After  section  of  the  cord,  say  in  the  mid-dorsal  region,  transverse  sections 
of  the  cervical  and  lumbar  regions  of  the  cord,  taken  at  the  appropriate 
period  after  the  lesion  has  been  inflicted,  show  patches  of  degenerated  fibres 
in  the  white  matter.  The  fibres  which  are  degenerated  above  the  section 
represent  the  ascending  tracts,  whereas  those  which  degenerate  below  the 
section,  i.e.  in  the  lumbar  region,  are  the  descending  tracts  of  the  cord  {cp. 
Figs.  174  and  175).    In  this  way  the  following  tracts  have  been  distinguished  : 

A.  DESCENDING  TRACTS 
(1)  PYRAMIDAL  TRACTS.  If  the  spinal  cord  be  divided  in  the  upper 
cervical  region,  degeneration  of  two  distinct  tracts  on  each  side,  in  the  an- 
terior and  postero-lateral  columns,  is  produced.  These  are  the  anterior  or 
direct  and  the  crossed  pyramidal  tracts.  The  fibres  composing  these  tracts 
are  derived  from  large  nerve-cells  in  the  motor  area  of  the  cerebral  cortex, 
and  therefore  degenerate  if  the  motor  area  of  the  cortex  is  destroyed.  The 
pyramidal  tracts  are  derived  from  the  cerebral  cortex  of  the  opposite  side, 
having  crossed  the  middle  hne  at  the  lower  level  of  the  medulla  oblongata  in 
the  pyramidal  decussation.  The  anterior  pyramids  represent  a  certain 
number  of  fibres  which  have  not  crossed  with  the  others,  but  continue  the 
course  of  medullary  pyramids  for  a  time,  crossing  gradually  by  the  anterior 
commissure  on  their  way  down  the  cord,  so  that,  as  a  rule,  they  come  to  an 
end  in  the  mid-dorsal  region,  all  the  fibres  having  passed  into  the  lateral 
columns  of  the  opposite  side.  A  few  fibres  of  the  pyramids  on  their  way  from 
the  cerebral  cortex  pass  into  the  lateral  columns  of  the  same  side  ;  these  are 
the  uncrossed  pyramidal  fibres.  The  greater  number  of  the  fibres,  however, 
finally  reach  the  crossed  pyramidal  tracts,  in  which  they  can  be  traced  as  far 


THE  SPINAL  CORD  AS  A  CONDUCTOR 


353 


as  the  lower  end  of  the  cord.  They  end  in  the  spinal  cord  by  turning  into  the 
grey  matter  where  they  break  up  into  a  fine  bunch  of  fibrils  in  close  con- 
nection wath  the  motor  cells  of  the  anterior  horn,  or,  according  to  Schafer, 
with  the  cells  of  the  posterior  horn. 

On  their  way  down  the  cord  they  give  off  fine  side  branches  or  collaterals, 
which  run  into  the  grey  matter,  thus  establishing  connections  between  one 
cortical  cell  and  the  anterior  cornual  cells  of  several  different  segments  of 
the  spinal  cord.  These  fibres  carry  voluntary  motor  impulses  from  the 
cerebral  cortex  to  the  reflex  motor  mechanisms  of  the  cord.  Their  destiuc- 
tion  by  disease,  or  otherwise,  causes  the  abolition  of  voluntary  control  over 
the  muscles,   without,  however, 

interfering  with  the  reflex  motor  ^^     '^     -^v  .^■<^^\\\^^fr,J^- 

functions  of  the  cord,  which,  as  a 
matter  of  fact,  are  increased  in 
cases  where  these  tracts  have  un- 
dergone degeneration. 

(2)  RUBRO-SPINAL  OR 
PREPY  RAMI  DAL  TRACT  (also 
called  Monakow's  Bundle).  This 
is  a  fairly  compact  group  of 
fibres  which  degenerate  down- 
wards after  section  of  the  cord. 
It  is  situated,  in  cross-section, 
ventral  to  the  pyramidal  tracts. 
Its  fibres  can  be  traced  up  to 
the  cells  in  the  red  nucleus,  a 
mass  of  grey  matter  in  the  mid- 
brain lying  ventrally  to  the 
nucleus  of  the  third  nerve. 

(3)  V  E  S  T  I  B  U  L  0-S  P  I  N  A L 
TRACT.  This  consists  of  scat- 
tered fibres  in  the  antero-lateral 
column,  which  degenerate  in  the 
downward  direction.  They  were  formerly  supposed  to  be  derived  from 
the  cerebellum  of  the  same  side,  but  it  has  been  shown  that  they  are 
in  all  probability  derived  from  Deiters'  nucleus  in  the  medulla— an 
important  transmitting  station  between  the  cerebellum  and  cord. 

(4)  OLIVO-SPINAL  AND  THALAMICO-SPINAL  TRACTS  (Bundle  of 
Helweg).  This  tract  is  also  situated  in  the  antero-lateral  colunm,  opposite 
the  head  of  the  anterior  horn.  It  consists  mainly  of  fibres  which  pass  from 
the  thalanuis  (the  fore  brain)  through  the  inferior  olive  of  the  medulla  down- 
wards in  the  cord  as  far  as  the  lower  cervical  region. 

(5)  COMMA  TRACT.  This  tract  lies  in  the  posterior  columns  at  the 
junction  of  the  postero-median  and  postero-lateral  portions.  It  consists 
for  the  most  part  of  the  descending  branches  of  the  aft'erent  dorsal  nerve- 
roots  which  enter  the  cord.     These  divide  as  they  enter  the  cord,  and  their 

12 


Fig.  174.  Diagram  (/row  Schafer)  showing  the 
ascending  (right  side)  and  the  descending  (left 
side)  tracts  in  the  spinal  cord. 
1,  crossed  pyramidal;  2,  direct  pyramidal; 
3.  antero-lateral  descending :  3«,  spino-olivary 
descending  (bundle  of  Helweg) ;  i,  pre-pyramidal 
(rubro-spinal) ,  .5,  comma;  0,  postero-mesial ; 
7.  postero-lateral;  8.  Lissauer's  tract;  9,  dorsal 
(ascending)  cerebellar  ;  10,  antero-lateral  ascend- 
ing ;  s/w,  septo-marginal;  s;j/,  dorsal  root  zone; 
n,  anterior  horn-cells ;  /.  intermedio-lateral  horn; 
/},  cells  of  posterior  horn ;  d,  Clarke's  column. 
The  fine  dots  represent  the  situation  of  the 
'internuncial"  or  '  endogenous  '  fibres  of  the  s])inal 
cord. 


354  PHYSIOLOGY 

descending  branches  pass  down  for  two  or  three  segments  in  the  comma  tract 
before  turning  into  the  grey  matter.  The  tract,  however,  contains  fibres  of 
other  origin,  some  of  which  begin  and  end  in  the  spinal  cord  itself. 

(6)  TRACT  OF  MARIE.  This,  also  in  the  anterior  column,  contains 
both  descending  and  ascending  fibres  and  is  largely  a  continuation  of  the 
posterior  longitudinal  bundle,  the  connections  of  which  we  shall  have  to 
study  later  on.  A  small  tract  of  fibres,  which  degenerate  in  the  descending 
direction,  is  also  found  in  the  posterior  part  of  the  cord  adjoining  the  posterior 
longitudinal  fissure. 

(7)  SEPTO-MARGINAL  BUNDLE.  This  is  largely  proprio-spinal,  but 
may  contain  fibres  coming  from  the  mid-brain. 

B.      ASCENDING  TRACTS 

These  may  be  divided  according  as  they  are  situated  in  the  posterior,  the 
lateral,  or  the  anterior  columns. 

[a)  THE  POSTERIOR  COLUMNS.  Almost  the  whole  of  the  fibres  making 
up  these  columns  are  exogenous,  being  axons  of  cells  in  the  posterior  root 
gangha.  They  can  be  divided  into  long,  medium,  and  short  fibres,  all  of 
which,  on  their  way  up,  give  off  collaterals,  which  pass  into  the  grey  matter 
and  ramify  round  nerve-cells,  especially  in  the  posterior  horns  {cp.  Fig.  160). 
The  longest  fibres  pass  to  the  upper  end  of  the  cord,  where  they  end  in  the 
posterior  column  nuclei,  the  nucleus  gracihs  and  the  nucleus  cuneatus  of  the 
medulla.  These  fibres  remain  entirely  on  the  side  of  the  cord  on  which  they 
have  entered.  As  they  pass  up  they  are  displaced  towards  the  middle  line 
by  each  incoming  and  higher  placed  root.  Thus  in  the  cervical  region,  and 
indeed  from  the  fifth  dorsal  segment  upwards,  two  columns  can  be  dis- 
tinguished in  the  posterior  part  of  the  cord,  viz.  the  postero-median  and 
postero-lateral  columns,  the  division  between  which  is  indicated  by  a  small 
groove  on  the  surface.  The  postero-median  column  contains  from  within 
outwards  the  fibres  from  the  sacral  region,  those  from  the  lumbar  region, 
and  those  from  the  inferior  dorsal  region.  The  postero-lateral  column,  or 
column  of  Burdach,  contains  mesially  the  four  upper  dorsal  root  fibres  and 
more  laterally  the  fibres  from  the  cervical  nerves. 

(h)  THE  LATERAL  COLUMNS.  In  these  columns  are  found  the  two 
cerebellar  tracts,  as  well  as  scattered  fibres  passing  to  the  fore-  and  mid- 
brain. 

(1)  The  Direct  or  Dorsal  Cerebellar  Tract  arises  from  the  cells 
of  Clarke's  column  on  its  own  side.  It  consists  of  large  fibres,  which  pass 
through  the  grey  matter  to  the  lateral  columns  of  the  same  side,  and  ascend 
in  the  cord  immediately  ventral  to  the  incoming  posterior  root  fibres,  and 
external  to  the  crossed  pyramidal  tract.  In  the  medulla  they  are  joined 
by  a  bundle  of  fibres  from  the  opposite  inferior  olive  and  pass  with  the  resti- 
form  body  into  the  cerebellum,  where  they  terminate  in  the  superior  vermis 
of  this  organ. 

(2)  The  Ventral  or  Anterior  Cerebellar  Tract,  often  called  the 
tract  of  Gowers,  ariges  iii  cells  scattered  through  the  grey  matter,  chiefly  of 


THE  SPINAL  CORD  AS  A  CONDUCTOR 


355 


III 


II 


IV 


VII 


VIII 


Flu.  175.  Diagram  of  sections  of  the  spinal  cord  of  the  monkey  showing  the  position  of 
degeneratecl  tracts  of  nerve  fibres  after  specific  lesions  of  the  cord  itself,  the  afferent 
nerve-roots,  and  of  the  motor  region  of  the  cerebral  cortex.  (Schafer.  )  (The  degenera- 
tions are  shown  bv  the  method  of  ^larchi.)  The  left  side  of  the  cord  is  at  the  reader's 
left  hand. 

I.  Degenerations  resulting  from  extirpation  of  the  motor  area  of  the  cortex  of  the 
left  cerebral  hemisi)here. 

II.  Degenerations  produced  bj-  section  of  the  posterior  longitudinal  bundles  in  the 
upper  part  of  the  medulla  oblongata. 

Ill  and  IV.  Result  of  section  of  posterior  roots  of  the  first,  second,  and  third  lumbar 
nerves  on  the  right  side.  Section  III  is  from  the  segment  of  cord  between  the  last 
thoracic  and  first  lumbar  roots  ;   section  IV  from  the  same  cord  in  the  cervical  i-egion. 

V  to  VIII.  Degenerations  resulting  from  (right)  semi-section  of  the  cord  in 
the  upper  region  thoracic.  V  is  taken  a  short  distance  above  the  level  of  section  ; 
^'I  higher  up  the  cord  (cervical  region) ;  \'II  a  little  below  the  level  of  section  ; 
VIII  lumbar  region. 


356  PHYSIOLOGY 

the  posterior  horn  of  the  opposite  side,  though  a  few  fibres  are  derived  from 
cells  of  the  same  side.  The  tract  consists  of  fine  fibres  which  pass  upwards 
in  the  peripheral  margin  of  the  lateral  column,  extending  from  the  direct 
cerebellar  tract  behind  to  the  level  of  the  anterior  roots  in  front ;  it  passes 
upwards  through  the  cord,  the  medulla,  and  the  pons,  then  turns  round  to 
enter  the  cerebellum  through  the  superior  cerebellar  peduncle,  ending  chiefly 
in  the  ventral  portion  of  the  superior  vermis. 

(3)  The  Spino-thalamic  and  Spino-tectal  Tracts.  These  fibres  form 
a  scattered  bundle  lying  internally  to  the  anterior  cerebellar  tract,  and  are 
practically  part  of  Gowers'  tract.  They  may  be  traced  through  the  cord, 
medulla,  and  pons  and  end,  partly  in  the  anterior  corpora  quadrigemina  of 
both  sides,  but  to  a  greater  extent  in  the  optic  thalamus  of  the  same  side. 

(c)  ANTERIOR  COLUMNS.  A  number  of  scattered  fibres  pass  up  the 
anterior  columns,  mingled  with  the  descending  fibres  of  the  tract  of  Marie 
in  the  angle  of  the  anterior  fissure.  Others  pass  up  partly  to  end  in  the 
ohvary  body,  partly  to  run  on  with  the  mesial  fillet  towards  the  thalamic 
region. 

The  white  matter  of  the  cord  can  thus  be  regarded  as  made  up  of  short 
and  of  long  tracts,  which  maintain  direct  connection  between  the  following 
parts  of  the  central  nervous  system  : 

(1)  Different  levels  of  the  cord  itself  by  means  of  the  proprio-spinal 
fibres. 

(2)  Hind-brain  and  spinal  cord,  by  the  anterior  and  posterior  cerebellar 
tracts,  the  posterior  columns,  and  the  spino-ohvary  fibres  among  the  ascend- 
ing tracts,  and  the  vestibulo- spinal  and  olivo-spinal  among  the  descending 
tracts. 

(3)  The  mid-brain  and  cord  connections  are  represented  by  the  spino- 
tectal tracts  in  the  lateral  columns  as  a  direct  ascending  path,  and  by  the 
rubro-spinal  tract  which  furnishes  a  direct  efferent  connection  between 
mid-brain  and  cord. 

(4)  The  fore-brain,  viz.  the  thalamus,  receives  the  spino-thalamic  fibres, 
which,  though  scattered,  are  of  considerable  importance.  They  run  chiefly  in 
the  lateral  and  anterior  columns.  Its  efferent  fibres  cannot  be  traced  below 
the  lower  cervical  region. 

(5)  The  cerebral  cortex,  the  master  tissue  of  the  body,  receives  no  fibres 
directly  from  the  cord  or  periphery  of  the  body,  but  by  the  pyramidal  tracts 
is  able  to  influence  directly  the  activities  of  the  motor  mechanisms  at  every 
level  of  the  cord.  These  fibres,  so  far  as  is  known,  exist  only  in  mammals, 
and  show  a  great  increase  in  relative  extent  when  traced  from  lower  to  higher 
types.  While  in  the  rabbit  the  pyramidal  tract  is  hardly  perceptible,  in  the 
monkey  it  is  the  best  marked  of  all  the  tracts,  and  in  man  is  still  more  highly 
developed.  This  relative  increase,  which  is  probably  associated  with  the 
shunting  of  more  and  more  of  the  reactions  of  the  body  from  the  region  of 
the  unconditioned  reflex  to  that  of  the  educatable  reaction,  is  shown  not 
merely  by  the  tract  occupying  a  larger  proportion  of  the  transverse  area 
of  the  cord,  but  by  its  fibres  being  more  densely  set  within  that  area. 


THE  SPINAL  CORD  AS  A  CONDUCTOR  357 

THE  PATHS  OF  IMPULSES  IN  THE  CORD 
The  greater  part  of  the  white  matter  is  thus  concerned  in  transmitting 
impulses  to  nerve-cells  in  the  brain,  and  from  the  brain  towards  the  cord. 
The  complex  reactions  determined  by  these  impulses  are  in  many  cases  as 
unconscious  and  automatic  as  those  we  have  studied  in  the  spinal  cord,  even 
though  they  may  involve  the  activity  of  the  cerebral  cortex  itself.  Others, 
however,  influence  consciousness,  so  that  their  afferent  side  appears  in  con- 
sciousness as  sensations  of  various  Cj[ualities,  and  their  efferent  side  as  the 
result  of  volition,  i.e.  as  willed  or  emotional  movements. 

The  posterior  spinal  (sensory)  roots  at  their  entrance  into  the  cord  divide 
into  two  bundles.  The  smaller  of  the  two,  situated  more  laterally  and 
consisting  of  fine  fibres,  enters  opposite  the  tip  of  the  posterior  horn  and  turns 
up  at  once  in  Lissauer's  tract,  a  bundle  of  fine  longitudinal  fibres  close  to  the 
periphery  of  the  cord.  The  fibres  seem  to  pass  into  and  end  in  the  substance 
of  Rolando.  The  larger  median  bundle  of  coarse  fibres  passes  into  the  pos- 
tero-external  column.  Here  each  fibre  divides  into  a  descending  and  an 
ascending  branch,  the  former  running  in  the  comma  tract,  the  latter  in  the 
posterior  columns  up  as  far  as  the  gracile  and  cuneate  nuclei  of  the  medulla. 
Both  of  these  branches  give  off  collaterals  in  the  whole  of  their  course,  most 
numerous  near  the  point  of  entry  of  the  nerve.  These  collaterals  may  be 
divided  into  four  sets  according  to  their  destination  : 

(1)  Fibres  ending  round  cells  of  anterior  horn  on  same  side  or  crossing  by 
posterior  commissure  to  grey  matter  on  other  side. 

(2)  Fibres  ending  in  grey  matter  of  posterior  horns. 

(3)  Fibres  ending  round  cells  of  Clarke's  column. 

(4)  Fibres  to  lateral  horn. 

Since  the  motor  nerves  arise  from  the  anterior  horn-cells,  the  first  set, 
the  '  sensori-motor  '  collaterals,  represent  the  shortest  possible  spinal  reflex 
path.  The  second  group  may  also  represent  a  spinal  reflex  path  with  two 
relays  of  cells,  and  therefore  greater  choice  of  response  and  longer  reaction 
time.  The  third  set  puts  into  action  the  cerebellar  tracts  which  arise  from 
the  cells  of  Clarke's  column,  and  therefore  call  into  play  a  much  more  com- 
plicated mechanism,  the  limits  of  whose  action  it  would  be  difficult  to  define. 
The  collaterals  to  the  lateral  horn  probably  represent  the  afferent  tracts  of 
the  various  visceral  and  vaso-motor  reflexes  which  we  shall  study  later. 

We  find  no  special  tracts  devoted  to  those  impulses  which  afl'ect  con- 
sciousness as  sensations.  All  tracts  going  towards  the  cerebral  hemispheres 
are  interrupted  by  cell  relays,  in  the  medulla  or  cerebellum,  and  must  serve  as 
afferent  channels  for  unconscious  as  well  as  for  conscious  reactions.  The 
quality  of  an  afferent  impulse  can  only  be  defined  by  its  origin,  or  by  its 
effect  on  consciousness,  and  much  discussion  has  arisen  as  to  the  exact 
path  of  the  various  cutaneous  and  nniscular  sensations  in  the  cord. 

Tt  is  evident  that  an  impulse  may  travel  to  the  cortex  by  way  of  the  two 
cerebellar  tracts  through  the  cerebellum,  or  by  way  of  the  posterior  columns 
through  the  intermediation  of  the  bulbar  nuclei,  or  by  a  series  of  relays  from 


358 


PHYSIOLOGY 


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THE  SPINAL  CORD  A8  A  CONDUCTOR  359 

one  segment  of  the  cord  to  another  through  grey  and  white  matter  alter- 
nately. It  is  supposed  that  all  of  the  ascending  tracts  may  convey  afferent 
impulses  from  the  posterior  spinal  roots  to  the  brain,  although  evidence  as  to 
the  part  taken  by  each  tract  is  very  conflicting.  The  following  account 
represents  the  views  which  may  be  regarded  as  the  most  probable  (Page  May) 
(Fig.  176)  :  Pain  impulses,  on  entering  the  cord  by  the  posterior  roots,  cross 
to  the  other  side  at  once,  and  then  pass  up,  chiefly  in  the  antero-lateral  column, 
by  the  spino-thalamic  fibres,. as  far  as  the  optic  thalamus.  Sensations  of  heat 
and  cold  take  a  very  similar  course.  Hence  they  are  generally  affected  by 
lesions  of  the  cord  in  the  same  way  as  pain  sensations.  Impulses  of  touch 
and  pressure,  after  entering  the  cord,  pass  up  in  the  posterior  column  of 
the  same  side  for  four  or  five  segments,  then  cross  gradually  and  pass  up  in  the 
opposite  anterior  column.  Impulses  serving  muscular  sensibility,  including 
the  impulses  from  joints  and  tendons,  take  two  courses.  Those  which  do  not 
reach  consciousness,  and  are  involved  in  the  involuntary  guidance  of  mus- 
cular movements,  run  up  chiefly  in  the  anterior  and  posterior  cerebellar 
tracts  of  the  same  side.  Those  w^hich  furnish  the  material  for  conscious 
sensations  and  give  information  as  to  the  position  of  the  Umbs,  &c.,  are 
entirely  homolateral,  and  travel  up  in  the  posterior  columns  of  the  same  side 
of  the  cord.  All  impulses  which  reach  the  brain  cross  finally  to  the  optic 
thalamus  and  thence  to  the  cerebral  cortex  of  the  opposite  side. 

Hemisection  of  the  cord  on  one  side,  as  was  first  pointed  out  by  Brown 
Sequard,  causes  the  following  symptoms  : 

(1)  Paralysis  of  the  voluntary  motor  conductors  on  the  same  side. 

(2)  A  paralysis  also  of  the  vaso-motor  conductors  on  the  same  side,  and, 
as  a  consequence,  a  greater  afflux  of  blood,  and  a  higher  temperature.  There 
may  be  some  degree  of  hypersesthesia  on  this  side. 

(3)  There  is  anaesthesia  affecting  all  kinds  of  sensibihty,  excepting  the 
muscular  sense,  in  the  opposite  side  to  that  of  the  lesion,  owing  to  the  fact 
that  the  conductors  of  sensitive  impressions  from  the  trunk  and  limbs 
decussate  in  the  spinal  cord  ;  so  that  an  injury  in  the  cervical  region  of  that 
organ  in  the  right  side,  for  instance,  alters  or  destroys  the  conductors  from 
the  left  side  of  the  body. 

(4)  There  is  some  degree  of  anaesthesia  also  on  the  side  of  the  lesion,  in 
a  very  limited  zone,  above  the  hypera^sthetic  parts,  and  indicating  the  level 
of  the  lesion  in  the  cord.  This  anaesthesia  is  due  to  the  fact  that  the  con- 
ductors of  sensory  impressions,  reaching  the  cord  through  the  posterior  roots, 
at  the  level  or  a  little  below  the  seat  of  the  alteration,  have  to  pass  through 
the  altered  part  to  reach  the  other  side  of  the  cord. 

The  only  direct  unbroken  cortico-spinal  fibres  are  those  contained  in  the 
pyramidal  tracts.  Motor  impulses,  which  start  from  the  cerebral  cortex  on 
one  side,  pass  down  that  side  till  they  reach  the  lower  part  of  the  medulla. 
Here  the  greater  number  of  the  fibres  cross  over  in  the  pyramidal  decussation 
to  run  down  in  the  crossed  pyramidal  tract  on  the  other  side  of  the  cord. 
The  few  fibres  which  do  not  cross  over  in  the  pyramidal  decussation  are 
continued  as  the  direct  or  anterior  pyramidal  tract.    These,  however,  also 


560  PHYSIOLOGY 

cross  to  the  other  side  in  their  passage  down  the  cord  before  becoming  con- 
nected with  the  anterior  cornual  cells.  Hemisection  therefore  of  the  spinal 
cord  in  the  dorsal  region  will  produce  paralysis  of  motion  and  loss  of  or 
impaired  muscular  sensation  in  the  parts  supplied  by  the  nerves  on  the 
same  side  below  the  lesion. 

A  great  part  of  the  white  matter  of  the  cord  is  concerned  then  in  main- 
taining connection  between  the  brain  and  higher  parts  of  the  nervous  system 
and  the  periphery,  through  the  intermediation  of  the  cells  of  the  grey  matter 
of  the  cord.  Corresponding  to  this  function  we  find  a  gradual  increase  in 
the  number  of  fibres  in  the  white  matter  as  we  ascend  from  the  sacral  part 
of  the  cord  to  the  medulla,  the  white  matter  being  continually  reinforced  as 
it  ascends  the  cord  by  fibres  establishing  connection  with  the  ganglion- cells 
forming  the  nuclei  of  the  nerve-roots. 

Vaso-motor  impulses  to  the  limbs  travel  down  the  lateral  columns  of  the 
cord  on  the  same  side. 


THE  BRAIN 

SECTION  XI 
THE  STRUCTURE   OF   THE   BRAIN   STEM 

The  physiology  of  the  brain  falls  naturally  into  two  main  divisions,  namely, 
that  of  the  brain  stem,  including  the  medulla,  the  pons,  Sylvian  iter,  corpora 
quadrigemina  and  third  ventricle,  and  that  of  the  cerebral  hemispheres.  It 
is  usual,  in  treating  of  the  structure  of  the  brain  stem,  to  consider  it  as 
a  prolongation  forwards  of  the  spinal  cord  and  as  consisting,  like  this,  of  a 
central  tube  of  grey  matter  surrounded  by  a  tube  of  white  matter.  Like  the 
spinal  cord,  the  brain  stem  may  be  regarded  as  originating  primitively  by 
the  fusion  of  a  series  of  ganglia  presiding  over  the  local  reactions  of  their 
respective  somites.  The  modifications  in  this  segmental  arrangement,  which 
have  occurred  in  the  course  of  evolution,  have  been  so  profound  that  little 
trace  of  the  primitive  segmental  arrangement  is  to  be  observed.  At  the 
fore  end  of  the  body  have  been  developed  the  organs  of  special  sense,  which 
are  the  most  important  in  determining  the  reactions  of  the  animal  in  response 
to  present  or  approaching  changes  in  its  environment.  Indeed  the  whole 
course  of  evolution  is  conditioned  by  the  evolution  of  the  brain  stem  in  the 
first  place,  and  of  its  outgrowth,  the  cerebral  hemispheres,  in  the  second. 
Hence  we  cannot  expect  to  find  in  the  brain  stem  the  regularity  of  arrange- 
ment of  grey  and  white  matter  that  we  have  studied  in  the  cord.  The  typical 
division  of  the  grey  matter  into  cornua  becomes  altogether  lost.  While  some 
nerves  take  their  origin  from  or  terminate  in  the  central  tube  of  grey  matter, 
in  other  cases  the  collections  of  nerve  cells  and  fibres  forming  the  nuclei 
of  the  cranial  nerves  have  become  more  or  less  separated  from  the  central 
axis.  Moreover  the  central  grey  matter  is  by  itself  quite  inadequate  to  deal 
with  the  flood  of  afferent  impressions  entering  the  central  nervous  system 
through  the  organs  of  special  sense,  or  to  co-ordinate  these  with  one  another 
or  with  those  arriving  from  the  skin  and  lower  part  of  the  body.  Masses 
of  grey  matter,  which  have  no  representative  in  the  cord,  make  their  appear- 
ance, and  may  be  regarded  as  additional  sorting  stations  or  fields  of  conjunc- 
tion for  the  afferent  and  efferent  impulses  which  determine  the  nervous 
activities  of  the  animal. 

The  general  features  of  the  structure  of  the  bi'ain  will  he  best  umlerstood 
by  reference  to  the  mode  of  development  of  this  part  of  the  central  nervous 

3G1  12  ♦ 


362 


PHYSIOLOGY 


system.  At  the  front  end  of  the  body,  the  primitive  neural  tube,  formed  by 
the  invagination  and  growing  over  of  the  epiblast,  is  somewhat  enlarged 
and  is  marked  off  by  two  constrictions  into  the  three  primitive  cerebral 
vesicles,  which  are  named  respectively  the  fore-,  the  mid-,  and  the  hind-brain, 
or  the  prosencephalon,  the  mesencephalon,  and  the  rhombencephalon  (Fig. 
177).  At  their  first  formation  the  walls  of  these 
vesicles  are  composed  of  simple  epithehal  cells,  and 
show  no  trace  of  nervous  structure.  A  httle  later 
the  cells  forming  the  walls  present  a  difierentiation 
into  neuroblasts  and  spongioblasts,  the  former 
developing  into  nerve- cells,  while  the  latter  form 
the  neuroglial  supporting  tissues  of  the  brain  and 
probably  also  furnish  the  cells  of  the  sheath  of 
Schwann  to  the  outgrowing  cranial  nerves.  In 
some  places  the  wall  of  the  vesicles  remains  un- 
differentiated ;  no  nervous  tissues  develop  in  it,  and 

FiGf.  177.    Diagram  of  the  j^  forms  a  layer  of  epithehum  known  as  ependi/ma. 

cerebral  vesicles    oi   the  /                 ^                             _            .         . 

brain  of  a  chick  at  the  By  the  varying  growth  of  nervous  tissue  in  different 

second  day.    (Cadiat.)  ^^^^  ^f  ^^^  ^^jj  ^^^  .      -^^  structure  of  the  adult 

1,  2,  3,  cerebral  vesi-    ,       .     .    -,  ^        ^  ~J:         _^^        _,         .       ,      ,  •     t 

cles ;  0  optic  vesicles.        Dram  IS  brought  about  (Fig.  178).     Ihus  m  the  hmd- 

brain,  or  rhombencephalon,  the  roof  of  the  neural 

canal  posteriorly  fails  to  develop,  so  that  in  the  adult  brain  there  is  merely  a 

layer  of  epithehum  covering  the  expanded  central  canal,  here  known  as  the 

fourth    ventricle.     This    back   part    of  the    hind-brain  is  often  called  the 

myelencephalon,  the  anterior  portion  being'the  metencephalon.     The  floor 

of  the  myelencephalon  undergoes 

•^  ^  .  .  °  f/^(^  pin 

considerable  thickening  and 
forms  the  future  medulla  ob- 
longata. In  the  metencephalon, 
nervous  tissue  is  developed  all 
round  the  canal,  the  floor  of  the 
canal  forming  the  pons  Varohi, 
while  the  cerebellum  is  developed 

by  an   outgrowth  of  the  dorsal   ^  ^.,.,        .,        ,,.. 

,  ■      _       ^  .  Fig.  178.     Longitudinal  section  through  brain  oi 

wall.      In   the  region  of  the  con-  chick  of  ten  days.     (After  MiHALKOVicz.) 

Striction  between  the  hind-    and  olf    olfactory  lobes  ;     h,   cerebral   hemisphere  ; 

•j-u-1                      i  1      •   ii  Iv,  lateral  ventricle;   pin,  pineal  gland;    bo,  cor- 

mid-bram  known  as  the  isthmus,  p^^a  bigemina ;    cbl,  cerebellum  ;    oc,   optic   com- 

the  roof  or  dorsal  wall  forms  the  missure  ;    pit,  pituitary  body ;    pv,  pons  Varolii ; 

T     „              T         T           ,  mo,  medulla  oblongata ;    v^,  v*,  third  and  fourth 

superior  cerebellar  peduncles  at  ventricles. 

the  side,  and  between  them  a  thin 

layer  of  nervous  matter  known  as  the  valve  of  Vieussens,  or  superior  medul- 
lary velum.  The  cavity  of  the  third  vesicle  corresponds  in  the  adult  brain 
to  what  is  known  as  the  fourth  ventricle. 

The  mesencephalon,  or  second  cerebral  vesicle,  takes  a  relatively  small 
part  in  the  formation  of  the  adult  human  brain,  though  very  conspicuous 
in  many  of  the  lower  types  of  brain.     The  whole  of  its  wall  is  transformed 


THE  STRUCTUKE  OF  THE  BRAIX  STEM  363 

into  nervous  tissue,  the  roof  or  dorsal  wall  forming  the  corpora  quadrigeniina , 
while  the  two  crura  cerebri  are  developed  in  its  ventral  wall.  The  cavity  of 
the  second  cerebral  vesicle  is  retained  as  a  narrow  canal  known  as  the  aque- 
duct of  Sylvius,  and  connects  the  fourth  ventricle  with  the  third  ventricle. 

Very  soon  after  its  first  appearance  the  first  cerebral  vesicle  is  modified 
by  the  formation  of  lateral  expansions,  known  as  the  optic  vesicles,  which 
later  on  are  constricted  off  from  the  central  part  of  the  cavity  so  as  to  be 
connected  with  this  by  two  short  tubular  passages,  the  optic  stalks.  From 
the  optic  vessels  are  ultimately  developed  the  retinae  of  the  eyes.  By  the 
development  of  nerve-cells  in  the  optic  cup  the  ganglion-cell  layer  of  the 
retinae  is  produced,  and  from  these  cells  fibres  grow  back  along  the  optic 
stalk  and  make  connection  with  the  grey  matter  developed  in  the  lateral 
wall  of  the  fore-brain  and  w^ith  the  adjacent  parts  of  the  mid-brain,  viz.  the 
superior  corpora  quadrigemina.  The  large  masses  of  nervous  tissue  de- 
veloped in  the  lateral  walls  of  the  fore-brain  are  the  optic  thalami,  which 
represent  the  head  ganglia  of  the  brain  stem.  The  front  portion  of  the  first 
cerebral  vesicle  expands  in  a  forward  and  downward  direction,  and  from  the 
upper  and  lateral  aspects  of  the  outgrow^th  thus  formed  the  cerebral  hemi- 
spheres are  produced  as  two  hollow  pouches.  The  original  back  part  of  the 
fore-brain  is  sometimes  spoken  of  as  the  diencephalon,  while  the  anterior 
part  of  the  cerebral  hemisphere  growing  from  it  is  the  telencepha[lon.  The 
floor  or  ventral  wall  of  the  fore-brain  undergoes  moderate  thickening  to  form 
the  nervous  structures  which  occupy  the  '  interpeduncular  space  '  at  the 
base  of  the  brain,  viz.  the  posterior  perforated  spot,  the  corpora  mammillaria 
and  the  tuber  cinereum.  The  roof  of  the  first  cerebral  vesicle  remains  thin 
and  in  its  primitive  epithehal  condition,  like  the  roof  of  the  back  part  of  the 
fourth  ventricle. 

In  the  course  of  development  the  cerebral  hemisplieres  become  larger 
than  the  whole  of  the  rest  of  the  brain  put  together,  growing  backwards 
over,  the  latter  as  far  as  the  middle  of  the  cerebellum  (Fig.  l79).  Their 
dorsal  and  lateral  walls  become  much  thickened  and  consist  of  white  matter 
internally  and  grey  matter  externally.  The  part  of  the  hemisphere  which 
lies  over  the  first  cerebral  vesicle  is  undifferentiated  and  remains  as  a  simple 
epithelial  layer.  This  becomes  closely  applied  to  the  similar  layer  forming 
the  roof  of  the  third  ventricle,  from  which  it  is  separated  only  by  a  process 
of  the  pia  mater  carrying  numerous  blood-vessels  (the  velum  interpositum). 
Tn  the  adult  brain  the  cavities  of  the  cerebral  hemispheres  are  known  as  the 
lateral  ventricles,  the  remains  of  the  first  cerebral  vesicle  receiving  the  name 
of  the  third  ventricle.  The  lower  and  outer  part  of  the  hemispheres,  i.e. 
the  part  which  is  first  formed,  becomes  much  thickened  and  forms  the  corpus 
striatum,  which  is  closely  applied  to  the  front  and  outer  part  of  the  optic 
thalamus.  In  the  corpus  striatum  two  masses  of  grey  matter  are  developed, 
namely,  the  nucleus  caudatus  and  the  nucleus  lenticularis.  A  layer  of  nerve 
fibres  ascends  from  the  brain  stem  to  be  distributed  throughout  the  whole 
of  the  cerebral  hemispheres.  This  forms  a  sort  of  capsule  to  the  optic 
thalamus,  lying  between  this  body  and  the  corpus  striatum  beliind.  but  in 


364 


PHYSIOLOGY 


It  is  called  the 


front  piercing  the  corpus  striatum  between  its  two  nuclei, 
internal  capsule. 

The  development  of  the  different  parts  of  the  brain  stem  from  the 
three  cerebral  vesicles  and  their  gradual  subordination  and  overshadowing 
in  the  course  of  development  by  the  cerebral  hemispheres  is  well  shown  if  we 


Lamina  terminalis 

Optio  recess 

Optic  nerve 

Optic  commissure 

Hypophysis 

Anterior  commissure 
Foramen  of  Monro 
3rd  nerve 
Corpus  mammillare 
3rd  ventricle 
Cerebral  peduncle  /  / 

Pons  '  /  /  /  /  /  V     \r-w- 

suprapineal  recess  /  /  /  /  /  / ^\  ,,  ,  „       Cerebellum 

/  '  \  Medulla  oblongata 

Pineal  bodv  /  /  /  '  4th  ventricle 

I  ■'  Superior  medullary  velum 
Cerebral  aqueduct    Corpora  quadrigemina 

Fig.  179.     Median  section  of  an  adult  human  brain.     (J.Symington.) 


compare  the  brain  of  a  fish  with  that  of  a  reptile  and  again  with  that  of 
a  mammal  (Fi g .  1 80) .  Man's  position  in  the  scale  of  animal  life  is  determined 
not  by  increasing  complexity  of  the  structures  forming  his  brain  stem,  but  by 
the  gradual  subordination  of  these  to  the  latest  formed  cerebral  hemispheres, 
and  the  enormous  growth  of  his  capacity  to  adapt  himself  to  a  varying 
environment  consequent  on  the  increase  in  size  of  his  cerebral  hemispheres. 


THE  STRUCTURE  OF  THE  BRAIN  STEM 


365 


Ammocietes 


Telkustka 


Amphibia 


,CB 


CB 


Mammalia 


^  jy,       CO  /  P  i  1  R I A 


,*^ri^y(/^P 


Fig.  180.     Diagrammatic  view  of  the  brain  in  different  classes  of  vertebrates. 

(Gaskei.l.) 
tB,eercbelhnn;  ft.  pituitary  body  :  pn.  pinea  body;  c.str,  corpus  striatum  ; 
GHR,  right  ganglion  babenulje  ;  i,  olfactory  ;  n.  optic  nerves. 


366 


PHYSIOLOGY 


THE  HIND-BRAIN 
It  will  be  convenient  to  trace  first  the  modifications  undergone  by  the 
axial  part  of  the  nervous  system  in  the  brain,  and  then  to  deal  with  the 
new  masses  of  grey  matter  which  have  no  homologies  in  the  spinal  cord,  as 


Fig.  181.  Section  through  the  lower  border  of  the  medulla  oblongata,  at  the 
pyramidal  decussation.  (Bechterew.) 
fla,  anterior  fissure  ;  d,  decussation  of  the  pyramids  ;  F,  anterior  columns  ; 
Ca,  anterior  cornu  ;  cc,  central  canal ;  S,  lateral  columns  ;  fr,  formatio  reti- 
cularis ;  ce,  neck,  and  g,  head  of  the  posterior  cornu  ;  rpCl,  posterior  root  of 
first  cervical  nerve  ;  nc,  beginning  of  nucleus  cuneatus  ;  ng,  nucleus  gracilis  ; 
fP,  funiculus  gracilis  ;   H^,  funiculus  cuneatus  ;   sip,  posterior  fissure. 

well  as  the  long  tracts  of  white  matter  serving  to  connect  different  levels 
or  different  sides  of  the  brain. 

In  examining  successive  sections  from  the  spinal  cord  up  through  the 
medulla,  the  first  change  which  makes  its  appearance  is  due  to  the  decussa- 
tion of  the  pyramids  (Fig.  181).  Throughout  the  spinal  cord,  fibres  have 
been  crossing  from  one  side  to  the  other  through  the  anterior  white  com- 
missure, many  of  them  belonging  to  the  pyramidal  system.  But  at  the  lower 
border  of  the  medulla  we  see  a  large  mass  of  fibres  crossing  between  the 
anterior  columns  and  the  postero -lateral  columns,  at  first  cutting  off  the  head 
of  the  anterior  horn  and  later  on  breaking  this  up  altogether,  so  that  the 
only  definite  collection  of  grey  matter  left  in  this  situation  is  a  small  part 
of  the  lateral  column  of  grey  matter  known  as  the  lateral  nucleus.  In  this 
way  are  formed  the  big  anterior  columns  of  the  medulla,  which  are  known 
as  the  pyramids,  and  contain  all  the  fibres  that  in  the  cord  are  represented  by 
the  direct  and  crossed  pyramidal  tracts. 

The  next  change  is  due  to  the  ending  of  the  posterior  columns  (Fig.  182). 
These  are  the  central  ascending  branches  of  dorsal  nerve  roots,  having  there- 
fore an  origin  outside  the  cord.  On  their  way  up  the  cord  they  send  in 
collaterals  to  end  in  the  grey  matter  of  the  posterior  horn.  The  main  mass 
terminates  in  the  medulla,  just  above  the  pyramidal  decussation,  in  two 
collections  of  grey  matter — the  nucleus  gracilis  and  the  nucleus  cuneatus — 


THE  STRUCTURE  OF  THE  BRAIN  STEM 


367 


which  are  formed  by  a  great  hypertrophy  of  the  grey  matter  at  the  root 
of  the  posterior  horn.  The  effect  of  this  development  in  the  dorsal  region 
of  the  medulla  is  to  push  the  head  of  the  posterior  horn  outwards.  At  the 
same  time  this  mass  of  gelatinous  substance  becomes  enlarged,  so  that  in 
section  we  have  three  grey  masses  from  within  outwards,  the  nucleus  gracilis, 
the  nucleus  cuneatus,  and  the  nucleus  of  Rolando. 


Funiculus  gracili 
Funiculus  cuiicita'""' 


Sp.  root  of  5th  I)  — y^f 


Formatio  reticuliii  j 


Lower  end  of  oli\  m 
eminence 


nucleus 
■Cuneate  nucleus 

^ubst.  gel.  Rolandi 
Decussation  of  fillet 

Int.  access  olivary  n. 
>fcrve  XII. 


Fig.  182.     Transverse  section  through  medulla  of  foetus,  immediately  above  pj'ramidal 
decussation.     (Cunningham.)     Stained  by  Pal- Weigert  method. 

The  fibres  of  the  postero- median  column,  which  are  derived  chiefly  from 
the  lower  limb,  end  in  arborisations  round  the  cells  of  the  micleus  gracihs, 
while  those  of  the  postero- external  column,  or  column  of  Burdach,  of  which 
the  majority  is  formed  by  fibres  from  the  upper  limbs,  terminate  in  the 
grey  matter  of  the  nucleus  cuneatus.  The  cells  of  these  two  masses  of 
grey  matter  of  course  give  off  axons,  which  can  carry  on  the  impulses 
brought  to  them  by  the  fibres  of  the  posterior  columns.  These  axons  speedily 
leave  the  dorsal  aspect  of  the  medulla,  bending  round,  as  the  arcuate  fibres, 
to  the  deeper  parts  of  its  structure.  Thus  nothing  is  left  to  take  the  place  of 
the  posterior  columns  on  the  posterior  aspect  of  the  cord.  With  the  dis- 
appearance of  these  columns  and  the  development  of  the  pyramids  we  get  a 
practical  obliteration  of  the  anterior  fissure  and  a  displacement  of  the  central 
canal  towards  the  dorsal  surface.  A  little  higher  up  (Fig.  183)  the  canal 
opens  out  altogether,  forming  the  fourth  ventricle,  covered  on  its  dorsal 
surface  only  by  a  thin  layer  of  ependyma,  a  simple  epithelium  representing 
all  that  is  left  of  the  dorsal  wall  of  the  primitive  cerebral  vesicle.  The 
appearance  of  the  section  is  now  modified  by  two  structures.  In  the  first 
place,  a  new  mass  of  grey  matter,  consisting  of  a  thin  layer  shaped  like  a 
Hask  with  its  orifice  directed  inwards,  is  developed  in  the  lateral  part  of  the 
medulla,  between  the  pyramids  in  front  and  the  tubercle  of  Rolando  behind. 
This  is  the  olivary  body,  and  has  on  its  inner  and  dorsal  sides  two  little  grey 
masses  which  are  the  accessor//  olivary  bodies.     The  other  feature  is  the  new 


368 


PHYSIOLOGY 


relay  of  sensory  fibres  which  start  from  the  dorsal  nuclei,  the  nuclei  gracihs 
and  cuneatus.  These  fibres  run  outwards  and  forwards  from  the  nuclei 
right  round  the  medulla.  Some  fibres  pass  into  the  restiform  body  of  the 
same  side.  A  larger  number,  forming  the  superficial  arcuate  fibres,  pass 
superficially  to  the  ohve  to  join  the  restiform  body  of  the  opposite  side, 
while  others,  the  deep  arcuate  fibres,  pass  deeply  to  the  olives,  and  crossing 
in  the  median  raphe  turn  upwards  in  the  broken  mass  of  grey  and  white 


■Posterior  longitudinal  fasciculus 

Substantia  gelatinosa  Kolandi 
Spinal  root  of  fifth  nerve 
Xucleus  ambiguus 
t  erebello-olivary  fibres 
wgr  JJorsal  accessory  olivary  nucleus 
Vnterior  superficial  arcuate  fibres 
J  ilkt 

,r  M(  -,1  il  accessory  olivary  nucleus 
-'Inferior  olivary  nucleus 


—  Pyramid 


Arcuate  nucleus 


Anterior  superficial  arcuate  fibres 


Fig.  1 83.     Transverse  section  through  the  middle  of  the  olivary  region  of  the  human 
medulla.     (Cunningham.) 


matter  which  hes  between  the  olives  and  the  superficial  grey  matter  of  the 
fourth  ventricle.  This  decussation,  which  is  known  as  the  '  decussation 
of  the  fillet '  or  the  sensory  decussation,  takes  place  immediately  above  the 
level  of  the  decussation  of  the  pyramids.  In  its  upward  course  it  forms  a 
conspicuous  strand  of  fibres,  lying  close  to  the  mesial  plane  and  separated 
from  its  fellow  of  the  opposite  side  simply  by  the  median  raphe.  To  this 
collection  of  fibres  is  given  the  name  of  the  jillet  or  lemniscus.  It  is 
perhaps  the  most  important  of  the  afferent  tracts  of  the  brain  stem,  receiving 
as  it  does  continuations  of  the  posterior  columns  of  the  cord  as  well  as 
contributions  from  the  various  sensory  cranial  nerves.  It  may  be  traced 
forwards  as  far  as  the  thalamus  and  subthalamic  region,  where  its  fibres 
terminate.  The  region  corresponding  to  the  anterior  column  of  the  spinal 
coid  is  thus  invaded  in  the  medulla  by  two  great  longitudinal  tracts  of 
fibres    namely,  the  pyramids  and  the  tracts  of  the  fillet.     The  region  corre- 


THE  STRUCTURE  OF  THE  BRAIN  STEM 


369 


sponding  to  the  anterior  basis  bundle,  i.e.  that  part  of  the  anterior  colmnns 
occupied  chiefly  by  intra-spinal  fibres,  is  thus  pushed  further  backwards  and 
finally  comes  to  lie  immediately  beneath  the  grey  matter  of  the  floor  of  the 
fourth  ventricle.     Immediately  dorsally  to  the  fillet  is  to  be  seen  another 


Fibres 


Subdel.Bol.-V- 


FiG.  184.     Diagram  to  show  the  sources  of  the  fibres  making  up  the  reatiform  body. 
Ar.N,  arcuate  nucleus  ;    Ar  fibres,  arcuate  fibres  ;    Pyr,  pyramid ;  C.Sp. 
Tract,   direct   cerebellar  tract;   C.Ol    fibres,    cerebello-olivar}-    fibres;    Pl.B, 
posterior  longitudinal  bundle  ;   DN.  nucleus  of  Deiters  ;   NB,  nucleus  of  Bech- 
terew  ;   Ro.N,  roof  nuclei ;   Vest.  N,  vestibular  nerve. 

well-marked  bundle  of  longitudinal  fibres,  knowai  as  the  posterior  longi- 
tudinal bundle.  These  fibres,  which  serve  to  connect  the  nuclei  of  many  of 
the  cranial  nerves,  can  be  regarded  as  analogous  to  the  constituent  fibres  of 
the  anterior  basis  bundle  in  the  cord,  and  can  in  fact  be  traced  into  this  part 
of  the  anterior  columns  in  the  first  and  second  cervical  segments  of  the  cord. 

The  fourth  ventricle  is  covered  in  by  the  cerebellum,  which  is 
attached  to  the  axial  part  of  the  brain  by  three  peduncles,  the  inferior 
peduncles  or  restiform  bodies,  the  lateral  peduncles,  which  form  the  great 
mass   of    transverse  fibres   known    as    the  pons  Varolii,  and  the  superior 


370  PHYSIOLOGY 

peduncles,  which  run  forward  to  the  posterior  corpora  quadrigemina.  The 
restiform  bodies  can  be  regarded  as  the  direct  continuation  forwards  of  the 
lateral  columns  of  the  cord,  minus  the  pyramidal  tracts,  the  chief  remaining 
tract  therefore  being  the  posterior  or  direct  cerebellar  tract.  In  the  region 
of  the  dorsal  nuclei,  however,  it  receives  accession  of  fibres  from  the  gracile 
and  cmieate  nuclei  of  the  same  side  and,  through  the  superficial  arcuate 
fibres,  from  the  nuclei  of  the  opposite  side,  and  thus  passes  as  a  thick  white 
bundle  into  the  cerebellum.  Among  these  arcuate  fibres  are  also  a  number 
derived  from  the  olivary  body  of  the  opposite  side,  known  as  the  cerebello- 
ohvary  fibres.  On  its  way  it  is  joined  by  a  smaller  bundle,  the  '  internal 
restiform  body,'  which  conveys  fibres  from  the  vestibular  division  of  the 
eighth  nerve  and  also  serves  to  connect  Deiters'  nucleus  with  the  cerebellum. 
The  restiform  body  is  thus  made  up  of  the  following  fibres  (Fig.  184)  : 

(1)  The  direct. or  posterior  cerebellar  tract,  derived  from  the  cells  of 
Clarke's  column  on  the  same  side  of  the  cord. 

(2)  The  posterior  superficial  arcuate  fibres,  derived  from  the  gracile  and 
cuneate  nuclei  of  the  same  side. 

(3)  The  anterior  superficial  arcuate  fibres,  from  the  gracile  and  cuneate 
nuclei  of  the  opposite  side. 

(4)  The  cerebello-olivary  fibres. 

(5)  The  veatibulo-cerebellar  fibres. 

A  section  through  the  pons  shows  the  fourth  ventricle  widely  dilated, 
with  a  floor  formed  of  grey  matter  as  in  the  medulla.  The  chief  difference 
in  the  appearance  of  the  section  is  due  to  the  great  masses  of  transverse 
fibres  which  pass  into  the  pons  by  the  lateral  peduncles  of  the  cerebellum, 
cross  by  the  median  raphe,  anct  turn  either  upwards  or  downwards  on  the 
opposite  side  or  end  in  connection  with  the  nerve-cells  which  are  scattered 
throughout  the  white  fibres.  The  pyramids  can  still  be  seen  as  thick  longi- 
tudinal bundles  on  each  side  in  the  midst  of  the  transverse  fibres.  They  are 
considerably  larger  than  in  the  medulla  and  become  larger  as  we  trace  them 
up  towards  the  mid-brain,  owing  to  the  presence  of  a  number  of  fibres 
which  are  derived  from  the  cortex  cerebri  and  end  in  the  grey  matter  of  the 
pons.  The  tract  of  the  fillet  hes  on  each  side  of  the  middle  line  dorsally  to 
the  transverse  fibres.  A  little  to  the  outside  of  the  fillet  is  seen  a  special 
mass  of  grey  matter,  known  as  the  superior  olive.  The  nervous  mass  lying 
behind  the  transverse  fibres  of  the  pons,  between  them  and  the  grey  matter 
of  the  fioor  of  the  fourth  ventricle,  is  known  as  the  formatio  reticularis.  It 
is  divided  into  a  lateral  and  mesial  part  by  the  fibres  of  the  hypoglossal 
nerve.  In  the  lateral  portions  there  is  a  considerable  quantity  of  grey 
matter,  which  can  be  regarded  as  continuous  with  the  grey  matter  of  the 
lateral  horns  of  the  cord.  The  '  lateral  nucleus  '  is  simply  a  condensed  part 
of  this  grey  matter,  lying  between  the  olive  and  the  gelatinous  substance  of 
Rolando.  The  mesial  part  of  the  formatio  reticularis  is  almost  free  of  nerve- 
cells.  The  reticular  appearance  of  this  part  of  the  pons  is  due  to  the  inter- 
section of  fibres  which  run  longitudinally  and  transversely.  The  transverse 
fibres  are  a  continuation  of  the  deep  arcuate  fibres.     The  longitudinal  fibres 


THE  STRUCTUKE  OF  THE  BRAIN  STEM 


371 


in  the  outer  part  of  the  formatio  reticularis  are  the  representative  of  the 
lateral  columns  of  the  cord  after  the  removal  of  the  direct  cerebellar  and  the 
crossed  pyramidal  tracts.  They  include  therefore  the  antero-lateral  ascend- 
ing tract  (tract  of  Gowers)  and  a  number  of  other  fibres  corresponding  to  the 


Supr.  ccr.  pedunclf 


lit    ot  otli  II 


Valve  of  Vieussens 


Alotor  nucleu-.  ot  jtli  ii 
Hot  or  root  of  5tli  11  __  Jfp^'     ,  T^'  ■  •   •' 

Supr.  olive  --^^  _i^J>         I'     '        /'.^ 

Sensory  root  ..^ /  :  ■>       n>---^    ^         ,  ~    S/ f 

ofStlin.  7' ~~  -  yj^^^ :i-^~^//i  ' 


Sensory  iiuduiis  of  5tli  n.  — . 


r-      ^^i--Form. reticularis 


r  orpus 

irapczoides 


[iddic  pedum 
ot  cerebellum 


Fig.  185.     Transverse  section  through  middle  of  pons  Varolii  of  orang  on  level  of 
nuclei  of  fifth  nerve.     (Cunningham.) 


lateral  basis  bundle  in  the  cord.  In  the  mesial  part  of  the  formatio  reticu- 
laris the  longitudinal  tracts  are  the  tract  of  the  fillet  and  the  posterior  longi- 
tudinal bundle  on  each  side  of  the  middle  line.  In  the  upper  part  of  the  pons 
Varolii  a  well-marked  collection  of  transverse  fibres  are  to  be  seen  lying 
dorsally  to  the  tracts  of  the  fillet.  This  collection  is  called  the  corpus 
trapezoides  and  is  made  up  of  ascending  fibres  derived  from  the  nuclei  of  the 
cochlear  nerve,  the  auditory  part  of  the  eighth  nerve. 

A  little  further  forward  a  section  will  escape  the  cerebellum  altogether, 
being  bounded  ventrally  by  the  upper  or  anterior  part  of  the  pons  and 
dorsally  by  a  thin  mass  of  grey  matter,  the  valve  of  Vieussens  (Fig.  18()). 
On  each  side  of  the  valve  of  Vieussens  may  be  seen  the  superior  peduncles  of 
the  cerebellum.  As  these  peduncles  are  traced  upwards  they  sink  gradually 
deeper  into  the  pons  until  they  lie  on  the  outer  side  of  the  tegmental  region 
or  formatio  reticularis.     They  are  made  up  of  fibres  which  run  from  the 


372 


PHYSIOLOGY 


dentate  nucleus  of  grey  matter  in  the  cerebellum  to  the  mid-brain,  where 
they  decussate  below  the  Sylvian  iter  and  end  in  the  red  nucleus  and  in  the 
thalamus  of  the  opposite  side.  They  also  contain  the  continuation  upwards 
of  the  antero- lateral  ascending  tract,  which,  passing  up  in  the  superior 
peduncles,  bends  dorsally  round  the  fourth  nerve  and  then,  turning  back- 
wards, ends  in  the  superior  vermis  of  the  cerebellum.  In  a  section  through 
the  upper  part  of  the  pons  the  division  into  the  formatio  reticularis  or 


4th  ventricle 
Meseuc .  root  of  5th  n 


Postr.  long,  bundk 


Valve  of  Vieussens 

,"'''lo"r  of  4+h  ventricle 

'Supr  ceiebcUar 
peduncle 

'Lateral  fillet 


Form,  reticularis 
Nucleus  of  lateral  fllkt 


Commencing  de- 
cust;atinnof  supr. 
cerebellar  ped. 

Mesial  fillet 


Trinsverse 
fibres 


P  J  ramids 


Fig.  186.     Section  across  upper  part  of  pons  Varolii  of  the  orang.     (Cunningham.) 


tegmentum  and  the  part  made  up  of  transverse  and  longitudinal  fibres,  the 
pedal  portion,  is  well  marked  {v.  Fig.  186).  The  fourth  ventricle  has  now 
become  constricted  to  a  narrow  canal  triangular  in  section  and  closed  above 
by  the  valve  of  Vieussens.  It  is  surrounded,  especially  on  its  ventral  side, 
by  gi'sy  matter  containing  the  cells  of  origin  of  the  fourth  nerve.  In  the 
tegmental  portion  we  may  distinguish  on  each  side  the  superior  cerebellar 
peduncle.  Outside  the  longitudinal  fibres  of  this  peduncle  are  a  number 
of  transverse  fibres  derived  from  the  corpus  trapezoides  seen  in  the  previous 
section.  To  these  fibres  is  given  the  name  of  the  '  lateral  fillet.'  They  are 
on  their  way  to  end  in  the  roof  of  the  mid-brain  in  the  posterior  corpora 
quadrigemina.  The  posterior  longitudinal  bundle  hes  near  the  middle  hne, 
immediately  under  the  grey  matter  of  the  floor  of  the  fourth  ventricle,  while 
the  longitudinal  fibres  of  the  fillet,  now  called  the  mesial  fillet,  form  a  distinct 
mass  in  the  ventral  portion  of  the  formatio  reticularis.  The  pedal  portion 
contains  the  longitudinal  fibres  of  the  pyramids,  now  much  increased  in 
amount,  cut  up  into  bundles  by  transverse  fibres  derived  from  the  middle 
peduncles  of  the  cerebellum. 

The  cerebellum,  which  covers  in  the  fore  part  of  the  fourth  ventricle, 
will  have  to  be  described  in  greater  detail  later  on.     At  present  it  will  suffice 


THE  STRUCTURE  OF  THE  BRAIN  STEM 


373 


to  say  that  it  consists  of  a  middle  and  two  lateral  lobes.  The  surface  of  the 
middle  lobe  turned  towards  the  fourth  ventricle  is  known  as  the  inferior 
vermis,  the  dorsal  surface  forming  the  superior  vermis.  Each  vermis  and 
each  lateral  lobe  is  subdivided  into  a  number  of  smaller  lobes.  The  intimate 
structure  of  all  parts  of  the  cerebellum  is,  however,  very  uniform.  It  consists 
of  a  mass  of  white  matter  internally,  covered  by  a  layer  of  grey  matter,  the 


Inf.  corpus  (juadrigeminum 


Grey  matter - 
Aqueduct  of  Sylvius- 


Mesenc.  root  of  5th  n. 

Nucleus  of  4th  nerve 
luf .,  brachium 


._!l^l'usti.long 


f^fs,;^- 


-.X  J 


Substantia  uiara 


Crusta 


Fii!.  1,S7.     Transverse  section  through  human  mid-brain,  on  level  of  the  inferior 
corpora  quadrigcmina.     (Cunninghaji.) 

extent  of  grey  matter  being  largely  increased  by  the  formation  of  numerous 
parallel  and  more  or  less  curved  grooves  or  sulci  which  give  the  whole  organ 
a  laminate  appearance.  In  the  mass  of  white  matter,  which  forms  the 
core  of  each  lateral  hemisphere,  is  an  isolated  nucleus  of  grey  matter  known 
as  the  corpus  dentatum.  In  the  white  matter  of  the  middle  lobe  is  another 
mass  of  grey  matter  known  as  the  roof  nucleus  or  nucleus  fastigii.  Be- 
tween the  nucleus  fastigii  and  the  nucleus  dentatum  are  two  other  nuclei, 
the  nucleus  globosus  and  the  nucleus  cmhoUJormis. 


THE  MID-BRAIN 

A  little  further  forward  the  fourth  ventricle  comes  to  an  end,  and  the 

section  passes  through  the  mid-brain  (Fig.  187),  the  cavity  of  the  second 

cerebral  vesicle  being  represented  by  the  narrow  Sylvian  a(iueduct.  bounded 

dorsally  by  the  corpora  quadrigomina  and  ventrally  by  the  crura,  the  stalks 


374  PHYSIOLOGY 

of  the  biain.  The  crura  are  divided  by  an  irregular  mass  of  grey  matter,  the 
substantia  nigra,  into  two  parts.  The  ventral  portion  is  known  as  the  'pes  or 
crusta.  It  is  composed  ahnost  entirely  of  longitudinal  white  fibres,  among 
which  is  the  continuation  forwards  of  the  pyramids  of  the  medulla.  The 
pyramids,  however,  form  only  about  two-fifths  of  the  total  mass  of  white 
fibres,  the  rest  consisting  of  fibres  which  rim  from  the  difierent  parts  of  the 

Superior  quadri- 
geminal  body 


Extl.  gen.  body 
Infr.  brachium 

Intl.  gen.  body 

\  ucleus  of  3id 
nerve 

Mesial  fillet 


Crusta 


Optic  tract 


Supr.  cerebellar 
peduncle 


3rd  nerve 


Substantia 
nigra 


^  Corpus 

mamniillare 


Fig.  188. 


Transverse  section  through  human  mid-brain  at  the  level  of  the  superior 
corpus  quadrigeminum.     (Cunningham.) 


cerebral  cortex,  especially  from  the  frontal  and  temporal  lobes,  to  end  in  the 
formatio  reticularis  of  the  pons,  probably  in  relation  with  the  grey  matter  in 
this  situation  and  with  the  endings  of  the  transverse  fibres  derived  from  the 
cerebellum  and  forming  the  middle  peduncles  of  the  cerebellum.  The  dorsal 
part,  the  tegmentum,  is  a  direct  prolongation  forwards  of  the  formatio  reticu- 
laris of  the  medulla  and  pons,  and  hke  this  contains  much  scattered  grey 
matter.  On  a  level  with  the  inferior  corpora  quadrigemina  a. number  of 
decussating  fibres  are  to  be  seen  in  the  tegmentum,  which  are  derived  from 
the  superior  cerebellar  peduncles.  Their  decussation  is  complete  at  the  level 
of  the  upper  border  of  the  inferior  corpora  quadrigemina.  Here  each 
peduncle  turns  upwards,  and  a  large  proportion  of  its  fibres  end  in  the  red 
nucleus  (Fig.  188),  a  mass  of  grey  matter  forming  a  conspicuous  feature  of 
sections  through  the  anterior  part  of  the  mid-brain.  Many  of  the  fibres  pass 
round  the  red  nucleus,  forming  a  sort  of  capsule  over  it,  to  the  ventral 


THE  STRUCTURE  OF  THE  BRAIN  STEM  375 

part  of  the  optic  thalamus,  in  which  they  probably  end.  It  is  possible  that  a 
certain  proportion  pass  through  the  optic  thalamus  and  run  straight  to  the 
cerebral  cortex  of  the  Rolandic  area.  The  lateral  fillet  has  disappeared  fiom 
the  region  of  the  tegmentum  and  passed  into  the  inferior  corpora  quadri- 
gemina.  The  mesial  fillet  forms  a  flat  band  lying  to  the  outer  side  of  the  red 
nucleus  and  comes  into  close  relation  with  a  ganglion  of  the  fore-brain,  known 
as  the  internal  geniculate  body.  The  roof  of  the  mid-brain  is  formed  by  the 
corpora  quadrigemina.  The  inferior  corpora  quadrigeniina  are  composed  of 
central  grey  matter  encapsulated  by  white  matter,  derived  chiefly  from 
the  lateral  fillet.  The  superior  corpora  quadrigemina  are  composed  of  several 
layers  of  grey  matter  traversed  by  nerve  fibres,  derived  partly  from  the 
fillet,  partly  from  the  optic  tract,  and  partly  from  the  occipital  lobe  of  the 
cerebral  hemisphere. 

THE  FORE-BRAIN 
In  the  fore-brain  the  most  important  feature  is  the  optic  thalami,  the 
two  head  ganghonic  masses  of  the  brain  stem  (Fig.  189).  In  this  region 
the  central  neural  canal,  which  in  the  mid-brain  forms  the  Sylvian  iter, 
widens  out  to  the  third  ventricle,  in  the  lateral  walls  of  which  are  developed 
the  two  optic  thalami.  It  is  a  narrow  cleft,  rapidly  deepening  in  depth  fi'om 
behind  forwards.  As  we  trace  sections  forwards  we  see  that  the  two  crura 
cerebri  diverge  from  one  another.  The  floor  of  the  third  ventricle  is  thus  left 
thin.  It  is  formed  from  behind  forwards  by  a  thin  layer  of  grey  matter  with 
numerous  vessels,  the  locus  perforat us  posticus,  two  small  eminences,  the 
corpora  mammillaria,  and  in  front  of  these  another  lamina  of  grey  matter 
known  as  the  tuher  cinereum.  In  front  of  the  tuber  cinereum  is  the  infun- 
dihulum,  which  leads  to  the  posterior  lobe  of  the  pituitary  body.  In  front 
of  the  infundibulum  the  optic  chiasma  is  closely  attached  to  the  lowest  part 
of  the  anterior  wall  of  the  ventricle.  The  front  wall  is  formed  by  a  thin  layer 
of  nervous  matter,  the  lamina  cinerea,  at  the  upper  border  of  which,  project- 
ing shghtly  into  the  ventricle,  is  a  strand  of  white  fibres  connecting  the  an- 
terior parts  of  the  two  optic  thalami  and  kno^vn  as  the  anterior  commissure. 
The  roof  of  the  third  ventricle  is  formed  entirely  of  epithelium,  the  ependyma, 
along  the  upper  surface  of  which  is  the  layer  of  pia  mater,  the  velum  inter- 
positum.  The  roof  is  invaginated  into  the  ca^'ity  by  two  delicate  vascular 
fringes,  the  choroid  plexuses.  At  the  back  part  of  the  roof  is  attached  the 
stalk  of  the  pineal  body,  and  behind  this  stalk,  between  the  anterior  parts 
of  the  anterior  corpora  quadrigemina,  is  a  small  space  knowni  as  the  trigonum 
habenulcp,  which  contains  a  well-marked  collection  of  nerve-cells  known  as  the 
ganglion  habenulce.  The  lateral  walls  are  formed  entirely  by  the  optic 
thalami.  The  upper  surface  of  the  optic  thalamus  looks  into  the  lateral 
ventricle  of  the  cerebral  hemispheres,  from  which  it  is  separated  by  the 
velum  interpositum  and  by  the  ependyma,  the  epithelium  completing  the 
inferior  wall  of  the  lateral  ventricle  in  this  region.  It  consists  of  three 
masses  of  grey  matter — the  anterior  nucleus,  the  lateral  nucleus  (the  largest 
of  the  three),  and  the  mesial  nucleus.  Its  outer  surface  is  in  contact  with  the 
laver  of  nerve  fibres  formed  bv  the  crusta  of  each  cms  cerebri  as  it  diverges 


376 


PHYSIOLOGY 


from  its  fellow  to  pass  up  into  the  cerebral  hemispheres.  Into  this  layer, 
'  the  internal  capsule/  fibres  proceed  from  all  parts  of  the  thalamus  to  pass 
to  the  cerebral  cortex.  The  anterior  extremity  of  the  thalamus,  known  as  the 
anterior  tubercle,  forms  a  marked  projection  into  the  lateral  ventricle.     In 


Corpus  callosum 
Lateral  ventricle 
Nucleus  caudatus 

Internal  capsule 

Thalamus 
Nucleus  lentiformis 

Anterior  commissre 


CoUiculus  superior 
Inferior  brachium 

CoUiculus  inferior 

4th  nerve 

TrigonuxQ  lemnisci 
5th  nerve, 

Brachium  conj  unctivum 
Pons 

8th  nerve 

Hestiform  body 

9th  nerve 

10th  nerve 

OUve 


7th  nerve 


12th  nerve 


Fig.  1 89.     Right  lateral  aspect  of  brain  stem,  with  a  part  of  the  cerebrum. 
(J.  Symington.) 

front  of  this,  the  foramen  of  Monro  leads  from  the  third  ventricle  into  the 
lateral  ventricle.  This  foramen  is  bounded  anteriorly  by  a  strand  of  fibres, 
known  as  the  '  anterior  pillar  of  the  fornix,'  which  hes  just  behind  the  anterior 
commissure  and  forms  a  conspicuous  feature  in  the  anterior  part  of  the 
lateral  wall  of  the  third  ventricle.  It  passes  in  the  wall  down  to  the  corpus 
mammillare.  From  the  corpus  mammillare  a  well-marked  bundle  of  fibres 
passes  up  into  the  optic  thalamus  to  end  round  the  large  cells  in  the  anterior 
nucleus  of  the  thalamus.  The  posterior  extremity  of  the  thalamus 
forms  a  definite  prominence,  the  jmlvinar.  To  the  outer  and  back 
part  of  the  pulvinar  two  bodies  are  developed,  known  as  the  geniculate 


THE  STRUCTURE  OF  THE  BRAIN  STEM 


377 


bodies.  These  may  be  regarded  as  special  outgrowths  of  the  grey  matter 
of  the  optic  thalamus,  one  of  which,  the  external  geniculate  body,  is  in  close 
connection  with  the  fibres  from  the  optic  tracts,  while  the  other,  the  internal 
geniculate  body,  receives  fibres  from  the  lateral  fillet  ultimately  derived  from 
the  organ  of  hearing.  In  a  section  through  the  fore  part  of  the  mid-brain 
(Fig.  190)  these  two  bodies  maybe  seen  lying  to  the  outer  side  of  the  anterior 
corpora  quadrigemina,  so  that  the  fore-brain,  to  a  certain  extent,  enfolds  the 
anterior  part  of  the  mid-brain.  Below  the  thalamus  at  its  back  part  is  the 
prolongation  forwards  of  the  tegmentum  of  the  crus.  This  is  often  spoken 
of  as  the  subthalamic  region.     The  red  nucleus  is  a  conspicuoiLS  object  in 


/?M 


Fig.  190.  Transverse  section  through  upper  part  of  mid-brain. 
Th,  thalamus ;  hrs.  ))rachium  superior ;  cq^.  anterior  (or  superior)  corpus 
quadrigeminum  ;  ccjl,  ccjc.  internal  and  external  geniculate  bodies  ;  /,  fillet ;  .«,  aque- 
duct;  pi,  posterior  longitudinal  bundle;  r,  raphe;  ///.  third  nerve;  nil  I.  its 
nucleus;  I  pp.  posterior  perforated  space;  sn.  substantia  nigra;  cr.  crusta  ;  //. 
optic  tract  ;  J/,  medullary  centre  of  the  hemisphere  ;  iic.  nucleus  caudatus  ;  .«/. 
stria  tcrminalis. 

sections  through  the  back  part  of  this  region,  but  gradually  diminishes  as  we 
proceed  forwards,  and  disappears  before  the  level  of  the  corpora  mammillaria 
is  reached.  The  mesial  fillet,  which  in  the  mid-brain  lies  on  the  lateral  and 
dorsal  aspect  of  the  red  nucleus,  is  prolonged  upwards  together  with  fibres 
from  the  superior  cerebellar  peduncle  into  the  ventral  part  of  the  thalamus, 
where  probably  all  of  the  fibres  end  in  connection  with  the  thalamic  cells. 
The  substantia  nigra  gradually  disappears.  Before  it  has  disappeared  we 
may  see  on  its  outer  side  a  special  collection  of  grey  matter  called  the  nucleus 
of  Luys  or  the  corpus  snbthalaniicum.  In  addition  to  the  anterior  and 
posterior  commissures  already  described  as  connecting  the  two  optic  thalami 
at  the  front  and  back  of  the  third  ventricle,  the  two  sides  are  connected  about 
the  middle  of  the  cavity  by  the  middle  or  soft  commissure.  The  optic 
thalamus  is  often  described  together  with  the  corpus  striatum  as  forming 
the   basal   ganglia.     The   corpus   striatum   is,    however,   genetically,    and 


378 


PHYSIOLOGY 


probably  functionally,  part  of  the  cerebral  hemisplieres,  and  its  connections 
^^dll  therefore  be  best  dealt  with  when  describing  the  latter  bodies. 


THE   AXIAL  GREY  MATTER 

In  the  spinal  cord  we  could  distinguish  between  the  anterior  grey  matter 
giving  origin  to  the  motor  nerves,  the  posterior  grey  matter  serving  as  an  end 
station  for  a  number  of  the  sensory  posterior  root  fibres,  and  a  lateral  horn, 


,     X. 

fVACUS] 


.         \ 
ARCUATE 
NUCLEUS 


XII. 

[hypoglossal] 


Fig.  191. 


Cross-section  of  medulla  showing  nuclei  of  nerves  x  and  xii. 
(Cunningham.) 


less  well  marked,  probably  giving  origin  to  the  visceral  system  of  nerves. 
As  the  central  canal  widens  out  to  form  the  fourth  ventricle,  the  relative 
position  of  these  various  parts  becomes  altered,  the  anterior  grey  matter 
being  now  nearest  the  median  line,  while  the  posterior  grey  matter  lies  more 
laterally.  Part  of  the  lateral  grey  matter  seems  to  lie  deeper  than  the  rest, 
from  which  it  is  separated  by  the  tangle  of  fibres  and  cells  known  as  the 
formatio  reticularis.  All  the  cranial  nerves  from  the  third  to  the  twelfth 
arise  or  end  in  the  axial  grey  matter,  or  in  close  proximity  to  it.  So  great, 
however,  is  the  complexity  of  this  part  of  the  nervous  system,  and  so  in- 
volved are  the  genetic  relations  of  the  various  nerves,  that  it  is  difficult  or 
impossible  in  many  cases  to  state  definitely  the  spinal  analogies  of  these 
nerves. 

The  cranial  nuclei  (of  origin  or  termination)  may  be  roughly  classed  as 
follows  : 

( 1 )  Motor  Somatic  Nuclei.  These  consist  of  an  almost  continuous  column 
of  multipolar  cells,  lying  close  to  the  middle  line  on  each  side  in  the  floor  of 


THE  STRUCTUEE  OF  THE  BRAIN  STEM 


179 


the  fourth  ventricle,  the  Sylvian  iter,  and  the  back  part  of  the  third  ventricle. 
From  below  upwards  these  groups  of  cells  give  origin  to  the  fibres  of  : 

(a)  The  hypoglossal  nerve. 

(6)  The  sixth  nerve. 

(c)  The  fourth  nerve. 

(d)  The  third  or  oculo-niotor  nerve. 

(2)  SphncJinic  Sensory   Nuclei.     Immediately   outside   the   column   of 
motor  cells  is  a  column  of  grey  matter  which  receives  the  terminations  of 


Fig.  192.     Diagram  showing  tiie  brain  connections  of  the  vagus,  glosso-pharytigeal 
auditory,  facial,  abducent,  and  trigeminal  nerves.     (Cunningham  after  Obkr- 

STEINER.) 

the  afferent  fibres  belonging  to  the  ninth,  tenth,  and  eleventh  nerves,  and 
is  sometimes  called  the  vago-glossopharyngeal-accessory  nucleus.  This  grey 
matter  of  course  does  not  give  rise  to  the  fibres  of  these  nerves,  which,  like 
other  sensory  nerves,  are  axons  of  ganglion-cells  lying  outside  the  central 
nervous  system. 

(3)  Splanchnic  Motor  Nuclei.  These  lie  more  deeply  at  some  distance 
from  the  middle  line,  and  include  the  7iuclciis  ombiguus  for  the  eft'erent  fibres 
of  the  vago- glossopharyngeal,  the  nucleus  of  the  seventh  or  facial  nerve 


380 


PHYSIOLOGY 


(originally  splanchnic  or  branchial,  now  typically  somatic),  and  the  motor 
nucleus  of  the  fifth  nerve  with  its  prolongation  into  the  mid-brain. 

(4)  Sensory  Somatic  Nuclei.  The  chief  representative  of  this  group 
is  the  great  sensory  root  of  the  fifth  nerve.  The  fibres  of  this  nerve  arise 
from  the  Gasserian  ganglion,  pierce  the  fibres  of  the  pons  Varohi,  and  run 
to  the  dorso-lateral  part  of  the  pons,  where  they  divide  into  ascending  and 
descending  fibres.  These  fibres  form  a  cap  to  the  substantia  gelatinosa, 
the  descending  branches,  which  are  longer,  being  conspicuous  in  sections  of 


FIBRES  TO  NUCL.LEMNISCI 
&CORPORA  QUADRIGEMINA 

I! 


\s.a. 


PYRAMID 


NERVE-ENDINGS 

iN  ORGAN  OF  CORTI 

Fig.  193.     Plan  of  the  course  and  connections  of  the  fibres  forming  the  cochlear 
root  of  the  auditory  nerve.     (Schafer.) 
r   restiform  body;    V,  descending  root  of  the  fifth  nerve;    tuh.ac,  tuberculum 
acusticum  ;    n.acc,  accessory  nucleus  ;    s.o,  superior  olive  ;  n.fr,  nucleus  of  trape- 
zium ;   n.VI,  nucleus  of  sixth  nerve  ;    VI,  issuing  root-fibre  of  sixth  nerve. 


the  medulla  as  low  down  as  the  first  or  second  cervical  nerve.  This  nerve 
gives  common  sensation  to  practically  the  whole  of  the  head. 

It  is  doubtful  in  what  group  we  should  place  the  fibres  of  the  eighth 
nerve.  This  nerve  really  consists  of  two  parts  very  different  in  function, 
the  cochlear  or  auditory  nerve,  and  the  vestibular  or  labyrinthine  nerve. 
The  fibres  of  each  are  derived  from  ganghon-cells  in  the  internal  ear,  pass  to 
the  medulla  at  its  widest  part,  and  then,  dividing  into  two,  terminate  in 
masses  of  grey  matter  situated  at  the  extreme  lateral  part  of  the  floor  of  the 
fourth  ventricle. 

The  branches  of  the  cochlear  nerve  (Fig.  193)  make  connection  with  two 
collections  of  cells,  the  dorsal  nucleus,  apparently  embedded  in  the  fibres  of 
the  root  itself,  and  the  accessory  nucleus,  a  little  triangular  mass  of  grey 
matter  situated  in  the  angle  between  the  cochlear  and  vestibular  nerves. 
From  these  nuclei  fibres  are  given  off  which  take  two  courses.  Some,  follow- 
ing the  previous  course  of  the  cochlear  nerve,  pass  across  the  surface  of  the 
fourth  ventricle  as  the  stricB  medullares  or  stricB  acousticce,  and  then  bending 
inwards  pass  into  the  tegmentum  of  the  opposite  side.  Others  pass  deeply 
and  form  a  mass  of  transverse  fibres  in  the  ventral  part  of  the  tegmentum,  the 


THE  STRUCTUEE  OF  THE  BRAIN  STEM 


381 


corpus  trapezoides  or  trapezium.  After  making  connections  with  the  superior 
oUvary  body  and  a  special  nucleus,  they  join  the  superficial  set  of  fibres,  and 
run  up  in  the  tegmentum  to  the  inferior  corpora  quadrigemina,  forming  the 
lateral  fillet. 

The  vestibular  nerve  (Fig.  19-1)  also  has  two  nuclei  of  termination,  the 
median  nucleus  with  small  cells,  and  the  lateral  or  Deiters'  nucleus  with  large 
cells.  Some  fibres  pass  also  to  the  nucleus  of  Bechterew,  which  is  in  close 
relation  with  the  roof  nuclei  of  the  cerebellum.     The  descending  fibres  end 


TO  VERMIS 


FIBRES    O 

VESTIBULA 

ROOT 


NERVE 

ENDINGS 
IN  MACUI->£ 
?.  AMPULL/E 


Fn;.  194.  Plan  of  the  course  and  connections  of  the  fibres  forming  the  vestibular 
root 'of  the  auditor}^  nerve.  (Schafer.) 
/■,  restiforni  body  ;  y.  descending  root  of  fifth  nerve  ;  p,  cells  of  principal  nucleus 
of  vestibular  root  ;  d.  fibres  of  descending  vestibular  root  ;  nd.  a  cell  of  the  descend- 
ing vestibular  nucleus;  d,  cells  of  nucleus  of  Deiters;  B.  cells  of  nucleus  of  Bech- 
terew; ill,  cells  of  luicleus  tccti  (fastigii)  of  the  cerebellum;  jylb.  fibres  of  posterior 
longitudinal  bundle.  No  attempt  has  been  made  in  this  diagram  to  rejiresent  the 
actual  positions  of  the  several  nuclei.  Thus  a  large  part  of  Deiters'  nucleus  lies 
dorsal  to  and  in  the  immediate  vieinitv  of  the  restiform  bodv. 


chiefly  in  the  median  nucleus,  while  the  ascending  fibres  end  in  Deiters' 
nucleus.  From  the  latter  a  distinct  band  of  fibres  passes  up  to  the  cere- 
bellum, forming  the  median  division  of  the  restiform  body,  while  other  fibres 
run  across  to  the  tegmentum  of  the  opposite  side,  where  they  take  part  in  the 
formation  of  the  posterior  lomjitudinal  bundle. 

In  a  section  through  the  fourth  ventricle  through  the  middle  of  the  pons, 
a  group  of  large  cells  is  seen  in  the  position  occupied  by  the  nucleus  of  the 
hypoglossal  below.  These  cells  give  rise  to  the  fibres  of  the  sixth  nerve. 
Another  group  is  seen  lying  laterally  and  more  deeply,  evidently  belonging  to 
the  lateral  horn  system.  This  is  the  nucleus  of  the  seventh  or  facial  nerve, 
the  fibres  of  which  pass  dorsally  and  anteriorly,  looping  round  the  sixth 
nerve-nucleus,  before  issuing  as  tiie  root  of  the  seventh  nerve. 

In  the  upper  part  of  the  pons  we  find  the  fifth  nerve  (Fig.  195)  %\nth  its 
two  roots.     The  fibres  of  the  sensory  root  derived  from  the  cells  of  the 


382 


PHYSIOLOGY 


Gasserian  ganglion  bifurcate.  The  upper  divisions,  which  are  short,  end 
in  a  mass  of  grey  matter  at  the  lateral  part  of  the  formatio  reticularis,  the 
so-called  sensory  root,  while  the  descending  divisions  form  a  long  strand 
of  white  fibres  passing  down  as  far  as  the  second  cervical  nerve  and  lying 
over  the  substantia  gelatinosa  of  Rolando,  around  the  small  cells  of  which  the 

fibres  finally  terminate.  The  motor  fibres 
arise  partly  fi-om  the  motor  nucleus,  a  mass 
of  cells  lying  internally  to  the  sensory 
nucleus,  and  belonging  probably  to  the  lateral 
horn  system.  A  large  number  are  derived 
from  a  long  column  of  cells,  which  stretches 
forward  from  the  nucleus  as  far  as  the  level 
of  the  anterior  corpora  quadrigemina.  These 
fibres  are  known  as  the  descending  motor 
root  of  the  fifth  nerve. 

In  the  region  of  the  mid-brain,  besides 
the  root  of  the  fifth  nerve  just  mentioned, 
we  find  only  the  motor  nuclei  of  the  third 
and  fourth  nerves,  which  are  situated  near 
the  median  line  in  the  ventral  part  of  the 
central  grey  matter,  corresponding  in  situa- 
tion to  the  sixth  and  twelfth  nerves  lower 
down. 


INTERMEDIATE  GREY  MATTER  OF 
THE  CEREBRAL  AXIS 

The  masses  of  grey  matter  which  are 
found  throughout  this  region  may  be  re- 
garded as  extra  shunting  stations  (or  associa- 
tion centres  for  various  systems  of  nuclei  and 
conducting  paths),  which  have  arisen  in  con- 


i'lG.  195.  Diagram  showing  cen- 
tral connections  of  fifth  nerve. 
(Cajal.) 


A,  Gasserian  ganglion  ;    b,  acces- 
sory motor  nucleus ;   c,  main  motor  sequence  of  the  great  complexity  of  reaction 
nucleus ;  d,  facial  nucleus ;  e,  nucleus  ■      i      £  •■!  x.       • 

of  hypoglossal;  f,  sensory  nucleus  of  reqmred  of  the  nerve  mechanisms  m  connec- 
fifth  nerve ;  g,  cerebral  tract  (fillet)  tion  with  the   organs  of  special  sense.     We 

of  fifth  nerve.  ,  r  ^  t  .       Vi-i 

must  confine  ourselves  iiere  to  little  more 
than  the  enumeration  of  the  chief  masses,  though  we  shall  have  occasion 
to  refer  to  some  in  more  detail  when  dealing  with  the  co-ordinating 
mechanisms  of  the  cerebral  axis.  From  below  upwards  we  may  enumerate 
the  following  grey  masses  : 

In  the  medulla  is  the  large  olivary  body,  with  the  accessory  olive  lying  on 
its  inner  side.  Each  ohve  sends  fibres  across  the  middle  fine  to  the  opposite 
cerebellar  hemisphere,  and  must  be  regarded  as  connected  with  this  body 
in  its  functions,  since  atrophy  or  removal  of  one  side  of  the  cerebellum  is 
followed  by  atrophy  of  the  opposite  olive. 

In  the  pons  we  find  a  similar  but  smaller  body,  the  superior  olive,  in  the 
neighbourhood  of  the  nucleus  of  the  seventh  nerve.     The  superior  ohve  is 


THE  STRUCTURE  OF  THE  BRAIN  STEM  383 

closely  connected  with  the  co-ordination  of  visual  and  auditory  impressions 
with  the  eye  movements. 

Deiters'  nucleus,  which  occurs  in  the  same  region,  although  described  as 
one  of  the  nuclei  of  the  eighth  nerve,  might  equally  well  be  included  in  this 
class  owing  to  its  manifold  connections  with  both  afferent  and  efferent 
mechanisms. 

In  close  connection  with  Deiters'  nucleus  are  a  number  of  grey  masses 
in  the  cerebellum,  the  roof  nuclei  in  the  roof  of  the  fourth  ventricle. 

In  the  mid- brain  we  must  mention  the  superficial  grey  matter  covering 
the  corpora  cpadrigemina. 

On  the  ventral  side  of  the  Sylvian  iter  are  the  various  masses  of  gi-ey 
matter  in  the  crura,  the  red  nucleus,  a  large  mass  in  the  tegmentum  just  below 
the  oculo-motor  nucleus,  and  the  substantia  nigra,  which  divides  each  crus 
into  two  parts,  the  dorsal  tegmentum  and  the  ventral  pes  or  crusta. 

Finally  at  the  fore  part  of  the  cerebral  axis  we  come  to  the  great  ganglionic 
mass  already  described,  the  optic  thalamus  and  the  geniculate  bodies.  The 
geniculate  bodies  may  be  regarded  as  outgrowths  of  the  optic  thalamus 
which  have  developed  in  connection  with  the  terminations  of  the  auditory  and 
the  optic  nerve  fibres.  The  optic  thalamus  is  connected  by  fibres  with  all 
parts  of  the  cortex  and  represents  the  termination  of  the  whole  tegmental 
system,  so  that  in  many  ways  it  may  be  regarded  as  a  sort  of  foreman  of  the 
central  nervous  system,  controlling  the  activities  of  the  lower  level  centres 
and  bringing  all  parts  of  this  system  in  relation  with  the  supreme  cerebral 
cortex. 

THE  CHIEF  LONG  PATHS  IN  THE  BRAIN  STEM 

In  dealing  with  the  spinal  cord  we  were  able  to  treat  it  as  one  organ, 
very  largely  on  account  of  the  uniformity  of  the  afferent  and  eft'erent 
mechanisms  connected  with  its  various  segments.  Every  afferent  impulse 
arriving  at  the  cord  has  many  possible  paths  open  to  it,  on  account  of  the 
branching  of  the  nerve  fibres  as  they  enter  the  cord  and  the  connection  of 
these  branches  with  different  neurons  of  varying  destination.  The  exact 
path  taken  by  any  given  impulse  under  any  given  set  of  circumstances 
is  determined  by  the  varying  resistance  at  the  synapses  which  intervene 
between  the  terminations  of  the  afferent  fibres  conveying  the  impulse 
and  the  next  relay  of  neurons.  These  resistances  in  their  turn  are  altered 
by  the  processes  of  facilitation  and  inhibition,  which  may  be  due  to 
contemporaneous  or  previous  events.  A  conspicuous  example  of  these 
conditions  is  aft'orded  by  the  phenomena  of  simultaneous  and  successive 
spinal  induction. 

The  uniformity  of  afferent  and  efferent  mechanisms  disappears  when  we 
include  the  brain  stem  with  the  spinal  cord.  The  main  efferent  channel 
of  impulses  is  still  through  the  spinal  cord,  since  here  are  found  the  efterent 
mechanisms  for  all  the  skeletal  muscles  of  the  trunk  and  limbs,  the  chief 
servants  of  the  central  nervous  system  in  the  daily  events  of  life.  Other 
efferent  channels  are  added,  which  acquire  special  importance  with  the 
gi'owth  of  the  upper  brain  or  cerebral  hemispheres.     These  mechanisms 


384  PHYSIOLOGY 

include  those  for  the  movements  of  the  eye  muscles,  those  concerned  in  facial 
expression,  and  those  responsible  for  the  movements  of  the  mouth  in  mastica- 
tion and  deglutition,  and  in  man,  in  speech.  Important  visceral  efferent 
fibres  are  also  contained  in  the  vago-glossopharyngeal  nerves,  which  leave 
the  brain  stem  at  its  hindmost  part  in  the  region  of  the  medulla  oblongata, 
and  influence  the  condition  of  the  heart  and  the  ahmentary  canal  with 
its  accessory  organs.  On  the  other  hand,  the  afferent  mechanisms  of  the  brain 
stem  far  transcend  in  importance,  i.e.  in  their  influence  on  the  reactions  of 
the  animal,  those  of  the  spinal  cord.  Among  these  afferent  mechanisms  are 
those  which  we  have  spoken  of  as  '  projicient '  sense  organs  or  organs  of 
foresight,  the  impulses  from  which  must  predominate  over  all  reactions 
determined  by  the  immediate  environment  of  the  animal.  Into  the  medulla 
oblongata  are  poured  the  impulses  from  the  greater  part  of  the  alimentary 
canal  and  from  the  heart  (the  chief  factor  in  the  circulation)  and  the  lungs. 
At  the  junction  of  the  medulla  and  pons  is  the  great  eighth  nerve,  really  con- 
sisting of  two,  one  of  which,  the  cochlear  nerve,  carries  impulses  from  the 
projicient  sense-organ  of  hearing,  while  the  other,  the  vestibular  nerve,  has 
its  terminations  in  the  labyrinth,  the  sense-organ  of  equihbration.  To  the 
impressions  received  from  this  organ  all  the  complex  co-ordinating  motor 
mechanisms  of  the  spinal  cord  have  to  be  subordinated,  in  order  that  they 
may  co-operate  in  the  maintenance  of  the  equihbrium  of  the  body  as  a  whole. 
Into  the  pons  enters  the  fifth  nerve,  carrying  sensory  impressions  from  the 
whole  of  the  head,  while  in  the  mid-  and  fore-brain  we  find  the  endings  of 
the  optic  tracts  derived  from  the  eyes  and  carrying  visual  impressions.  From 
the  front  of  the  fore-brain  are  produced  the  olfactory  lobes. 

At  each  segment  or  level  in  the  brain  stem  the  afferent  fibres  from  these 
various  sense-organs  enter  and  join  afferent  tracts,  carrying  impulses  on  from 
the  spinal  cord— impulses  originally  derived  from  the  muscles  and  skin  of 
the  trunk  and  hmbs.  At  each  level  there  may  be  an  immediate  '  reflection  ' 
back  to  the  cord,  so  that  the  spinal  afferent  impressions  may  co-operate 
with  the  cranial  afferent  impressions  in  the  production,  through  the  spinal 
cord,  of  reactions  affecting  the  viscera  or  the  skeletal  muscles.  On  the 
other  hand,  both  kinds  of  afferent  impressions  may  pass  on  up  the  brain  stem 
to  involve  higher  centres,  and,  mingling  with  impulses  from  other  afferent 
nerves  or  from  the  projicient  sense-organs,  may  result  at  some  higher  level 
in  an  efferent  discharge,  which  may  include  reactions  not  represented  in  the 
cord,  or  reactions  of  far  greater  complexity  than  are  possible  in  the  purely 
spinal  animal. 

In  consequence  of  the  endless  complex  interminghng  of  afferent  im- 
pulses, any  diagrammatic  representation  of  tracts  is  apt  to  be  misleading 
unless  it  be  remembered  that  at  each  break  or  synapse  in  the  chain  of  neurons 
there  are  numerous  possibilities  of  branching  discharge,  and  that  in  our 
diagrams  we  can  only  give  the  course  of  such  impulses  as,  by  the  frequency 
of  repetition  in  the  average  hfe  of  the  animal,  have  involved  the  grouping 
of  a  large  number  of  nerve  paths  of  similar  function  into  tracts.  The  con- 
stituent elements  of  these  tracts  will  present  similar  destinations  and  possi- 


THE  STRUCTUEE  OF  THE  BRAIN  STEM 


385 


bilities  of  interruption,  i.e.  of  reactions  involving  the  motor  mechanisms  at 
the  different  levels  in  the  brain  stem.  It  is  thus  much  more  difl&cult  in  the 
brain  stem  than  in  the  spinal  cord  to  describe  a  '  way  in  '  and  a  '  way  out.' 
In  a  chain  consisting,  say,  of  six  neurons,  a,  h,  c,  d,  e,  f  (Fig.  196),  though 
a  is  certainly  afferent  and /efferent,  it  must  always  be  more  or  less  a  question 
of  words  whether  we  regard  neurons  c  and  d  as  afferent  or  efferent  in  character. 
It  is  usual  in  our  classifications  to  be  guided  chiefly  by  the  direction  of  such 
impulses  in  relation  to  the  cerebral  hemispheres.  All  tracts  going  up  to 
the  cerebral  hemispheres  may  be  involved  more  or  less  in  the  production  of 
such  changes  in  the  nervous  matter  of  these  hemispheres  as  are  associated 
with  conscious  sensation.  In  the  same  way  there 
is  a  possibiUty  that  the  chains  of  neurons  which 
carry  impulses  in  a  descending  direction  may  be 
involved  in  the  production  of  voluntary  move- 
ment. It  is  therefore  usual  to  classify  these  two 
sets  of  tracts  as  ascending  and  descending,  or  as 
afferent  and  efferent.  If  we  adopt  such  a  classifi- 
cation it  must  be  with  a  distinct  reservation  that 
tracts  which  apparently  are  going 
downwards  may  play  a  greater  part 
in  the  determination  of  sensation  than 
in  the  determination  of  movement, 
and  that  there  may,  and  indeed  must, 
be  a  reverberation  of  impulses  through 
these  ascending  and  descending  tracts, 

so  that  it  must  be  difficult  to  dissociate  the  various  elements  in  the  extremely 
complex  neural  events  which  are  involved,  say,  in  the  simplest  kind  of 
conscious  sensation. 

As  we  trace  out  the  evolution  of  the  brain  we  find  an  ever-increasing 
subordination  of  the  lower  to  the  higher  centres,  so  that  in  man  himself 
many  reactions  which  in  the  lower  animals  are  carried  out  by  the  spinal 
cord  alone,  involve  the  educated  co-operation  of  the  cerebral  hemispheres. 
With  this  increased  control  there  is  a  corresponding  increase  in  the  develop- 
ment of  long  paths.  In  the  brain  of  a  fish,  for  instance,  the  cerebral  hemi- 
spheres are  connected  only  with  the  fore-brain  ;  a  httle  higher  up  there  are 
connections  between  the  hemispheres  and  the  mid-brain  as  well.  The  chief 
long  tracts  are  those  which  run  between  the  thalamus,  the  mid-brain  or  the 
hind-brain,  and  the  spinal  cord.  With  the  huge  development  of  the  cerebral 
hemispheres  in  man  there  is  also  development  of  long  paths,  the  pyramidal 
tracts,  from  the  hemispheres  down  to  all  the  motor  mechanisms  of  the  cord, 
and  of  tracts  which  connect  all  parts  of  the  cortex  with  the  grey  matter  of 
the  pons  and  indirectly  with  the  cerebellum.  The  tracts  which  in  the  lower 
animals  were  of  supreme  importance  in  determining  subordination  of  lower 
to  higher  centres,  of  immediate  reactions  to  those  determined  by  the  organs 
of  foresight,  dwindle  therefore  in  importance.  Those  tracts,  such  as  the 
thalamo-spinal,  tecto-spinal,  vestibulo-spinal,  which  form  the  main  mass 

13 


Fig.  196. 


386  PHYSIOLOGY 

of  the  white  matter  of  the  brain  stem  in  lower  types  of  vertebrates,  become 
reduced  to  a  few  scattered  fibres  in  the  brain  of  man  and  are  insignificant 
as  compared  with  the  great  cerebro-bulbar  and  cerebro- spinal  tracts. 

ASCENDING  TRACTS 

The  Teacts  of  the  Fillet.  The  fibres  which  enter  the  spinal  cord 
by  the  posterior  roots  pass  into  the  posterior  columns  and  along  these  to 
the  dorsal  column  nuclei,  the  nucleus  gracihs  and  the  nucleus  cuneatus, 
where  they  end  by  arborisations  among  the  cells  composing  these  nuclei. 
From  these  nuclei  the  axons  of  the  cells  pass  in  various  directions,  the  chief 
mass  of  them  forming  the  deep  arcuate  fibres.  These  emerge  from  the  inner 
side  of  the  nuclei  and  pass  through  the  raphe  to  the  other  side  of  the  medulla 
where  they  join  the  spino-thalamic  fibres  and  form  the  definite  collection 
of  longitudinal  fibres,  lying  dorsally  to  the  pyramids,  which  is  known 
as  the  main  tract  of  the  fillet,  or,  often,  the  mesial  fillet.  As  these 
fibres  traverse  the  pons  they  are  joined  at  the  outer  side  by  a  number 
of  bundles  which  are  derived  from  the  central  continuation  of  fibres 
connected  with  those  derived  from  the  cochlear  nerve.  This  part  is 
known  as  the  lateral  fillet.  The  cells  of  the  accessory  and  lateral 
nuclei  of  the  cochlear  nerve  send  their  axons  by  the  trapezium  to  the 
s;uperior  ohvary  nucleus  and  other  small  masses  of  grey  matter  on  the  other 
side.  In  these  nuclei  the  fibres  for  the  most  part  terminate,  but  a  fresh  relay 
of  neurons  carries  on  the  impulses  and  forms  the  main  part  of  the  lateral 
fiUet.  These  pass  up,  getting  more  dorsal  as  they  ascend,  and  finally 
terminate  in  the  inferior  corpora  quadrigemina.  The  mesial  fillet,  which 
we  can  regard  as  a  continuation  of  certain  spinal  tracts  upwards,  is  reinforced 
throughout  the  whole  extent  of  the  medulla  and  pons  by  fibres  originating 
from  the  masses  of  grey  matter  in  which  the  sensory  cranial  nerves  terminate. 
Certain  of  these  fibres  may  form  a  distinct  tract  in  the  forma tio  reticularis, 
known  as  the  central  or  thalamic  tract  of  the  cranial  nerves.  Another 
similar  tract  in  the  formatio  reticularis  is  derived  from  the  central  termina- 
tions of  the  fifth  nerve,  and  is  known  as  the  trigemino-thalamic  tract.  All 
these  fibres  pass  up  in  the  tegmentum  of  the  mid-brain  and  finally  end,  partly 
in  the  grey  matter  of  the  subthalamic  region  and  partly  in  the  grey  matter  of 
the  thalamus  itself.  To  the  thalamus  are  also  continued  a  few  fibres  from  the 
lateral  fillet.  By  this  means  the  head  ganghon  of  the  fore-brain  is  in  a  posi- 
tion to  receive,  so  to  speak,  samples  of  the  afferent  impressions  derived  from 
every  sense-organ  of  the  body. 

The  Visual  Paths.  Two  classes  of  afferent  impressions  which  arrive  at 
the  optic  thalamus  are  probably  of  equal  importance  to  all  the  other  afferent 
impressions  taken  together.  These  are  impulses  derived  from  the  organs  of 
vision  and  of  smell.  The  greater  part  of  the  fibres  composing  the  optic  nerves 
arise  as  axons  of  the  ganghon-cells  of  the  retinae.  Passing  backwards,  the 
nerves  of  the  two  sides  join  in  the  optic  chiasma,  which  is  closely  attached 
to  the  floor  of  the  third  ventricle.  After  joining  in  the  chiasma  the  optic 
nerves  are  apparently  continued  round  the  crura  cerebri  as  the  optic  tracts. 


THE  STRUCTURE  OF  THE  BRAIN  STEM 


387 


Corpus  CaIIoSUiti  ^^ 


Thilamo-CorrKil  FibrfS 


__  _.CI&usrrum 


5ubst&.nri6  Nipr6^ 

Peduncle 

Ctrebellum   --' 


Sfiino-CerebelUr 
Tracfs 


(Co- ordination  &■ 
Muscular  Tone 


PyrevfTiid 

Dee\>  A/cuaffe  Fibres 


Dorsal  Column  (direct) 
/stnst  of  posiTion     ■) 
y  "       ••   movemenf/ 


Sf)in^l  Nerve  _ 


Sylvian  Iftr 
Medl^.n  Flllet- 


^tntd.tt  Nucleus 


Crossed  Sensory  Fibres 
/Pdin.  Hei.t&  Cold\ 
vTouch  &  Pressure  I 

Inferior  Olivi 


^sceMPiMG  neRve 

TRACTS. 


Fio.   197.     Diagram  of  ascending  tracts  between  the  spinal  conl  and  brain  (Gordon 
HoLSiES),  with  the  probable  path  of  sensory  impulses. 


388- 


PHYSIOLOGY 


These  pass  round  on  each  side  and  can  be  seen  to  make  connection  with  the 
back  part  of  the  thalamus,  the  external  geniculate  body,  and  the  superior 
corpus  quadrigeminum.  Part  of  the  tract,  which  is  sometimes  called  the 
mesial  root,  passes  into  the  internal  geniculate  body.  This  part  of  the  tract 
has  probably  nothing  to  do  with  vision  and  forms  a  commissure  running 
in  the  optic  chiasma  connecting  the  internal  geniculate  bodies  of  the  two 
sides.  The  course  of  the  optic  fibres  is  shown  in  the  diagram  (Fig.  198).  In 
man  and  in  some  other  mammals,  e.g.  dog,  monkey,  the  nerve  fibres  decussate 

incompletely  in  the  chiasma.  The 
uncrossed  bundle  is  derived  from 
the  outer  half  of  the  retina  of  the 
same  side,  whereas  the  crossed 
bundle  is  derived  from  the  mesial 
half  of  the  retina  on  the  other  side. 
The  right  optic  nerve  thus  carries 
all  the  impulses  originating  in  the 
right  eye.  The  right  optic  tract 
carries  all  the  impulses  originating 
from  stimuh  occurring  in  the  left 
field  of  vision.  It  must  be  remem- 
bered that  vision  in  man  is  bin- 
ocular, both  retinae  being  concerned 
in  the  perception  of  each  field  of 
vision.  The  external  and  internal 
geniculate  bodies  may  be  regarded 
as  extensions  of  the  optic  thala- 
mus, the  former  in  special  relation 
with  the  organ  of  vision,  the 
latter  with  the  organ  of  hearing. 

The  olfactory  bulb  is  also  con- 
nected by  tracts  with  the  thalamic 
region,     probably     through     the 
column    of    the    fornix    and    the 
bundle    of   Vicq    d'Azyr.      Since, 
however,  the  chief  connections  of 
the  olfactory  lobe  are  with  the  more  primitive  portions  of  the  cerebral  hemi- 
spheres,  the   olfactory   tracts    will    be   more  conveniently']  treated  of  in 
connection  with  the  latter. 

The  Cerebellar  Paths.  We  have  already  traced  out  the  course  of 
spinal  fibres  which  terminate  in  the  cerebellum.  They  may  be  shortly 
summarised  as  follows  : 

(!)  The  posterior  or  direct  cerebellar  tract,  originating  in  Clarke's 
column  of  cells  of  same  side,  passing  up  in  the  lateral  columns  and 
by  the  restiform  body  into  the  superior  vermis  of  the  middle  lobe  of  the 
cerebellum. 

(2)  The  anterior  cerebellar  tract  or  tract  of  Gowers,  originating  in  the  grey 


CORP,  GEN. INT. 


Fig.  198.  Diagram- 
matic representa- 
tion of  the  optic 
tracts  and  their 
connections. 
(Cunningham. 


UOB* 


THE  STRUCTURE  OF  THE  BRAIN  STEM  389 

matter  of  both  sides  of  the  cord  and  passing  in  the  lateral  columns  through 
the  lateral  part  of  the  medulla  and  pons,  and  finally  attaining  the  superior 
vermis  through  the  superior  cerebellar  peduncles. 

(3)  The  posterior  columns,  ending  chiefly  in  the  homolateral  posterior 
column  nuclei.  From  these  nuclei,  though  the  great  mass  of  fibres  passes 
into  the  fillet,  a  certain  number  from  the  nuclei  of  both  sides  join  the  resti- 
form  body  to  pass  into  the  middle  lobe  of  the  cerebellum. 

In  the  medulla  these  afferent  tracts  of  the  cerebellum  are  joined  by  the 
following  sets  of  fibres  : 

1.  The  ohvo-ccrebellar. 

2.  The  vestibulo-cerebellar. 

3.  A  few  fibres  from  the  chief  sensory  nuclei,  including  those  of  the  vago 
glossopharyngeal  nerves. 

AU  these  fibres  terminate  in  the  cortex,  chiefly  of  the  middle  lobe.  From 
the  cortex  of  this  lobe  fibres  pass  to  the  central  and  roof  nuclei  of  the  cere- 
bellum, namely,  the  nucleus  dentatus,  the  nucleus  embohformis,  the  nucleus 
fastigii,  and  the  nucleus  globosus.  The  efferent  tracts  of  the  cerebellum 
start  from  these  central  nuclei,  no  fibres  which  originate  in  the  cortex  of  the 
cerebellum  apparently  leaving  the  precincts  of  this  organ.  Some  of  these 
efierent  fibres  of  the  cerebellum  will  be  better  described  \^'ith  the  descending 
tracts  of  the  brain  stem.  Of  those  which  take  an  ascending  direction,  the 
great  bulk  are  contained  in  the  superior  cerebellar  peduncles.  These  origin- 
ate for  the  most  part  in  the  dentate  nucleus  and  the  nuclei  embohformis  and 
globosus.  As  the  superior  peduncles  run  forwards  they  sink  below  the 
posterior  corpora  quadrigemina,  and  in  the  tegmentiun,  below  the  Sylvian 
iter,  decussate  with  the  tract  of  the  opposite  side  to  pass  to  the  red  nucleus. 
In  the  red  nucleus  many  of  the  fibres  end,  some,  however,  passing  through  the 
nucleus  together  with  fibres  derived  from  the  cells  of  the  red  nucleus  itself 
to  end  in  the  thalamus  and  in  the  grey  matter   of  the  subthalamic  region. 

DESCENDING  TRACTS 
The  chief  descending  tracts  having  their  origin  in  the  brain  stem  are  the 
rubro-spinal  bundle  or  bundle  of  Monakow,  the  complex  system  of  fibres 
known  as  the  posterior  longitudinal  bundle,  and  the  vestibulo-spinal  fibres 
from  the  upper  part  of  the  medulla. 

(1)  The  RUBRO-SPINAL  FIBRES  Originate  in  the  red  nucleus.  They  cross 
the  median  fine  and  rim  down,  at  first  in  the  tegmentum  and  later  in  the 
lateral  column  of  the  medulla  oblongata  and  cord.  In  their  passage  they 
communicate  with  the  various  motor  nuclei  of  the  cranial  nerves.  They 
can  be  traced  to  all  segments  of  the  cord,  where  they  terminate  in  connection 
with  the  anterior  horn-cells. 

(2)  The  POSTERIOR  longitudinal  bundle.  This  bundle  is  to  be  seen  in 
all  sections  through  the  brain  stem  below  the  level  of  the  oculo-motor  nucleus. 
It  consists  of  fibres,  some  of  which  pass  upwards,  while  others  pass  do\\ni- 
wards.  Most  of  the  fibres  take  origin  in  the  cells  of  Deiters'  nucleus  and  of 
the  reticular  formation  of  the  pons,  medulla,  and  niid-braiu,  as  well  as  from 


390 


PHYSIOLOGY 


Optic 

ThjilMDuS 


lniernd>l ) 
CApsuiej 


LenticuUrl   ^ 
Nucleus  j 


Rubro-jpin&l  Tracf  — 


DiiUfs  Nucleus 


-j'M^-Oinfd^h  Nucleus' 


Inj^erior  Olive 


Vestibule  Spinal  Tract 


Crossed  Pvramidal  Tract >H^U^^""^  Pyramidal  Tract 

D65C6HDING  N£RV£ 
TRACTS. 


Fia.  199.  Schema  of  course  taken  by  chief  descending  tracts  of  brain  stem.  (Gordon 
Holmes).  The  tract  in  red,  to  the  right  of  the  rubro-spinal  tract,  includes  the  posterior 
longitudinal  bundle,  together  with  the  fibres  of  the  thalamo-spinal  and  tecto-spinal 
tracts. 


THE  STRUCTURE  OF  THE  BRAIN  STEM  391 

certain  cells  in  the  sensory  nucleus  of  the  fifth  nerve.  The  fibres  traced 
upwards  can  be  seen  to  send  collaterals  to  end  in  the  various  parts  of  the 
nuclei  of  the  third,  fourth,  and  sixth  nerves.  Lower  down  it  becomes  con- 
tinuous with  the  anterior  basis  bundle  of  the  spinal  cord  and  merges  in  the 
internuncial  fibres  which  serve  to  connect  the  various  levels  of  the  cord. 
Some  of  the  fibres,  which  are  descending,  are  derived  from  a  small  nucleus, 
the  so-called  nucleus  of  the  posterior  longitudinal  bundle,  which  is  found  in 
the  grey  matter  at  the  side  of  the  posterior  part  of  the  third  ventricle.  This 
bundle  also  receives  fibres  from  the  superior  ohvary  body.  It  is  one  of  the 
earhest  to  undergo  myehnation  in  the  foetus  {cp.  also  Fig.  205,  p.  408). 

(3)  The  VESTIBULO-SPINAL  TRACT  takes  origin  for  the  most  part  in  the 
cells  of  Deiters'  nucleus.  The  fibres  pass  down  in  the  anterior  part  of  the 
spinal  cord  and  terminate  in  the  anterior  horns.  They  are  sometimes  known 
as  the  antero-lateral  descending  tract.  It  is  probably  through  this  tract 
that  the  cerebellum  is  able  to  affect  indirectly  the  activity  of  the  motor 
mechanisms  of  the  cord. 

Two  other  descending  tracts  which  are  important  in  the  lower  vertebrates 
are  insignificant  in  man.  These  are  the  thalamo-spinal  tract,  consisting  of 
descending  fibres  derived  from  the  optic  thalamus,  and  the  tecto-spinal  tract, 
containing  fibres  derived  from  the  roof  of  the  mid-brain.  In  the  mid-  and 
hind-brain  these  fibres  run  in  the  tegmentum.  In  the  cord  they  are  found 
in  the  anterior  columns.  The  olivo-spinal  tract,  which  is  supposed  to 
originate  in  the  olivary  body,  forms  a  small  tract  in  the  cervical  region  near 
the  surface,  opposite  the  lateral  angle  of  the  anterior  horn. 


SECTION  XII 
THE  FUNCTIONS  OF  THE  BRAIN  STEM 

The  brain  stem  may  be  taken  to  include  all  those  parts  lying  between  the 
cerebral  hemispheres  and  the  spinal  cord,  from  the  optic  thalamus  in, front 
to  the  medulla  oblongata  behind.  The  brain  may  be  divided  into  the  follow- 
ing parts  from  before  back  : 

(1)  Thalamencephalon,  including  the  corpus  striatum,  the  cerebral 
hemispheres  and  rhinencephalon,  or  olfactory  lobes. 

(2)  Diencephalon,  i.e.  the  fore-brain,  especially  the  optic  thalamus. 

(3)  Mesencephalon,  or  mid-brain,  including  the  quadrigemina,  the  iter  of 
Sylvius,  and  the  crura  cerebri. 

(4)  Metencephalon,  composed  of  the  pons  Varohi,  the  upper  part  of  the 
fourth  ventricle,  and  cerebellum. 

(5)  Myelencephalon,  or  bulb,  consisting  of  the  medulla  oblongata. 

We  may  get  some  idea  of  the  part  played  by  these  different  regions  of 
the  brain  in  determining  the  reactions  of  the  individual  as  a  whole  by 
examining  the  behaviour  of  the  animals  in  whom  all  the  rest  of  the  brain 
in  front  of  the  part  in  question  has  been  removed.  If,  however,  we  take 
into  account  the  numberless  connections  existing  between  the  different  levels 
in  the  central  nervous  system,  the  interdependence  between  the  different 
portions,  and  the  subordination,  especially  in  the  higher  animals,  of  the 
functions  of  the  lower  to  those  of  the  higher  levels,  we  must  acknowledge 
that  such  experiments  can  only  give  us  an  imperfect  idea  of  the  possibihties 
of  each  level  when  in  connection  with  all  other  portions  of  the  nervous  system. 

THE  FUNCTIONS  OF  THE  MEDULLA  OBLONGATA 
OR  MYELENCEPHALON 
The  possibihties  of  any  given  nervous  centre  are  determined  by  the 
afferent  impressions  which  enter  it,  and  by  the  connections  made  by  the 
nerves  carrying  these  impulses  with  the  motor  tracts  within  the  centre.  The 
bulb  receives  afferent  impressions  of  '  taste '  from  the  tongue  through  the 
nervus  intermedins,  from  the  ahmentary  canal  as  low  as  the  ileocohc  sphinc- 
ter, from  the  lungs,  the  heart,  and  the  larger  blood-vessels,  i.e.  from  the  most 
important  of  the  viscera  of  the  body,  by  the  fibres  of  the  vago-glossopharyn- 
geal  nerves.  Its  only  skeleto-motor  centre  is  that  for  the  muscles  of  the 
tongue  (the  hypoglossal).  It  sends  also  efferent  fibres  to  the  viscera,  which 
arise  from  cells  in  the  nucleus  ambiguus.     These  fibres  carry  motor  impulses 

392 


THE  FUNCTIONS  OF  THE  BRAIN  STEM  393 

to  the  muscles  of  the  larynx  and  bronchi,  and  to  the  oesophagus,  stomach, 
and  intestines,  secretory  fibres  to  the  stomach  aiid  inhibitory  fibres  to  the 
heart. 

At  the  upper  border  of  the  bulb  enter  also  the  fibres  of  the  eighth  nerve, 
carrying  important  impressions  from  the  organ  of  hearing  and  the  organ  of 
static  sense.  These  will  be  in  all  probability  divided  or  injured  in  isolating 
the  bulb  from  the  higher  portions  of  the  brain.  While  in  connection  with  the 
upper  portions  of  the  brain,  the  bulb  receives  also  afferent  impressions 
from  the  skin  of  the  face,  and  the  mucous  membrane  of  the  nose  and  mouth 
through  the  descending  branches  of  the  root  of  the  fifth  nerve,  which  pass 
down  superficially  to  the  tubercle  of  Rolando.  When  in  connection  with  the 
cord  the  medulla  receives  afferent  impressions  from  the  whole  surface  of  the 
body  and  from  all  the  muscles  and  joints  through  the  posterior  column 
nuclei. 

The  bulbo-spinal  animal,  i.e.  one  in  whom  a  section  has  been  carried  out 
at  the  upper  boundary  of  the  medulla,  differs  from  the  spinal  animal  chiefly 
in  the  maintenance  of  the  nexus  between  the  visceral  functions  and  the 
skeleto-motor  functions  of  the  body.  After  removal  of  all  the  brain  in 
front  of  the  bulb,  the  animal  still  continues  to  breathe  regularly  and  auto- 
matically. The  blood  pressure  and  the  pulse  rate  remain  normal,  and  all 
three  mechanisms,  respiration,  pulse  rate,  blood  pressure,  may  be  affected 
reflexly  by  appropriate  stimuli,  or  may  be  altered  in  consequence  of  central 
stimulation  of  the  medulla. 

In  addition  to  the  reflex  mechanisms  of  locomotion,  which  are  evident 
in  the  spinal  animal,  the  bulbo-spinal  animal  shows  a  greater  degree  of 
solidarity  in  its  responses.  It  is  easier  to  evoke  movement  of  all  four  limbs-. 
In  the  frog,  if  the  eighth  nerve  has  been  left  intact,  there  is  a  certain  power 
of  equilibration  left,  and  the  animal  when  laid  on  its  back  tries  to  right  itself 
and  usually  succeeds. 

It  is  in  this  portion  of  the  central  nervous  system  that  have  been  located 
the  great  majority  of  the  so-called  centres.  By  a  statement,  that  the  centre 
of  such-and-such  movement  or  function  is  situated  in  the  medulla,  we  mean 
merely  that  the  integrity  of  the  medulla,  or  certain  parts  of  it,  is  essential  for 
the  carrying  out  of  the  function.  Every  function,  for  instance,  in  which 
impulses  passing  up  the  vagus  nerves  are  involved,  is  necessarily  dependent 
on  the  integrity  of  these  nerves  and  their  central  connections,  and,  since  these 
are  situated  in  the  medulla,  the  centres  for  these  functions  are  also  located 
in  this  region.  From  a  broad  standpoii\t  the  medulla  or  bulb  may  be  looked 
upon  as  a  ganglion,  or  a  collection  of  ganglia,  whose  main  office  is  to  guard  and 
preside  over  the  working  of  the  mechanisms  at  the  anterior  opening  of  the 
body  ;  by  means  of  which  food  is  seized,  tasted,  taken  into  the  alimentary 
canal,  and  finally  digested.  The  respiratory  apparatus  belongs  to  the  same 
system  and  is  innervated  through  the  same  nerve  channels.  Hence  the 
various  events  in  alimentation,  such  as  deglutition,  vomiting,  mastication,' 
or  in  the  allied  respiratory  functions,  such  as  phonation,  coughing,  and' 
respiration  itself,  are  endowed  with  centres  in  this  part  of  the  brain.     In 

13* 


394  PHYSIOLOGY 

connection  with  the  termination  of  the  vagus  nerves  of  this  part  of  the  brain 
is  the  location  here  of  the  chief  vaso-motor  centre,  i.e.  in  a  region  which  is 
in  close  proximity  to  the  endings  of  the  chief  afferent  nerves  from  the  heart 
and  larger  blood-vessels  and  to  the  nucleus  of  the  efferent  controlhng  nerve 
to  the  heart. 

THE  METENCEPHALON  (PONS  VAROLII  AND  CEREBELLUM) 
Destruction  of  the  brain  at  the  front  of  the  fourth  ventricle  and  just 
behind  the  posterior  quadrigemina  will  leave  the  animal  with  a  central 
nervous  system,  which  is  in  connection  by  efferent  nerves  with  the  whole 
musculature  of  the  body  (with  the  exception  of  certain  eye  muscles)  and 
which  receives  impressions  through  the  spinal  cord  from  the  whole  surface 
of  the  trunk  and  limbs,  and  through  the  fifth  nerve  from  the  face  and  head, 
and  also  the  higher  speciahsed  impressions  from  the  organ  of  hearing  and 
the  organ  of  static  sense.  The  impressions  from  the  two  great  projicient 
senses  of  smell  and  sight  would  be  wanting. 

Such  an  animal  presents  considerable  advance  in  the  complexity  of  its 
reactions  above  one  possessing  only  spinal  cord  and  bulb.  The  frog,  for 
instance,  after  such  an  operation,  can  still  walk,  spring,  and  swim ;  when 
placed  on  a  turntable  it  reacts  to  passive  rotation  by  turning  its  head  in  the 
opposite  direction.  On  stroking  its  back  it  croaks.  If  the  cerebellum  be 
also  removed  the  animal  becomes  spontaneously  active  and  crawls  about  until 
it  is  blocked  by  some  obstacle.  In  this  condition  there  is  great  activity  of  the 
swallowing  reflex.  Anything  which  touches  the  mouth  is  snapped  at.  If 
placed  on  its  back  the  frog  at  once  rights  itself. 

In  the  mammal  a  similar  increase  of  reflex  activity  is  observed  though  the 
power  of  progression  is  not  retained. 

THE  MESENCEPHALON  OR  MID-BRAIN 
A  section  in  front  of  the  anterior  corpora  quadrigemina  would  leave 
the  animal  with  the  nervous  system  receiving  all  normal  sensory  impressions, 
with  the  exception  of  the  olfactory,  and  with  efferent  paths  to  all  the  muscles 
of  the  body,  including  those  of  the  eye.  In  the  mammal  such  an  operation 
brings  about  a  condition  known  as  '  decerebrate  rigidity.'  Though  respira- 
tory movements  continue  normally,  the  whole  musculature  is  in  a  cataleptic 
condition,  the  elbows  and  knees  being  extended  and  resisting  passive  flexion  ; 
the  tail  is  stiff  and  straight,  the  neck  and  head  retracted.  This  condition 
seems  to  depend  on  an  over-activity  of  the  reflex  tonic  functions  of  the  lower 
centres.  That  it  is  reflex  is  shown  by  the  fact  that  the  rigidity  is  at  once 
abolished  in  a  limb  on  dividing  the  appropriate  posterior  roots.  The 
position  of  the  limbs  may  be  also  modified  by  sensory  stimuh.  A  similar 
condition  of  increased  tonus  is  observed  in  the  frog. 

The  apparatus  for  emotional  expression  is  still  intact  though  somewhat 
modified,  and  an  impression  which  would  give  rise  to  pain  in  the  intact 
animal  may  cause  vocalisation  in  an  animal  in  whom  the  brain  above  the 
mesencephalon  has  been  destroyed. 


THE  FUNCTIONS  OF  THE  BRAIN  STEM  395 

THE  BRAIN  STEM   AS   A  WHOLE  (INCLUDING  THE  THALAM- 
ENCEPHALON,  OR  OPTIC  THALAMI) 

The  iutroductiou  of  the  head  gangha  of  the  brain  stem,  viz.  the  optic 
thalami,  completes  in  the  lower  animals  at  all  events  the  apparatus  for  im- 
mediate response  to  stimulus.  The  powers  of  such  an  apparatus  may  be 
studied  by  examining  the  behaviour  of  an  animal  in  whom  the  cerebral 
hemispheres  have  been  destroyed.  The  result  of  this  operation  varies 
according  to  the  type  of  animal  chosen,  though  all  types  present  certain 
common  features.  When  a  frog's  cerebral  hemispheres  have  been  excised,  a 
casual  observer  would  not  at  first  notice  anything  abnormal  about  the  animal. 
It  sits  up  in  its  usual  position,  and  on  stimulation  may  be  made  to  jump 
away,  guiding  itself  by  sight,  so  that  it  avoids  any  obstacles  in  its  path. 
Movements  of  swallowing  and  breathing  are  normally  carried  out.  The 
animal  thrown  on  to  its  back,  immediately  turns  over  again.  If  put  into 
water,  it  swims  about  until  it  comes  to  a  floating  piece  of  wood  or  any  support 
when  it  crawls  out  of  the  water  and  sits  still.  If  it  be  placed  on  a  board  and 
the  board  be  inchned,  it  begins  to  crawl  slowly  up  it,  and  by  gradually  in- 
creasing the  inchnation  may  be  made  to  crawl  up  one  side  and  down  the 
other.  But  a  striking  difference  between  it  and  a  normal  frog  is  the  almost 
entire  absence  of  spontaneous  motion — that  is  to  say,  motion  not  reflexly 
provoked  by  changes  immediately  taking  place  in  its  environment.  xA.ll 
psychical  phenomena  seem  to  be  absent.  It  feels  no  hunger  and  shows  no 
fear,  and  will  suffer  a  fly  to  crawl  over  its  nose  without  snapping  at  it.  "  In 
a  word,  it  is  an  extremely  complex  machine,  whose  actions,  so  far  as  they  go, 
tend  to  self-preservation  ;  but  still  a  machine  in  this  sense,  that  it  seems  to 
contain  no  incalculable  element.  By  applying  the  right  sensory  stimulus 
to  it  we  are  almost  as  certain  of  getting  a  fixed  response  as  an  organist  is 
when  he  pulls  out  a  certain  stop." 

According  to  Schrader  and  Steiner,  if  care  be  taken  not  to  injure  the 
optic  thalami,  spontaneous  movements  may  be  occasionally  observed  after 
removal  of  the  cerebral  hemispheres.  On  the  approach  of  winter  such  a 
frog  has  been  observed  to  bury  itself  in  order  to  hibernate,  and  with  spring  to 
resume  activity  and  to  feed  itself  by  catching  insects.  The  behaviour  of 
such  decerebrate  animals  depends  on  the  part  taken  in  the  initiation  of 
movement  and  adapted  reactions  by  stimuli  entering  through  the  higher 
sense-organs.  Thus  an  ordinary  bony  fish  after  ablation  of  the  cerebral 
hemispheres  maintains  its  normal  equiUbrium  in  water.  It  is  continually 
swimming  about,  stopping  only  when  it  reaches  the  side  of  the  vessel  or  when 
worn  out  by  fatigue.  Here,  again,  if  the  thalami  and  optic  lobes  be 
intact  the  fish  has  been  observed  to  show  very  httle  difference  from 
a  normal  animal  and  to  possess  the  power  of  distinguishing  edible 
from  non-edible  material.  On  the  other  hand,  in  the  elasmobranch 
fishes,  which  depend  mainly  upon  their  olfactory  apparatus  as  a  guide  to 
movement,  the  removal  of  the  cerebral  hemispheres  with  the  olfactory 
lobes,  or  of  the  latter  alone,  produces  complete  immobility  and  absence  of 


396  PHYSIOLOGY 

spontaneous  morement,  even  though  the  optic  thalami  and  optic  lobes  may 
be  intact. 

In  the  bird  the  cerebral  hemispheres  may  be  removed  with  ease.  A 
decerebrate  pigeon,  if  its  optic  lobes  be  intact,  walks  about  avoiding  all 
obstacles,  and  may  even  fly  a  short  distance.  In  the  dark,  i.e.  in  the  absence 
of  visual  impressions,  it  remains  perfectly  still.  The  bird,  however,  is  unable 
to  recognise  food,  or  enemies,  or  individuals  of  the  opposite  sex ;  it  shows 
no  fear  and  responds  to  stimuh  like  the  brainless  frog  described  above. 

Goltz  has  succeeded  in  the  dog  in  removing  the  whole  of  the  cerebral 
heruispheres  in  three  operations.  The  dog  was  kept  ahve  for  eighteen 
months  after  the  final  operation.  It  was  able  to  walk  in  normal  fashion 
and  spent  the  greater  part  of  the  "day  in  walking  up  and  down  its  cage. 
At  night  it  would  sleep  and  then  required  a  loud  sound  to  awaken  it.  It 
reacted  to  stimuh  in  a  normal  fashion,  shutting  its  eyes  when  exposed  to  a 
strong  Hght,  shaking  its  ears  in  response  to  a  loud  sound.  On  pinching  its 
skin  it  attempted  to  get  away,  snarhng  or  turning  round  and  biting  clumsily 
at  the  experimenter's  hand.  It  had  no  power  to  recognise  food  and  had  to  be 
fed  by  placing  food  in  its  mouth,  though,  if  this  food  were  mixed  with  a 
bitter  substance,  such  as  quinine,  it  was  at  once  rejected.  The  dog  never 
showed  any  signs  of  pleasure,  or  recognition  of  the  persons  that  fed  it,  or  of 
fear.  Removal  of  the  hemispheres  had  thus  produced  loss  of  all  understand- 
ing and  memory.  There  was  no  sign  of  conscious  intelligence,  and  all  the 
actions  of  the  animal  must  be  regarded  as  reflex  responses  to  immediate 
excitation. 

With  the  development  of  the  cerebral  hemispheres  in  the  higher  mammals 
there  is  a  considerable  shifting  of  motor  reactions  from  those  which  are 
immediate  and  '  fatal '  or  inevitable  to  those  which  are  educatable.  The 
cerebral  hemispheres  in  man  take  a  large  part  in  the  determining  of  even 
the  common  reactions  of  everyday  life.  Ablation  of  the  hemispheres 
therefore,  or  even  part  of  the  hemispheres,  in  the  ape  and  man  gives  rise 
to  much  more  lasting  symptoms  than  is  the  case  in  the  animals  we  have  just 
studied.  These  defects  we  shall  have  to  consider  more  fully  later.  The 
results,  however,  obtained  on  the  lower  animals,  from  the  dog  downwards, 
show  that  the  brain  stem,  from  the  head  ganghon  of  the  optic  thalamus  back 
to  the  medulla,  with  the  spinal  cord,  represents  a  complex  mechanism  which 
can  be  played  upon  by  impulses  received  through  all  the  sensory  apparatus 
of  the  body,  and  is  able  to  adjust  the  motor  and  visceral  reactions  to  the 
immediate  environment  of  the  animal. 

Certain  of  these  immediate  reactions  are  susceptible  of  further  physiologi- 
cal analysis.  We  have  seen  that  the  spinal  cord  contains  the  co-ordinated 
mechanism  for  the  movement  of  the  limbs.  We  may  now  discuss  how  the 
movements  of  the  limbs  are  co-ordinated  with  those  of  the  trunk  and  head  in 
the  maintenance  of  the  unstable  position  of  the  animal  in  standing  and  in 
locomotion.  For  this  purpose  there  has  been  developed  the  great  mass  of 
nerve  matter  in  the  roof  of  the  metencephalon,  viz.  the  cerebellum. 


SECTION  XIII 

THE   FUNCTIONS   OF  THE   CEREBELLUM 

The  carrying  out  of  co-ordinated  movements  is  associated  with  and  regu- 
lated by  afferent  impressions  which  can  be  divided  into  two  main  groups. 

In  the  first  group  may  be  placed  those  due  to  the  changes  in  the  environ- 
ment of  the  animal,  working  on  sensory  structures  or  '  receptors,'  of  varpng 
qualitative  sensibility,  in  the  surface  of  the  body.  These  receptors  may  be 
excited  by  the  mechanical  stimuli  of  pressure,  by  changes  of  temperature, 
or  by  nocuous  or  harmful  impressions,  such  as  Avould,  in  the  presence  of 
consciousness,  give  rise  to  pain.  At  the  fore  end  of  the  body  we  have  in 
addition  the  special  receptor  organs  excited  by  waves  of  light  or  of  sound. 
The  action  of  any  of  these  impressions,  if  of  sufl&cient  intensity,  is  to  evoke 
an  appropriate  reflex  movement,  such  as  the  flexor  reflex  in  response  to 
nocuous  stimulus  applied  to  the  foot,  or  the  stepping,  or  extensor,  reflex 
excited  by  steady  pressure  on  the  sole  of  the  foot. 

The  integrity  of  the  nerve  paths  carrying  these  afferent  impressions  and 
of  the  motor  paths  to  the  muscles  is  not,  however,  sufficient.  A  secondary 
set  of  afferent  impulses  is  essential  in  order  to  guide  and  regulate  the  extent 
of  the  resultant  discharge.  These  secondary  afferent  impulses  start  in  the 
deep  tissues,  viz.  the  muscles,  joints,  and  ligaments,  which  are  provided  with 
special  sense-organs  capable  of  being  stimulated  by  the  mechanical  changes 
of  tension  or  pressure  set  up  by  the  movements  themselves.  The  importance 
of  these  impressions  for  the  carrying  out  of  muscular  movements  is  shown 
by  the  ataxia  which  is  the  result  of  injury  to  the  corresponding  afferent 
nerves.  Degeneration  of  the  nerves  to  muscles,  or  section  of  the  afferent 
roots,  causes  marked  ataxia  of  the  movements  of  the  limb,  whereas  no  such 
result  follows  section  of  all  the  cutaneous  nerves  supplying  the  surface  of  the 
limb  with  sensibility.  To  this  system  of  aft'erent  nerves  Sherrington  has 
given  the  name  of  the  '  proprioceptive  '  system,  since  it  is  excited,  not  directly 
by  changes  in  the  environment,  b\it  by  alteration  in  the  animal  itself.  It  is 
responsible  for  reactions  difioring  in  many  respects  from  those  which  are  the 
immediate  result  of  stimulation  of  the  other  system,  the  '  exteroceptive,' 
which  is  distributed  over  the  surface  of  the  body.  Since  it  is  excited  by 
the  movement  of  the  nuiscles  themselves,  i.e.  by  the  first  result  of  the  reaction 
to  external  stimulus,  it  serves  as  a  governing  mechanism  to  regulate  the 
extent  of  each  motor  discharge.  Its  excitation  not  only  prevents  over-action 
of  the  muscles,  but  may  evoke  a  compensatory  reflex  in  an  opposite  direction 
to  the  reflex  inmiediately  excited  from  the  skin.     A  marked  feature  of  this 

397 


398  PHYSIOLOGY 

system  is  its  tendency  to  continued  or  tonic  activity.  The  steady  sliglit  con- 
traction, or  '  tone,'  which  is  observable  in  most  skeletal  muscles,  is  inde- 
pendent of  the  surface  sensibihty  and  depends  entirely  on  the  proprioceptive 
system  of  the  muscles  and  their  accessory  structures. 

In  the  decerebrate  animal  the  rigidity  of  a  limb  disappears  at  once  after 
section  of  its  afferent  roots,  though  it  is  unaltered  by  division  of  the  main 
skin  nerves.  This  tonus  does  not  affect  all  muscles  to  an  equal  degree. 
In  every  hmb  there  is  a  predominance  of  tonus  in  certain  muscles, 
so  that  the  result  on  the  whole  Hmb  is  an  attitude  or  posture  which 
is  typical  of  the  limb  or  the  animal.  Thus  the  spinal  frog  takes  up  an 
attitude  which  is  very  different  from  that  which  would  be  impressed  on  it  by 
gravity  in  the  absence  of  muscular  activity.  If  one  of  its  hind  hmbs  be 
extended  gently,  it  soon  draws  it  up  to  reproduce  the  same  crouching  position. 
The  posture  of  the  hmb  is  therefore  a  result  of  afferent  impressions  continually 
ascending  its  proprioceptive  nerves  and  exciting  a  tonic  activity  which 
predominates  in  certain  definite  muscles.  This  posture,  as  carried  out  by 
the  spinal  cord,  is  a  segmental  response.  It  determines  the  relation  of  the 
Hmb  to  the  trunk,  and  to  a  less  extent  of  the  four  Hmbs  to  one  another.  It  is 
not  concerned  with  the  relation  of  the  animal  as  a  whole  to  its  environment, 
and  only  to  a  slight  extent  with  the  maintenance  of  equihbrium  in  the 
presence  of  the  continually  acting  force  of  gravity. 

In  the  evolution  of  the  nervous  system  there^  has  been  a  continual 
subordination  of  the  hinder  parts  to  the  head  end,  in  consequence  of 
the  development  at  this  end  of  the  aU-important  distance  receptors, 
the  impulses  from  which  take  a  predominating  part  in  determining  the 
reactions  of  the  body  as  a  whole.  In  fact  the  subordination  of  one  part  of 
the  central  nervous  system  to  another  is  in  direct  relation  to  the  importance 
of  the  afferent  impulses  arriving  at  each  portion  of  the  system.  Thus  the 
vaso-motor  centres  segmentally  distributed  throughout  the  spinal  cord  are 
subject  to  the  vaso-motor  centre  in  the  medulla,  which  is  developed  at  the 
point  of  entry  of  the  vagus  nerves,  i.e.  the  chief  afferent  nerves  from  the  heart 
and  large  blood-vessels.  The  collections  of  grey  matter  presiding  over  the 
segmental  reactions  of  the  intercostal  muscles  are  entirely  subordinated  to 
the  grey  matter  in  the  medulla  around  the  entry  of  the  vagus  fibres  from 
the  lungs. 

This  subordination  of  the  hinder  to  the  anterior  sense-organs  is  paralleled 
in  the  case  of  the  proprioceptive  system.  Entering  the  hind-brain  at  the 
upper  border  of  the  medulla  is  the  eighth  nerve,  composed  of  two  parts  which 
differ  widely  in  functions,  viz.  the  cochlear  division  and  the  vestibular 
division.  The  former  is  entirely  concerned  with  the  reception  of  sound 
waves,  and  is  therefore  the  auditory  nerve.  The  vestibular  nerve,  which  is 
distributed  to  the  rest  of  the  membranous  labyrinth,  must  be  assigned  to  the 
proprioceptive  system.  The  labyrinth  is  practically  a  double  organ.  The 
primitive  auditory  sac  arises  as  a  simple  involution  of  the  surface.  In  the 
CQurse  of  development  the  front  part  is  modified  to  form  the  canal  of  the 
cochlea,  which  is  set  apart  entirely  for  the  reception  of  sound.     From  the 


THE  FUNCTIONS  OF  THE  CEREBELLUM 


399 


back  part  there  are  formed  two  sacs— the  saccule  and  utricle — and  the  three 
semicircular  canals.  The  saccule  and  the  utricle,  which  receive  each  a  larg ; 
branch  of  the  vestibular  nerve,  represent  the  otohth  organ,  which  is 
fomid  in  almost  all  classes  of  animals.  The  crayfish,  for  instance, 
at  the  base  of  its  antennae  presents  a  small  sac  lined  with  hairs  and 
richly  supplied  with  nerves.  In  this  sac  a  small  calcareous  particle  rests 
on  the  hairs.  It  is  evident  that  the  incidence  of  the  pressure  of  the  small 
stone  or  otohth  on  the  hairs  will  vary  according  to  the  position  of  the 
animal  (Fig.  200),  so  that  any  change  in  the  position  of  the  head  will  be 
attended  by  alteration  in  the  nerve  fibres  which  have  been  stimulated  by  the 

^     Mm  ^  mm' 

ot 


Fig.  200.  Diagram  of  an  otolith  organ,  to  show  how  alterations 
in  its  position  will  cause  the  weight  of  the  otolith  (of.)  to  press  on 
different  sense-cells,  and  therefore  to  affect  different  nerve  fibres. 

pressure  of  the  otohth,  and  therefore  in  the  nature  of  the  impulses  flowing  to 
the  central  nervous  system.  The  importance  of  these  impulses  in  regulating 
the  locomotion  and  the  maintenance  of  the  equihbrium  of  the  animal  is 
well  shown  if  the  otolith  be  replaced  by  a  small  fragment  of  iron.  Under 
normal  circumstances  the  iron  particle  will  act  quite  as  well  as  an  otohth. 
If,  however,  a  powerful  magnet  be  brought  in  the  neighbourhood  of  the 
animal,  the  pressure  of  the  particle  will  not  be  determined  simply  by  gravity 
and  therefore  by  the  position  of  the  animal,  so  that  there  will  be  a  dissonance 
between  the  impulses  arriving  from  the  otolith  organ  and  those  arising  from 
the  sense-organs  of  the  body,  and  marked  disorders  of  equilibrimn  are  the 
result. 

In  the  saccule  and  utricle  the  vestibular  nerve  ends  in  similar  otohth 
organs  known  as  the  maculae  acousticac.  These  are  small  elevations 
covered  with  long  hairs  and  supplied  with  nerves.  One  or  two  calcareous 
secretions  or  otoliths  are  embedded  in  the  hairs,  so  that  any  change  in  position 
will  cause  a  corresponding  change  in  the  nerve  fibres  which  are  being  excited 
by  the  weight  of  the  otoliths.  The  semicircular  canals,  which  he  in  the  three 
planes  of  space,  are  also  provided  wnth  end-organs,  somewhat  similar  in 
structure  to  the  maculae  acousticae,  but  devoid  of  otoliths.  They  are  excited 
by  mass  movements  of  the  fluid  endolymph,  filling  the  canals,  which  are  set 
up  by  rotation  of  the  head. 

Since  the  nervous  apparatus  of  the  labyrinth  is  excited  not  by  changes 
in  the  environment,  from  which  it  is  carefully  shielded,  but  by  changes  in  the 


400  PHYSIOLOGY 

animal  itself,  we  are  justified  in  assigning  it  to  the  proprioceptive  system,  of 
which  indeed  it  represents  the  most  important  receptor.  Just  as  the  pro- 
prioceptive nerves  of  a  hmb  are  responsible  for  the  tonus  of  the  limb  muscles, 
so,  as  Ewald  has  shown,  each  labyrinth  is  responsible  to  a  considerable  degree 
for  the  tonus  of  the  corresponding  side  of  the  body.  Extirpation  of  one 
labyrinth  causes  a  lasting  loss  of  tone  in  the  muscles  of  the  same  side.  A 
further  functional  resemblance  lies  in  the  part  played  by  the  labyrinth  in  the 
determination  of  posture.  The  resultant  effect  of  the  impulses  arising  in  it 
is  to  maintain  a  reflex  posture  of  the  head  and  eyes,  so  that  the  optic  axes  in 
a  position  of  rest  are  directed  towards  the  horizon.  Stimulation  of  the 
labyrinth  causes  therefore  movements  of  the  eyes  which  may  or  may  not  be 
associated  with  correlated  movements  of  the  head. 

As  in  the  case  of  the  other  sense-organs  of  the  anterior  end  of  the  body, 
the  reflexes  excited  from  the  labyrinth  dominate  over  those  evoked  by  pro- 
prioceptive impulses  from  the  hinder  portions  of  the  body.  At  the  entry 
of  its  nerve  into  the  brain  stem  a  mass  of  grey  matter  is  developed,  which 
must  be  regarded  as  the  head  ganghon  of  the  proprioceptive  system,  and 
the  chief  co-ordinating  organ  of  all  the  reflex  systems  which  determine 
posture  of  the  hmbs  and  of  the  whole  animal,  and  therefore  the  maintenance 
of  equilibrium  both  at  rest  and  during  locomotion.  This  organ  is  the 
cerebellum,  associated  with  the  grey  matter  in  the  upper  part  of  the  fourth 
ventricle  at  the  point  of  entry  of  the  vestibular  nerves.  The  cerebellum 
commences  in  early  foetal  life  as  a  small  elevation  in  the  dorsal  wall  of  the 
neural  tube,  where  the  eighth  nerve  enters.  Simple  in  structure  and  small 
in  extent  in  most  of  the  fishes  and  amphibia,  it  grows  in  extent  with  increasing 
complexity  of  the  animal's  motor  reactions,  and  attains  its  greatest  develop- 
ment in  the  mammaha.  In  this  class  the  cerebellum,  hke  the  cerebrum,  is 
most  highly  developed  in  man  and  the  higher  apes.  It  is  generally  described 
in  man  as  consisting  of  a  middle  lobe,  composed  of  the  superior  and  inferior 
vermis,  with  two  lateral  hemispheres,  and  these  are  subdivided  by  anatomists 
according  to  the  situation  of  the  chief  sulci.  From  the  physiological  point 
of  view  the  structure  of  the  organ  is  relatively  simple,  as  is  shown  by  the 
uniformity  of  its  structure  throughout  all  parts.  It  may  be  considered  as 
formed  of  two  main  structures,  viz.  the  cortex  and  the  central  or  roof  ganglia. 

The  surface  of  the  cerebellum  is  increased  by  being  thrown  into  folds  or  laminae, 
so  that  a  section  of  this  organ  has  a  tree-like  appearance.  A  section  through  a  lamina 
shows  three  distinct  zones  :  an  outer  molecular  layer  presenting  a  granular  appearance 
with  a  few  nuclei  ;  internal  to  this  a  granule  layer  composed  of  many  nuclei  of  nerve - 
cells  ;  and  most  deeply  a  central  core  of  white  matter.  Between  the  molecular  and 
granular  layers  are  situated  the  cells  of  Purkinje,  large  flask -shaped  cells  each  with  one 
apical  dendrite,  distinguished  above  all  other  dendrites  of  the  central  nervous  system 
by  the  richness  of  its  branching,  and  with  one  axon,  which  leaves  the  base  of  the  cell 
and  passes  down  into  the  central  white  matter,  giving  off  collaterals  in  its  course. 
In  preparations  made  by  Golgi's  method  we  are  able  to  distinguish  the  various  elements 
composing  these  layers  and  their  relations.  The  molecular  layer,  besides  neuroglia- 
ccUs  and  the  branching  dendrites  of  the  cells  of  Purkinje,  contains  certain  star -shaped 
cells  {a  Fig.  201),  which  give  off  an  axon  running  parallel  with  the  surface  in  the 
molecular  layer.     From  this  axon  branches  dip  down  towards  the  cells  of  Purkinje, 


THE  FUNCTIONS  OF  THE  CEREBELLl^ 


401 


where  they  end  in  a  rich  basket-work  of  fibres  around  the  body  and  beginning  of  the 
axon  of  these  cells.  The  nuclear  or  granular  layer  presents  two  kinds  of  cells.  The 
most  numerous  is  a  small  cell  with  a  few  short  dendrites,  each  of  which  terminates 
in  a  claw-shaped  arborisation,  and  a  single  long  axon,  which  passes  straight  up  into 
the  molecular  layer,  where  it  bifurcates.  The  two  branches  run  parallel  with  the 
surface  in  a  direction  at  right  angles  to  the  plane  of  expansion  of  the  dendrites  of 
Purkinje's  cells,  apparently  resting  against  the  serrations  on  the  edges  of  these  processes. 
The  second  kind  of  cell  in  the  granular  layer  is  the  so-called  Golgi's  cell — a  large  cell 


Central 

white 

matter. 


Fig.  201.  Schema  of  constituent  elements  of  cerebellum.  (Modified  from  Bom 
and  Daviuoff.)  On  the  left  is  a  section  of  the  cortex  as  it  appears  when 
stained  by  ordinary  methods.  The  middle  portion  represents  diagramniatically 
a  section  at  right  ansles  to  the  lamina^,  while  to  the  right  of  the  dotted  line  the 
section  is  taken  in  the  same  plane  as  the  laminre. 
a,  star-shaped  cells  of  molecular  lnyeT  ;   b,  b,  cells  of  Purkiiije;  c,  '  Golgi  cell '  ; 

d.  small  cells  of  nuclear  layer ;   e,  '  tendril  fibre  '  ;  /,  '  moss'  fibre  '  ;   g,  axon  of  cell 

of  Purkinje. 

with  many  dendrites  and  an  axon  which  terminates  by  frequent  branches  in  the  neigh- 
bouring grey  matter. 

The  Hbri's  making  up  the  white  matter  are  of  three  kinds — two  afferent  and  one 
efferent.  The  nto.s-s-  Jibres,  so  called  from  the  curious  thickenings  they  present  in  the 
nuclear  layer,  pass  up  into  the  grey  matter  and  terminate  by  frequent  branches  in 
this  layer.  The  tendril  Jibres,  also  afferent,  end  in  a  rich  arborisation  which  surrounds 
the  distal  part  of  the  bodies  and  the  bases  of  the  dendrites  of  the  cells  of  Purkinje. 
The  efferent  fibres  arc  represented  by  the  axons  of  the  cells  of  Purkinje,  which  acquire 
a  medullary  sheath  and  run  down  into  the  white  matter. 

This  slight  sketch  of  the  anatomy  gives  us  a  conception  of  the  extreme  complexity 
of  choice  presented  to  nervous  impulses  traversing  the  cerebellar  cortex.  Thus  a 
discharge  along  an  axon  of  the  cell  of  Purkinje  may  be  excited  (1)  by  an  impulse  ascend- 
ing the  tendril  fibres  ;  or  (2)  by  one  aseending  the  moss  fibres  through  the  granule 
cells,  and  then  i)assing  by  their  bifurcating  axon  to  the  dendrites  of  the  cells  of 
Purkinje;  or  (3)  by  the  star-shaped  cells  of  the  molecular  layer  and  their  basket-work 
round  the  body  of  Purkinje's  cells. 

The  rouj  gaivjlia  consist  of  the  nuclei  fastigii  near  the  middle  line,  the  nuclei  em- 


402  PHYSIOLOGY 

boliformes  situated  just  dorsal  to  these,  and  the  nuclei  dentati,  large  crenated  capsules 
of  grey  matter  lying  in  the  middle  of  each  lateral  lobe.  The  cells  composing  the  grey 
matter  of  the  central  nuclei  are  large  and  multipolar,  resembling  those  foimd  in  the 
nuclei  of  motor  nerves. 

The  cerebellum  receives  fibres  from  all  the  receptor  apparatus  of  the  body  which 
can  be  classed  in  the  proprioceptive  system.  The  greater  number  of  these  fibres 
run  directly  to  the  cortex,  especially  of  the  vermis,  and  there  is  no  evidence  of 
the  passage  of  any  efferent  fibres  from  the  cortex  directly  to  the  motor  apparatus  of  the 
cord. 

The  connections  of  the  cerebellum  are  established  by  means  of  its  three  peduncles, 
and  may  be  classified  as  follows  : 

AFFERENT  TRACTS.  Inferior  Peduncle.  By  this  peduncle  afferent  fibres 
pass  to  the  superior  vermis  : 

(1)  From  Clarke's  column  of  the  same  side  by  the  posterior  cerebellar  tract. 

(2)  From  the  dorsal  column  nuclei,  viz.  the  nucleus  gracilis  and  nucleus  cuneatus 
of  each  side,  so  that  connection  is  estabished  in  this  way  with  the  prolongations  of  the 
posterior  sensory  roots  which  run  into  the  posterior  columns  of  the  cord. 

(3)  By  the  internal  restiform  body  from  the  vestibular  division  of  the  eighth  nerve, 
part  of  the  fibres  passing  through,  and  perhaps  making  connections  with,  Deiters' 
nucleus. 

(4)  A  strong  band  of  fibres  passes  from  the  inferior  olivary  body  into  the  opposite 
cerebellar  hemisphere.  Atrophy  of  one  side  of  the  cerebellum  induces  a  corresponding 
atrophy  in  the  opposite  olivary  body. 

Middle  Peduncle.  The  broad  mass  of  fibres  making  up  these  peduncles  is  partly 
afferent  and  partly  efferent.  Many  fibres  originate  in  the  cells  in  the  formatio  reticu- 
laris of  the  pons,  cross  the  middle  line,  and  pass  up  into  the  lateral  cerebellar  hemi- 
sphere of  the  opposite  side.  Fibres  also  pass  from  the  cerebellum  to  the  pons  to  end 
round  cells  in  the  same  region.  By  this  means  connection  is  established  between  the 
cerebellar  hemispheres  and  the  corticopontine  fibres  which  pass  by  the  crura  cerebri 
between  the  pons  and  the  frontal  and  temporal  portions  of  the  cerebral  cortex  of  the 
opposite  side.  On  account  of  this  connection  there  is  a  close  association  between  the 
development  of  each  cerebellar  hemisphere  and  the  contralateral  cerebral  hemisphere. 
Atrophy  of  one  half  of  the  cerebrum  brings  about  atrophy  of  the  opposite  hemisphere  of 
the  cerebellum. 

The  Superior  Peduncle.  By  this  path  fibres  from  the  superior  corpora  quadri- 
gemina,  i.e.  from  the  terminations  of  the  optic  nerve,  pass  into  the  cortical  grey  matter 
of  the  cerebellum  (Fig.  202). 

EFFERENT  TRACTS.  The  cerebellar  cortex  must  be  regarded  as  a  receiving 
rather  than  as  a  discharging  station.  Stimulation  of  it  has  little  effect  unless  strong 
currents  are  employed,  and  a  inotor  response  is  obtained  more  easily  the  deeper  the 
electrodes  are  sunk  below  the  grey  matter.  The  fibres  which  form  the  axons  of  the 
cells  of  Purkinje  pass  partly  towards  the  pons  by  the  middle  peduncle,  largely,  how- 
ever, towards  the  roof  nuclei,  where  they  terminate.  These  nuclei  form  the  efferent 
stations  of  the  cerebellum.  From  them  fibres  pass  in  various  directions.  A  large 
bundle  leaves  the  dentate  nucleus,  runs  into  the  superior  peduncle,  or  brachium, 
and  passing  deeply  across  to  the  tegmentum  of  the  opposite  side,  traverses  the  red 
rmcleus  to  end  in  the  subthalamic  region  of  the  opposite  side  of  the  brain.  A  certain 
number  of  fibres,  chiefly  derived  from  the  central  nuclei,  such  as  the  nucleus  fastigii, 
pass  forward  to  the  corpora  quadrigemina  chiefly  on  the  same  side.  From  the  cerebellum 
itself  no  direct  tract  runs  into  the  spinal  cord.  The  nuclei  of  Deiters  and  of  Bechterew 
(the  paracerebellar  nuclei),  which  are  connected  with  the  endings  of  the  vestibular 
nerve,  are,  however,  closely  associated  with  the  roof  nuclei,  and  give  rise  to  descending 
fibres  which  pass  into  the  antero -lateral  region  of  the  cord  as  the  vestibulo-spinal 
tract. 

The  cerebellum  is  a  receiving  station  not  only  for  impulses  which  arise  in 
the  skin  and  eyes,  i.e.  on  the  surface  of  the  body,  but  especially  for  those 


THE  FUNCTIONS  OF  THE  CEREBELLUM 


403 


which  have  been  defined  as  proprioceptive,  and  originate  either  in  the  muscles 
and  tendons  or  in  the  labyrinth.  Activity  of  this  apparatus  is  roused  as  a  rule 
by  the  movement  of  the  organism  itself,  and  is  only  a  secondary  result  of  the 
environmental  stimulation  which  provoked  the  original  movement.  By  its 
efferent  tracts  starting  in  the  roof-  and  paracerebellar  nuclei,  the  cerebellum 
is  able  to  affect  the  musculature  of  the  same  side  of  the  body  by  a  direct 
influence  on  the  anterior  horns.  It  also  enters  to  a  much  greater  extent  into 
relation  with  the  opposite  cerebral  hemi- 
spheres, so  that  it  is  in  a  position  to 
control  or  modify  the  activity  of  these, 
whether  excited  on  their  sensory  or  on 
their  motor  sides. 

STIMULATION  OF  THE  CEREBEL- 
LUM. It  was  first  shown  by  Ferrier 
that  movements  of  the  same  side  of 
the  body  can  be  excited  by  stimulation 
either  of  the  cerebellar  hemispheres 
or  of  the  superior  vermis.  These  results 
have  been  confirmed  by  subsequent 
observers,  and  point  to  each  half  of  the 
cerebellum  being  connected  functionally 
with  the  skeletal  muscular  apparatus 
of  the  corresponding  side  of  the  body. 
The  cortex  cerebelh  is  not  excited 
with  ease.  To  evoke  movements  much 
stronger  stimuU  are  necessary  than, 
e.g.  for  the  excitation  of  the  motor 
area  of  the  cerebral  cortex.  This  again 
is  in  accordance  with  what  we  should 
expect  from  the  anatomy  of  the  organ, 
knowing  as  we  do  that  the  cortex  is  an 
end-station  for  a  number  of  afferent 
paths,  but  has  no  direct  efferent  paths 
from  it  to  the  lower  motor  mechanisms 
of  the  cord.  On  the  other  hand,  move- 
ments are  excited  by  minimal  stimuli  from  the  intrinsic  nuclei  of  the 
cerebellum. 

As  a  result  of  his  experiments  Horsley  has  concluded  that  the  cortex 
cerebelh  must  be  regarded  as  an  aft'erent  receptive  centre  from  which  axons 
pass  to  the  ventrally  placed  efferent  nuclei,  viz.  the  nuclei  dentati,  fastigii, 
emboliformes,  as  well  as  Deiters'  nuclei.  Whereas  excitation  of  the  roof  nuclei 
produces  more  especially  movements  of  the  eyes  and  head,  the  paracere- 
bellar {e.(].  Deiters'  nucleus)  are  responsible  more  especially  for  the  move- 
ments of  the  trunk  and  limbs.  The  movements  of  the  body  which  are  thus 
evoked  are  those  concerned  in  maintaining  equihbrium  and  are  involved  in 
every  alteration  in  the  position  of  the  body. 


Fig.  202.     Diagram  of  aflfcrent  and  efferent 

tracts  of  csrebellum. 

(After  V.   Gehuchten.) 

OT,   optic    thalamus  ;  rn,   red   nucleus ; 

POT,  posterior  cerebellar  tract;  act,  anterior 

cerebellar  tract :    v,  fifth  nerve. 


404 


PHYSIOLOGY 


EFFECTS  OF  ABLATION  OF  THE  CEREBELLUM.  Complete  unilateral 
extirpation  of  the  cerebellum,  after  the  irritative  effects  of  the  lesion 
itself  have  passed  away,  brings  about  a  condition  of  the  animal  charac- 
terised by :  ■ 

(1)  Shght  loss  of  power  on  the  same  side  of  the  body. 

(2)  Considerable  loss  of  tone  on  the  same  side. 

(3)  Tremors    or    rhythmical 


Sup.Vermis 


\---C.V.T. 


-  -  -,s.c 


movements  of  the  muscles  on 
the  same  side  accompanying  any 
willed  movements. 

These    three    symptoms   are 

denoted  by  Luciani  as  asthenia, 

atonia,    and    astasia.      At    first 

C.R.V-t/7  CB)(5P  \  the  animal  is    quite   unable   to 

stand,  and  lies  on  the  side  of 
the  lesion  with  neck  and  trunk 
curved  in  the  same  direction  ; 
when  it  attempts  to  stand  it 
always  falls  to  the  same  side. 
After  two  or  three  weeks  the 
power  to  stand  is  regained, 
though  when  it  attempts  to 
walk  the  hindquarters  drag 
and  tremors  accompany  every 
effort.  The  animal  attempts 
to  correct  the  tendency  to  fall 
towards  the  side  of  the  lesion 
by  an  exaggerated  abduction 
of  the  hmbs  to  that  side,  and 
Tig.  202a.  Schema  of  connections  of  Deiters'  jg  always  ready  to  take  ad- 
nucleus.  (Bkuce.)  ,  f  ,  1  .  p  n 
CR,restiformbody;  kk,  roof  nuclei ;  sf,  sagittal  vantage  of  the  support  of  a  wall 
fibres  from  cortex  to  roof  nuclei ;  cvt,  cerebello-  to  enable  it  to  maintain  its 
vestibular  tract;  dn,  Deiters'  nucleus;  iii,  vi,  ■■.■-.  ■  ^  .  .  .  , 
nuclei  of  third  and  sixth  nerves;  plf,  posterior  eqmhbnum.  Swimmmg  IS  much 
longitudinal  bundle;  viii,  vestibular  division  of •  better  carried  out  than  walking, 
eighth  nerve  ;  sc,  semicircular  canals  ;  vsT,  vesti-  , .  ,  ,  r  , i  ,  -n  ,i 
bulo  spinal  fibres.                                                    the  contact  01  the  water  with  the 

skin  furnishing  guidance  to  the 
spinal  mechanism  which  is  lacking  when  the  animal  attempts  to  walk. 

When  the  whole  cerebellum  is  removed  the  animal  is  unable  to  walk, 
sometimes  for  months.  After  a  time  it  gradually  learns  to  walk,  but  this  is 
carried  out  by  an  alteration  of  the  method  of  progression.  The  disorders  of 
locomotion  are  quite  distinct  from  the  spinal  ataxia  observed  after  interfer- 
ence with  the  afferent  tracts  from  the  muscles.  The  difficulty  now  is  that 
each  diagonal  movement  of  the  limbs  in  progression  tends  to  throw  the 
centre  of  gravity  to  one  side  or  other  of  the  basis  of  support,  and  it  is  the 
mechanism  for  maintaining  the  right  position  of  the  centre  of  gravity,  i.e.  the 
posture  of  the  body  as  a  whole  in  relation  to  its  environment,  which  is  at 


THE  FUNCTIONS  OF  THE  CEREBELLl^M  405 

fault.  The  animal,  in  the  case  of  the  dog,  therefore  attempts  to  correct  the 
tendency  to  fall  to  one  side  or  other  at  each  step  by  making  its  basis  of 
support  as  wide  as  possible,  and  gradually  acquires  a  peculiar  gait,  consisting 
of  a  series  of  springs,  in  which  the  two  fore  limbs  and  two  hind  limbs  act 
together,  the  diagonal  movements  of  the  fore  limbs  being  practically 
abandoned. 

In  lesions  of  the  cerebellum  in  man  the  most  marked  symptoms  are 
the  cerebellar  ataxy  and  the  occurrence  of  tremors,  '  astasia,'  on  the  perform- 
ance of  willed  movements.  The  ataxy  has  the  same  origin  as  that  in  the  dog  ; 
each  spinal  act  of  locomotion  tends  to  throw  the  centre  of  gravity  outside 
the  line  of  support,  and  the  tendency  to  fall  thus  brought  about  is  voluntarily 
compensated  by  abduction  of  the  corresponding  limb.  A  staggering  gait  is 
thus  produced,  which  is  practically  identical  with  that  of  a  drunken  man,  and 
presents  no  trace  of  the  over-action  of  muscles  so  characteristic  of  spinal 
ataxy.  That  the  compensation,  which  is  slowly  acquired  after  extirpation  of 
the  cerebellum,  is  of  cerebral  origin  is  shown  by  the  fact  that  extirpation  of 
the  cerebral  hemispheres,  or  even  of  the  motor  areas  of  the  hemispheres, 
after  extirpation  of  the  cerebellum,  at  once  abohshes  the  power  of  movement 
which  has  been  reacquired,  and  after  the  motor  areas  are  destroyed  on  both 
sides  the  loss  of  power  of  progression  is  permanent. 

These  experiments  show  that  the  cerebellum,  in  Sherrington's  words, 
must  be  regarded  as  the  head  ganghon  of  the  proprioceptive  system,  acting 
as  a  centre  where  arrive  the  afferent  impulses  from  the  cord,  the  fifth  nerve 
and  especially  from  the  labyrinth.  It  influences,  through  the  superior 
peduncle,  the  cerebral  cortex  and  furnishes  the  subconscious  basis  for  the 
guidance  of  the  motor  functions  of  the  latter  organ.  Through  its  connections 
with  the  nuclei  of  the  bulb  and  the  efferent  tracts  arising  therefrom,  it  aug- 
ments the  tonic  activity  of  all  the  muscles  of  the  body,  an  effect  which  is 
especially  marked  in  the  absence  of  the  cerebral  hemispheres  and  is  respon- 
sible for  the  condition  known  as  decerebrate  rigidity.  As  a  centre  of  conjunc- 
tion for  the  afferent  impressions  from  the  muscles  and  those  from  the  laby- 
rinth it  co-ordinates  the  segmental  reflexes,  which  determine  the  relative 
posture  of  each  limb,  with  those  originating  in  the  labyrinth  and  determining 
the  position  of  the  head.  Thus  the  whole  mechanism  provides  for  a  mainten- 
ance of  equilibrium  of  the  body  as  a  whole,  and  for  the  proper  balancing 
of  the  reflex  movements  of  the  different  hmbs  with  those  of  the  trunk 
during  all  the  changes  in  the  position  of  the  centre  of  gravity  attending 
locomotion. 

The  view  liere  put  forward  really  includes  the  various  descriptions  of  the  functions 
of  the  cerebellum  which  have  been  given  by  different  authorities.  Thus  Luciani 
describes  the  cerebellum  as  an  organ  wliich  by  unconscious  processes  exerts  a  continual 
reinforcing  action  on  the  activity  of  all  the  spinal  centres.  Munk  ascribes  to  the 
cerebsllum  the  function  of  maintaining  bodily  equilibrium.  Lewandowsky  regaids 
the  cerebellum  as  the  central  organ  of  the  muscular  senses.  Huglilings  Jackson  ex- 
pressed many  years  ago  an  important  characteristic  of  the  cerebellum  when  he  WTote 
that  the  cerebellum  is  the  centre  for  continuous  movements,  and  the  cerebrum  for. 
changing  movements.  All  these  descriptions  come  under  Sherrington's  conception 
of  the  cerebellum  as  head  ganglion  ot  the  proprioceptive  system. 


SECTION  XIV 


VISUAL   REFLEXES 

Foremost  among  the  afferent  impulses  determining  the  reactions  of  higher 
animals  are  those  arising  in  the  eyes.  Each  retina,  or  rather  the  two 
retinae  acting  together  as  a  single  organ,  can 
be  regarded  as  a  sensory  surface,  every  point 
of  which  corresponds  to  a  point,  or  series 
of  points,  lying  in  a  given  direction  outside 
the  body.  Each  optic  nerve  contains  about 
half  a  milhon  nerve  fibres,  i.e.  as  many  as 
enter  the  cord  by  the  posterior  roots  from 
the  whole  of  the  body.  The  two  optic  nerves 
coming  from  the  retinae  meet  together  in  the 
floor  of  the  fore-brain  and  form  the  chiasma. 
A.t  the  chiasma  a  decussation  of  fibres  takes 
place,  which,  in  animals  such  as  the  rabbit, 
with  no  fusion  of  the  fields  of  the  two  eyes, 
is  practically  complete.  In  man  only  those 
fibres  which  arise  in  the  mesial  half  of  each 
retina  cross  the  mesial  plane  ;  these,  together 
with  the  uncrossed  fibres  from  the  temporal 
half  of  the  other  retina,  form  the  optic  tract 
of  the  opposite  side  (Fig.  203).  The  optic  tract 
passes  backwards  across  the  crus  cerebri  and 
finally  divides  into  three  branches,  in  the  roof 
of  the  mid-  and  fore-brain,  which  end  in  the 
giey  matter  of  the  anterior  corpora  quadri-  optifdecus'St?o'n(!hL7maT;'o^% 
gemina  and  in  the  external  geniculate  body  optic  tract ;  NC,  nucleus  caudatus; 
,     ,,  1    .  p     ,1  J.-       xT-    1  LN,  lenticular  nucleus ;    Th,  optic 

and     the     pulvmar     of     the     optic     thalamus,    thalamus;    G,  external  geniculate 

Kunning    in    the    optic    tract    are    also    fibres  body;  AQ,  anterior  corpus  quadri- 

,.■,■,  •  1,1  r  eeminum ;  P,  pulvinar ;  OpR,  optic 

which  are  simply  commissural;    these  form  radiations  running  to  00,  the  occi- 

the  mesial  root  of  the  optic  tract.     They  cross  pital  cortex;  llln  nucleus  of  third 

-,  .    .1        nerve  in  floor  of  Sylvian  aqueduct ; 

m  the  optic  chiasma  and  serve  to  connect  the  ly,  fourth  ventiicle. 
two  internal  geniculate  bodies.     In  addition 

to  the  afferent  fibres  from  the  retina  to  the  brain  the  optic  tract  contains  a 
certain  number  of  efferent  fibres  which  pass  out  and  end  in  the  retinae. 
It  is  evident  from  these  connections  that  whereas  section  of  one  optic 

406 


Fig.  203.  Diagram  to  show  con- 
nections of  optic  tracts.  (After 
Sherbington.) 


VISUAL  REFLEXES 


407 


NUCL.  EOfNGEt;- 


NUCL.  LAT.  MT 
(DARKSCHEWITSCM^ 


NUCt.OORS 


IL'CL.VENT.I.  f«NT.).__ 


•JUCl-.DORS.Il/POSTl 
(V.  GUDOENJ 


NUCL.  CEfJTRAUS--' 


NUCt.VENT.Il.(p0ST.) 


nerve,  say  the  right,  will  only  cause  loss  of  vision  in  the  right  eye,  section 
of  the  right  optic  tract  Avill  cli^^de  the  fibres  coming  from  the  right  halves  of 
both  retinae.  This  portion  of  the  retina  in  each  eye  is  stimulated  in  the 
normal  position  of  the  eyes  by  rays  of  hght  coming  from  the  objects  lying  to 
the  left  of  the  field  of  vision.  Section  of  the  right  optic  tract  therefore  causes 
bhndness  to  all  objects  to  the  left  of  the  median  line,  left  hemianopia. 
Section  of  both  optic  tracts  of  course  causes  complete  blindness. 

Every  movement  of  the  head  involves  compensatory  movements  of  the 
eyes,  and  conversely,  in  any  change  in  the  environment  of  the  animal  which 
demands  its  attention,  there  is 
a  movement  of  the  eyes  so  as  to 
turn  the  gaze  on  to  the  origin  of 
the  disturbance  as  an  antecedent 
to  any  body  movement.  In  the 
absence  of  normal  regulative  im- 
pulses from  the  skin,  or  from  the 
semicircular  canals,  the  afierent 
impressions  from  the  eyes  may 
serve  for  the  maintenance  of 
fairly  well  co-ordinated  move- 
ments— a  compensation  which  is 
rendered  possible  by  the  power 
of  the  cerebral  cortex  to  learn 
new  reactions  by  experience. 

The  centres  for  the  eye  move- 
ments are  contained  in  the  grey 
matter  in  the  floor  of  the  back 
part  of  the  third  ventricle  and  of 
the  iter  of  Sylvius.  Here  we  find 
the  nucleus  of  the  third  or 
oculo-motor  nerve.  The  oculo- 
motor nucleus  consists  of  several  divisions,  viz.  a  lateral  part  containing 
large  motor  cells,  a  superficial  median  nucleus  with  small  cells,  and  a 
deeper  median  nucleus  with  large  ceUs.  By  localised  stimulation  it  has  been 
found  possible  to  differentiate  the  functions  of  the  different  parts  of  the 
micleus  (Fig.  204).  Stimulation  of  the  back  part  of  the  third  ventricle  causes 
contraction  of  the  cihary  muscles,  and  a  little  behind  this  contraction  of  the 
pupil.  On  stimulating  the  floor  of  the  iter,  from  before  backwards  we  obtain 
contractions  in  order  of  the  rectus  internus,  the  rectus  superior,  the  levatoi- 
palpebrae  superioris,  the  rectus  inferior,  and  the  inferior  obhque  muscle.  On 
stimulating  more  laterally,  or  exciting  the  corpora  quadrigemina,  dilatation 
of  the  pupil  was  obtained. 

It  seems  probable  that  the  optic  thalamus  and  the  closely  related  external 
geniculate  body  are  mainly  concerned  Nvith  the  reception  of  visual  impulses 
and  their  forwarding  to  the  cerebral  cortex.  On  the  other  hand,  the  anterior 
or  superior  corpora  quadrigemina  are  mainly  concerned  with  the  co-ordination 


Fig.  204.  Diagram  to  show  origin  of  the  different 
fibres  of  the  third  and  fourtla  nerves  from  the 
oculo-motor  nuclei. 


408  PHYSIOLOGY 

of  visual  impressions  and  visual  movements  with  the  movements  of  every 
part  of  the  body,  and  especially  with  the  complex  mechanism  we  have  already 
studied  in  connection  with  the  labyrinth  and  cerebellum.  Stimulation  of  the 
corpora  quadrigemina  therefore  evokes  movements  of  the  eyes  and  of  the 
head  ;  extirpation  of  this  part,  though  it  may  interfere  with  co-ordination, 
does  not  necessarily  involve  loss  of  sight,  even  when  the  extirpation  is 
bilateral. 

The  multifarious  intercourse  which  is  continually  taking  place  between 


AntC.Quad. 


Optic  Tract 


•A  A/. 
^••■"  ^\////.Vestn 

o.  U. 


m^^\Ant'basf5  bundle 


Fig.  205.     Diagram  of  connections  of  posterior  longitudinal  bundle. 
Ant.C.Quad,  anterior  corpus  quadrigeminum  ;    oc.m.n,  oculomotor  nucleus  ; 
IV.n,  nucleus  of  fourth  nerve  ;  VI. n,  nucleus  of  sixth  nerve  ;  D.N,  Deiters'  nucleus  ; 
S.O,  superior  olive  ;    VIII.  Vest.n,  vestibular  nerve  ;    p.l.b,  posterior  longitudinal 
bundle  ;    Ist  c.n,  first  cervical  nerve. 

the  eye  centres  and  those  for  the  movements  of  the  body,  and  between 
afferent  impressions  from  the  eyes  and  those  from  the  semicircular  canals  and 
the  proprioceptive  system  generally,  is  effected  to  a  large  extent  through  the 
intermediation  of  the  posterior  longitudinal  bundle,  which  extends  through- 
out the  whole  length  of  the  mid-brain  and  the  hind-brain,  and  in  the  spinal 
cord  becomes  cojitinnous  with  the  anterior  basis  bundle  of  the  anterior 


VISUAL  REFLEXES  409 

columns.  Receiving  fibres  above  through  the  anterior  commissure  from 
the  optic  thalamus,  and  from  the  superior  corpora  quadrigemina,  it  is 
associated  in  its  course  with  the  three  motor  nuclei  that  give  origin  to  the 
nerves  supplying  the  muscles  of  the  eyeball,  viz.  the  third,  fourth,  and  sixth 
nerves.  Fibres  enter  the  posterior  longitudinal  bundle  from  the  auditory 
system,  and  from  the  superior  olive,  and  connections  are  also  estabhshed 
between  this  bundle  and  the  facial  nucleus,  and  the  nucleus  of  Deiters, 
representing  the  central  station  of  impulses  from  the  labyrinth.  The  general 
connections  of  the  bundle  are  shown  in  Fig.  205. 


SECTION  XV 

SUMMARY   OF   THE  CONNECTIONS   AND  FUNCTIONS 
OF   THE  CRANIAL  NERVES 

Cranial  nerves.  The  cranial  nerves  are  generally  reckoned  as  twelve  in 
number  :  1st,  olfactory  ;  2nd,  optic  ;  3rd,  oculo-motor  ;  4tli,  or  trochlear  ; 
5th,  or  trigeminus  ;  6th  ;  7th,  or  facial ;  8th,  auditory  ;  9th,  glossopharyn- 
geal ;  10th,  vagus  or  pneumogastric  ;  11th,  spinal  accessory  ;  12th,  hypo- 
glossal. 

Of  these  the  first  two  stand  on  a  different  footing  from  the  rest,  which, 
hke  the  spinal  nerves,  are  outgrowths  of  nerve  fibres  from  the  central  tube 
of  grey  matter  surrounding  the  neural  canal  or  from  gangha  corresponding 
to  the  spinal  posterior  root  ganghon. 

The  olfactory  bulb  and  the  retinae,  from  which  the  majority  of  the 
fibres  forming  the  olfactory  tract  and  the  optic  nerve  respectively  take  their 
origin,  are  analogous  rather  to  lobes  of  the  brain  than  to  peripheral  sense- 
organs.  Thus  in  the  retina  there  are  three  relays  of  neurons  through  which 
the  visual  impulse  must  pass  before  it  arrives  at  the  optic  nerve.  The 
olfactory  tract  and  optic  nerve  are  thus  comparable  with  the  association  or 
commissural  fibres  connecting  different  parts  of  the  central  nervous  system. 
The  connections  of  these  sensory  fibres  have  already  been  fully  dealt  with,  and 
the  structure  of  the  peripheral  sense-organ  will  be  treated  of  under  the  physi- 
ology of  the  special  senses.  Among  the  cranial  nerves  proper  we  may 
therefore  reckon  the  third  to  the  twelfth. 

The  third  or  oculo-motor  arises  from  an  extensive  nucleus  which  extends 
on  either  side  along  almost  the  whole  length  of  the  ventral  part  of  the 
aqueduct  of  Sylvius  close  to  the  middle  line,  the  most  anterior  part  lying  in 
the  back  part  of  the  third  ventricle  (Fig.  204).  The  anterior  part  is  com- 
posed of  small  cells  which  give  origin  to  the  fibres  innervating  the  intrinsic 
muscles  of  the  eye,  namely,  the  cihary  muscle  and  the  sphincter  pupillae. 
The  rest  of  the  nucleus  is  made  up  of  large  multipolar  cells,  arranged  in 
groups,  and  gives  origin  to  the  fibres  passing  to  most  of  the  extrinsic  muscles 
of  the  eye.  The  fibres  of  the  third  nerve  pass  through  the  tegmentum  to 
emerge  at  the  inner  margin  of  the  crusta  of  the  same  side.  The  fibres  from 
the  posterior  large-celled  nucleus  supply  the  following  muscles  :  levator 
palpebrarum,  superior  rectus,  inferior  rectus,  internal  rectus,  and  inferior 
obhque. 

Stimulation  of  the  trunk  of  the  third  nerve  causes  the  eyeball  to  look 

410 


CONNECTIONS  AND  FUNCTIONS  OF  CRANIAL  NERVES    411 

upwards  and  inwards,  with  contraction  of  the  pupil  and  spasm  of  accommo- 
dation. 

The  nucleus  of  the  fourth  nerve  is  situated,  just  behind  that  for  the  third, 
in  the  floor  of  the  Sylvian  aqueduct,  on  a  level  with  the  inferior  corpora 
quadrigemina.  The  fibres  run  from  here  down  towards  the  pons,  then  turn 
sharply  backwards  to  pass  into  the  valve  of  Vieussens,  which  they  cross  hori- 
zontally, decussating  with  the  nerve  of  the  opposite  side.  The  superficial 
origin  is  therefore  from  the  valve  of  Vieussens.  This  nerve  supphes  the 
superior  oblique  muscle  of  the  eyeball.  Its  stimulation  causes  the  eyeball  to 
look  downwards  and  outwards. 

The  sixth  nerve,  the  motor  nerve  for  the  external  rectus  muscle  of  the 
eyeball,  arises  from  a  group  of  large  multipolar  cells  lying  on  each  side  of 
the  middle  fine  in  the  floor  of  the  fourth  ventricle.  The  fibres  of 
the  nerve  pass  directly  outwards  to  emerge  from  the  anterior  ventral 
surface  of  the  medulla  between  the  pyramids  and  the  ohvary  eminence,  at 
the  lower  border  of  the  pons.  Stimulation  of  this  nerve  causes  the  eyeball 
to  look  directly  outwards.  All  these  three  oculo-motor  nuclei  receive 
collaterals  from  the  fibres  forming  the  posterior  longitudinal  bundle,  many 
of  which  are  axons  of  cells  in  Deiters'  nucleus.  It  is  by  this  means  that  the 
contractions  of  the  muscles  moving  the  eyeball  are  co-ordinated.  Sherring- 
ton has  shown  that  although  the  third,  fourth,  and  sixth  nerves  arise  directly 
from  the  brain  stem  and  have  no  ganglion  on  their  course,  they  are  really 
mixed  afferent- efferent  nerves.  Their  afferent  fibres,  which  must  arise 
from  the  cells  in  the  central  nervous  system  itself,  run  to  the  receptor  nerve 
endings  with  which  all  the  extrinsic  eye  muscles  are  richly  provided.  They 
are  exclusively  proprioceptive,  and  supply  no  organs  outside  the  muscles 
innervated  by  the  motor  fibres.  The  occurrence  of  afferent  fibres  in  these 
nerves  explains  the  fact  previously  observed  by  Sherrington,  that  after  total 
desensitisation  of  the  eyeball  by  means  of  cocaine,  or  by  section  of  the  first 
division  of  the  fifth  nerve,  the  ocular  movements  are  carried  out  with  as 
much  precision  as  in  the  normal  animal.  As  we  have  seen,  such  precision 
of  movement  requires  the  co-operation  of  afferent  impressions  from  the 
muscle,  and  the  only  possible  channels  for  these  impressions  are  the  pro- 
prioceptive sense-organs  and  the  afterents  of  the  third,  fourth,  and  sixth 
nerve  pairs  themselves. 

The  fifth  nerve,  or  trigeminus,  resembles  a  spinal  nerve  in  that  it  has  a 
motor  as  well  as  a  sensory  root.  The  motor  root  is  much  the  smaller  of  the 
two.  The  fibres  of  the  sensory  root  take  their  origin  in  the  cells  of  the 
Gasserian  ganglion,  which  is  in  all  respects  similar  to  the  ganglion  of  a 
posterior  spinal  nerve-root.  The  sensory  root  represents  the  somatic 
afferent  part  of  all  the  motor  cranial  nerves  from  the  third  to  the  hypoglossal 
and  has  a  correspondingly  wide  field  of  ending  in  the  brain  stem.  The 
aft'erent  fibres  of  the  fifth  nerve,  as  they  enter  the  pons,  bifurcate,  like  a  spinal 
afferent  nerve,  into  ascending  and  descending  branches.  The  ascending 
branches  are  short  and  pass  to  an  upper  sensory  nucleus,  situated  below  the 
lateral  part  of  the  fourth  ventricle  in  the  upper  part  of  the  pons.     The 


412  PHYSIOLOGY 

descending  branches,  wldch.  are  much  longer,  are  collected  into  one  or  more 
bundles  which  pass  downwards  in  the  lateral  part  of  the  reticular  formation, 
accompanied  by  the  downward  extension  of  the  sensory  nucleus  known  as  the 
substantia  gelatinosa.  The  descending  root  can  be  traced  down  in  the 
upper  part  of  the  cervical  cord,  its  fibres  in  this  region  forming  a  cap  to  the 
gelatinous  substance  of  Eolando.  From  the  "cells  of  the  sensory  nucleus 
fibres  pass  towards  the  median  raphe,  crossing  to  the  other  side  to  take  part 
in  the  formation  of  the  tract  of  the  fiUet  (the  trigemino- thalamic  tract).  The 
efferent  fibres  forming  the  motor  root  arise  from  two  nuclei.  The  chief  motor 
nucleus  consists  of  large  pigmented  multipolar  cells  situated  just  below 
the  surface  of  the  lateral  margin  of  the  fourth  ventricle  at  the  upper  part  of 
the  pons.  The  accessory  or  mesencephahc  nucleus  is  composed  of  large 
unipolar  ceUs,  situated  in  the  central  grey  matter  along  the  lateral  aspect  of 
the  anterior  end  of  the  fourth  ventricle,  and  in  a  corresponding  position  in 
mid-brain  as  far  as  the  upper  border  of  the  inferior  corpora  quadrigemina. 

The  fifth  nerve  is  the  motor  nerve  for  the  muscles  of  mastication,  and  for 
the  tensor  tympani  and  tensor  palati  muscles.  It  is  the  sensory  nerve  for  the 
whole  of  the  face  (including  eyeball,  mouth,  and  nose).  It  also  contains 
dilator  fibres  to  blood-vessels  derived  from  the  chorda  tympani,  and  is 
said  to  have  trophic  functions.  The  latter  conclusion  is  from  the  fact 
that  section  of  the  fifth  nerve  in  the  skull  is  followed  by  ulceration  and 
sloughing  of  the  cornea,  and  finally  by  destructive  changes  involving  the 
whole  eyeball.  Since,  however,  these  results  may  be  prevented  by  carefully 
shielding  the  eye  from  all  dust  and  deleterious  influences,  it  is  probable  that 
the  ulceration  is  merely  a  secondary  consequence  of  the  anaesthesia.  The 
cornea  being  anaesthetic,  foreign  objects  that  fall  on  its  surface  are  allowed 
to  remain  there,  and  so  give  rise  to  injurious  changes  and  ulceration. 

The  fifth  is  also  said  to  be  the  nerve  of  taste  for  the  anterior  third  of  the 
tongue,  but  it  is  probable  that  the  taste  fibres  which  run  in  the  fifth  are 
derived  from  the  glossopharyngeal  or  from  the  nervus  intermedins. 

The  eighth  nerve  and  its  connections  have  been  discussed  already  on 
several  occasions.  We  may  here  briefly  summarise  what  has  already  been 
stated.  In  describing  the  eighth  nerve  it  is  necessary  to  consider  separately 
its  two  divisions,  the  dorsal  or  cochlear  division  and  the  ventral  or  vestibular 
nerve.  The  fibres  of  the  cochlear  nerve  originate  in  the  bipolar  cells  of  the 
spiral  ganghon  of  the  cochlea.  They  carry  impulses  from  the  auditory  end- 
organ.  On  entering  the  medulla  they  bifurcate  into  ascending  and  descend- 
ing branches  which  terminate  in  two  nuclei,  the  ascending  branches  in  the 
ventral  nucleus,  the  descending  branches  in  the  dorsal  nucleus.  The  ventral 
or  accessory  nucleus  Hes  between  the  cochlear  and  vestibular  divisions  ven- 
trally  to  the  restiform  body.  The  dorsal  nucleus,  often  called  the  acoustic 
tubercle,  forms  a  rounded  projection  on  the  lateral  and  dorsal  aspects  of  the 
restiform  body.  From  these  two  nuclei  new  relays  of  fibres  start,  pass  to  the 
other  side,  by  crossing  the  median  raphe  (where  they  form  the  trapezium)  to 
lUfl  up  in  the  lateral  fillet  of  the  opposite  side.  From  the  ventral  nucleus 
tlie  fibres  pass  directly  to  the  opposite  side,  forming  the  greater  part  of  the 


CONNECTIONS  AND  FUNCTIONS  OF  CKANIAL  NERVES    413 

trapezium,  makiiig  connection  on  their  way  with  the  nucleus  of  the  trapezium 
and  with  the  superior  olive.  From  the  dorsal  nucleus  most  of  the  axons  pass 
dorsally,  forming  the  striae  acousticse  at  the  middle  of  the  floor  of  the  fourth 
ventricle.  On  arriving  at  the  middle  line  they  dip  down  and  join  the  fibres 
of  the  trapezium  of  the  opposite  side.  The  further  course  of  these  fibres 
up  to  the  internal  geniculate  body,  the  posterior  corpora  quadrigemina,  and 
the  auditory  radiations  of  the  cerebral  cortex,  have  been  described  on  p.  380. 

The  ventral  division  of  the  eighth  nerve,  or  vestibular  nerve,  originates 
in  the  bipolar  cells  of  the  vestibular  gangUon  or  ganglion  of  Scarpa.  These 
cells,  like  those  of  the  spiral  ganglion,  retain  the  primitive  bipolar  character. 
The  fibres  divide  into  ascending  and  descending  branches  which  become 
connected  with  two  nuclei.  The  dorsal  or  vestibular  nucleus,  or  principal 
nucleus,  which  receives  the  ascending  fibres,  is  a  mass  of  grey  matter  lying 
laterally  of  the  vago-glosso-pharyngeal  nucleus  and  corresponding  to  the 
lateral  triangular  area,  the  trigonum  acoustici,  which  is  seen  on  the  surface 
of  the  fourth  ventricle  outside  the  ala  cinerea.  The  descending  vestibular 
nucleus,  receiving  the  descending  branches  of  the  vestibular  nerve,  lies 
below  but  continuous  with  the  principal  nucleus.  The  fibres  of  the  vestibular 
nucleus  send  also  collaterals  to  the  nucleus  of  Deiters  and  the  nucleus  of 
Bechterew,  two  accumulations  of  large  multipolar  cells  lying  ventrally  and 
internally  to  the  vestibular  nucleus,  both  nuclei  being  in  close  relation  to  the 
roof  nuclei  of  the  cerebellum.  Many  fibres  of  the  vestibular  nerve  pass 
apparently  through  these  various  nuclei  on  the  inner  side  of  the  restiform 
body  into  the  cerebellum,  where  they  make  connection  with  the  roof  nucleus 
or  nucleus  fastigii.  By  the  nuclei  of  Deiters  and  Bechterew  the  vestibular 
nerve  is  connected  through  the  dorsal  longitudinal  bundle  and  the  descending 
vestibulo-spinal  tract  with  the  motor  nuclei  of  the  cranial  and  spinal  nerves. 

The  use  of  the  vestibular  nerve  is  entirely  connected  with  the  function 
of  equihbrium.  It  is  probably  not  concerned  in  conveying  auditory  im- 
pressions, all  its  nerve  fibres  being  derived  ultimately  from  the  nerve-endings 
in  the  saccule  and  utricle  and  semicircular  canals. 

The  seventh  cranial  nerve  or  facial  nerve  emerges  from  the  brain  at  the 
inferior  margin  of  the  pons,  lateral  to  the  point  of  exit  of  the  sixth  nerve. 
It  is  almost  entirely  a  motor  nerve,  but  carries  also  some  sensory  fibres 
for  taste  and  general  sensibility  which  it  receives  from  the  nervus  intermedius 
of  Wrisberg.  The  motor  nucleus  of  the  seventh  nerve  hes  in  the  reticular 
formation,  dorsally  to  the  superior  olive,  at  some  depth  below  the  floor 
of  the  fourth  ventricle.  From  this  nucleus  the  fibres  first  pass  inwards 
and  dorsally  towards  the  floor  of  the  ventricle,  where  they  collect  to  form 
a  bundle  which  runs  upwards  in  the  grey  matter  for  a  short  distance  and  then 
turns  sharply  in  a  ventro-lateral  direction  to  emerge  on  the  lateral  aspect  of 
the  pons.  The  fibres  from  the  motor  nucleus  supply  the  muscles  of  the  face, 
the  scalp,  and  the  ear.  Secretory  fibres  also  run  in  the  chorda  tympani, 
which  is  a  branch  of  the  facial.  These,  however,  are  probablv  derived,  like 
the  sensory  fibres,  from  the  nerve  of  Wrisberg.  The  sensory  fibres  of  the 
nerve  of  Wrisberg  originate  in  the  nerve-cells  of  the  geniculate  ganglion,  and 


414 


PHYSIOLOGY 


passing  inwards  with  the  main  root  of  the  facial,  divide  into  ascending  and 
descending  branches  and  end  in  the  upper  part  of  the  column  of  grey  matter 
which  receives  also  the  sensory  fibres  of  the  ninth  and  tenth  cranial 
nerves. 

The  ninth  and  tenth  cranial  nerves  arise  by  a  series  of  bundles  of  nerve 
fibres  from  the  side  of  the  medulla.  Both  the  ninth  and  tenth  are  mixed 
visceral  sensory  and  motor  nerves.  The  sensory  nucleus  is  a  column  of 
grey  matter  lying  laterally  to  the  hypoglossal  nucleus  just  below  the  promin- 
ence on  the  floor  of  the  fourth 
ventricle  known  as  the  ala 
cinerea.  The  descending  fibres 
of  these  nerves  form  a  well- 
marked  bundle  of  white  fibres 
known  as  the  fasciculus  soli- 
tarius,  or  sometimes,  from  its 
supposed  connection  with  the 
regulation  of  respiration,  the 
'  respiratory  bundle  of  Gierke.' 
It  may  be  traced  down  as  far  as 
the  uppermost  part  of  the  cer- 
vical cord,  its  fibres  losing 
themselves  on  their  way  down 
among  the  cells  of  the  enclosing 
Plan  of  the  origin  of  the  tenth  and  grey  matter.  The  efferent  fibres 

of  the  ninth  and  tenth  nerves 

pyramid ;     nXII,    nucleus    of    hypoglossal ; 


are   derived    partly    from    the 


Fig.    206. 

twelfth  nerves. 
pyr,   pyramia ;     nXII,    nucleus    of 
XII,  hypoglossal  nerve ;  diiX,  XI,  dorsal  nucleus  of 
vagus   and   accessory ;    n.amh,   nucleus  ambiguus  ;    dorsal  nucleus  of  the  vagUS  and 
js,  fasciculus  solitarius  (descending  root  of  vagus  and  ,    . 

glossopharyngeal);  fsn,  its  nucleus;  X,  crossing  accessory  nerveS  lymg  extern- 
motor  fibre  of  vagus  ;  g,  cell  in  ganglion  of  vagus  ally  to  the  nucleus  of  the  twelfth 
giving  origin  to  a  sensory  fibre ;  rfF,  descending  root         •' 

of  fifth ;  cr,  corpus  restiforme.  nerve,    and    partly    from    the 

nucleus   ambiguus,  a   mass  of 
grey  matter  lying  deeper  in  the  medulla  (Fig,  206). 

The  ninth  or  glossopharyngeal  nerve  supplies  motor  fibres  to  the  muscles 
of  the  pharynx  and  the  base  of  the  tongue,  and  secretory  fibres  to  the  parotid 
gland.  The  sensory  fibres  convey  impulses  from  the  tongue,  the  mouth,  and 
pharynx,  the  fibres  originating  outside  the  central  nervous  system  in  the 
gangHon-cells  of  the  ganglion  petrosum  and  the  ganghon  superius.  It  also 
contains  inhibitory  fibres  to  the  respiratory  centre. 

The  tenth  nerve,  vagus  or  pneumogastric,  is  joined  by  the  accessory  part 
of  the  spinal  accessory,  so  that  the  two  nerves  may  be  considered  together. 
It  has  both  afferent  and  efferent  functions  : 
Efferent  functions  : 

Motor  to  levator  palati  and  three  constrictors  of  pharynx. 

Motor  to  muscles  of  larynx. 

Inhibitory  to  heart. 

Motor  to  muscular  walls  of  oesophagus,  stomach,  and  small  intestine. 


CONNECTIONS  AND  FUNCTIONS  OF  CRANIAL  NERVES    415 

Motor  to  unstriated  muscle  in  walls  of  bronchi  and  bronchioles. 
Secretory  to  glands  of  stomach  and  to  pancreas. 

Afferent  functions  : 

Regulate    respiration.     Stimulation    of    central    end    may    quicken 
respiration  and  promote  inspiration,   or  may  inhibit    inspiration. 
Stimulation    of  central  end    of   superior   laryngeal  branch  causes 
stoppage  of  inspiration,  expiration,  cough. 
Depressor  and  pressor  (from  heart  to  vaso-motor  centre). 
Reflex  inhibition  of  heart. 

Its  afferent  fibres  arise  from  cells  in  the  gangha  on  the  trunk  of  the 
vagus,  namely,  the  jugular  ganghon  and  the  ganglion  trunci  vagi.  The 
spinal  accessory  nerve  arises  partly  in  connection  with  the  vagus,  partly  by 
a  series  of  roots  from  the  lateral  region  of  the  spinal  cord  as  low  as  the  sixth 
cervical  segment.  The  spinal  portion  of  the  nerve  is  purely  motor  and 
supplies  fibres  to  the  sterno-mastoid  and  trapezius  muscles. 

The  tivelfth  or  hypoglossal  nerve  arises  from  a  collection  of  large  multi- 
polar cells  in  the  floor  of  the  fourth  ventricle  at  its  lower  end  close  to  the 
middle  line.  The  nerve-trunk  issues  from  the  ventral  part  of  the  medulla 
in  the  groove  between  the  anterior  pyramid  and  the  olivary  body.  The 
hypoglossal  is  purely  motor  in  function,  supplying  the  muscles  of  the  tongue, 
the  extrinsic  muscles  of  the  larynx,  as  well  as  those  moving  the  hyoid  bone. 

Since  the  integrity  of  the  nuclei  of  the  cranial  nerves  is  a  necessary  con- 
dition for  the  carrying  out  of  various  reflex  acts  in  which  these  nerves  are 
involved,  the  grey  matter  of  the  fourth  ventricle  and  aqueduct  is  often 
spoken  of  as  if  it  were  cut  up  into  a  series  of  centres  distinct  for  every  act. 
The  chief  of  these  are  the  respiratory  and  the  vaso-motor  centres.  Other 
centres  that  may  be  enumerated  are  : 

Centres  for  movements  of  intrinsic  and  extrinsic  ocular  muscles. 

Cardiac  inhibition. 

Mastication,  deglutition. 

Sucking. 

Convulsive  (connected  with  respiratory). 

Vomiting. 

Diabetic  (connected  with  vaso-motor). 

Salivary. 

Centres  of  phonation  and  articulation. 

We  shall  have  to  consider  the  action  of  these  centres  more  fully  in  treating 
of  the  several  functions  of  the  body.  It  must  be  remembered,  however, 
that  when  a  dozen  or  more  centres  are  enumerated  as  being  situated  in  the 
fourth  ventricle,  it  is  not  meant  that  we  can  anatomically  distinguish  a  group 
of  cells  for  each  act  or  group  of  actions  named.  When  we  say  that  a  part  of 
the  nervous  system  is  a  centre  for  any  action,  we  merely  mean  that  this  part 
forms  a  necessary  link,  or  meeting  of  the  ways,  in  the  complicated  directing  of 
nerve  impulses  that  takes  place  in  every  co-ordinated  act. 


THE   CEEEBKAL  HEMISFHEEE8 


SECTION  XVI 

GENERAL   STRUCTURAL   ARRANGEMENTS  OF 
THE  CEREBRUM 

The  cerebral  hemisplieres  form  the  most  important  part  of  the  brain.  It  is 
to  the  development  of  this  part  that  is  due  the  rise  in  type  in  vertebrates. 
In  development  they  are  formed  as  two  diverticula  from  the  front  part  of  an 
outgrowth  of  the  first  cerebral  vesicle.  In  the  lowest  vertebrates  these 
outgrowths  are  connected  entirely  with  the  olfactory  sense-organs,  and  we 

may  regard  the   olfactory 

w 


part  of  the  brain  as  a  fun- 
damental part  on  which 
has  been  built  up  all  the 
rest  of  the  cerebral  hemi- 
spheres. In  a  cartilaginous 
fish  the  whole  of  the  upper 
brain  is  connected  with 
the  organ  of  smell,  and 
consists  of  a  thickening 
in  the  floor  of  the  out- 
growth from  the  fore-brain. 
The  roof  of  the  outgrowth  is  formed  of  1  simple  ^epithehum.  With 
the  development  of  the  visual  sensations  in  the  bony  fishes  there  is 
still  very  little  corresponding  growth  of  the  fore-brain,  most  of  the 
fibres  from  the  optic  nerves  going  to  the  roof  of  the  mid-brain  (the 
optic  lobes).  The  beginning  of  the  cerebral  hemispheres  is  associated 
with  the  development  of  nervous  tissue  in  the  roof  of  the  prosen- 
cephalon. At  its  first  appearance  this  higher  brain  material  still  receives 
chiefly  olfactory  impressions.  But  the  structure  of  the  cerebral  cortex  thus 
laid  down  differs  from  that  of  the  centres  forming  the  brain  stem  or  the  ol- 
factory lobe  itself  in  that  it  provides  for  a  very  rich  association  of  impulses 
between  all  its  parts.  The  fibres  entering  the  cortex  break  up  into  a  fine  mesh- 
work  of  fibres  which  run  tangentially  to  the  surface  and  come  in  contact 
with  innumerable  dendrites  of  nerve-cells  situated  at  some  little  distance 
below  the  surface  (Fig.  207).  We  have  here  the  first  germ  of  an  apparatus 
in  which  the  nerve-paths  can  be  determined  by  education,  i.e.  in  consequence 
of  inhibitions  by  pain,  rather  than  by  the  limits  set  by  heredity.  In 
the  amphibian  brain,  and  still  more  in  the  brain  of  the  reptile,  the  cerebral 

416 


Tig.  207.     Section  through  cerebral  cortex  of  the  frog. 
(After  Edingee.) 


STRUCTURAL  ARRANGEMENTS  OF  CEREBRUM  417 

cortex  extends  over  the  whole  of  the  roof  of  the  cerebral  hemispheres, 
though  even  here  a  very  large  proportion  of  it  is  devoted  to  the  association 
of  olfactory  impulses.  The  importance  of  these  olfactory  association  fibres 
is  well  shown  in  the  figure  (Fig.  208)  of  a  diagrammatic  section  through  a 
Uzard's  brain.  Above  the  reptiles  there  is  a  divergence  in  the  course  of 
development.  The  wider  reactive  powers  of  birds  are  based  chiefly  on  an 
enormous  development  of  the  corpus  striatimi,  whereas  in  mammals  the 
corpus  striatum  remains  relatively  small  and  the  chief  development  occurs 
in  the  roof  of  the  cerebral  hemispheres,  the  so-called  pallium  or  mantle. 
With  the  increased  entry  of  fibres  from  the  optic  thalamus  into  the  cerebral 
hemispheres,  carrying  mipulses  from  the  eyes,  ears,  and  all  the  other  sense- 
ortrans  of  the  body,  the  olfactory  part  of  the  brain  diminishes  in  importance, 


'  ""^^^^^^^Tf-^ 


Fig.  208.     Schematic  section  through  brain  of  lizard  showing  the  chief 
nerve-tracts.     (After  Edinger.) 

and  in  the  higher  mammals  and  man  is  altogether  overshadowed  by  the  newly 
formed  part  of  the  pallium.  On  this  account  those  parts  of  the  cerebral 
hemispheres  in  special  connection  with  the  olfactory  sense-organs  are  often 
spoken  of  as  the  archipallium,  in  distinction  to  all  the  rest  of  the  more 
newly  formed  brain  substance,  known  as  the  neopallium. 

In  man  the  cerebral  hemispheres  form  a  great  ovoid  mass  exceeding 
in  size  all  the  rest  of  the  brain  put  together.  The  two  hemispheres  are 
separated  by  a  deep  fissure,  the  great  longitudinal  fissure.  Before  and 
behind,  this  fissure  extends  to  the  base  of  the  cerebrum,  but  in  the  middle  the 
two  hemispheres  are  connected  by  a  mass  of  transverse  fibres  known  as  the 
corpus  callosum.  On  the  outer  side  each  cerebral  hemisphere  presents  a 
deep  cleft,  the  Sylvian  fissure.  The  whole  surface  of  the  brain  is  thrown 
by  fissures  (or  sulci)  into  convolutions,  by  which  means  a  very  large  increase 
of  the  surface  grey  matter  is  obtained.  By  these  fissures  the  brain  surface 
is  divided  into  lobes.  The  general  arrangement  is  shown  in  Figs.  209  and  210. 
The  chief  lobes  are  the  frontal,  the  parietal,  the  occipital,  the  temporal,  the 
insular,  the  limbic,  and  the  olfactory.  On  the  inner  side,  from' before 
baclvwards,  we  have  the  marginal,  the  paracentral,  the  pre-cuneus,  the 
cuneus ;    and  in  close  proximity  to  the  corpus  callosum,  the  cingulum  or 

U 


418 


PHYSIOLOGY 


S.precentralis  Inferior       5_preeentralls  superior 
,,,,,..   ^     .  I  S.centralis  (Rolandi) 

S.fronUds  inferior  l         S.postcentralis  inferior 

S.  frontalis  Superior  ^  -       ' 

S.frontalls  medius  ,  ^   su?c'^' 


Ramus 
ant.  horizontalis 
'  Ramus  ant.ascendens 
S. diagonal  is 

Ramus  post,  of  Sylvian  f. 


S.postcentralis  intermedius 

'.  postcentralis  superior 

S.  intraparietalis 


S.temporalis  medius 


S.occipitalis  lateralis 

S.occipitalis  transi/ersus 


Fig.  209.     Left  cerebral  hemisphere  of  man,  lateral  aspect.     (Symington.) 


S.precentralis  mesial  is 
S.cenf rail's  (Roland, 
fiars  marainalis  s.cinduli 

S-parietalis  superior 
S.pariefo-occipitalis 


nfull 


S-Corporh  callosi 


5.  rosfralis 
Incisura  iemporalis 


S.subparietalis 
5.  calcarinus  fr-,^^-^  dentata 


S.collaterall:   \  •  S.collanrslis 

S.  temporalis  inferior 


Fig.  210.     Left  cerebral  hemisphere  of  man,  from  the  mesial  aspect.     (Symington.) 


STRUCTURAL  ARRANGEMENTS  OF  CEREBRUM  419 

supra- callosal  convolution  above,  and  the  hippocampal  convolution  and  the 
uncus  below.     The  chief  fissures  separating  these  are  the  Sylvian  fissure,  the 

A 


Forebfaln 


\':.  Midbrain 

Cerebellum 


£yer 


Cortex 


-■■  Occipital  cortex 


Midbrain  .^^ 
Cerebellum 


Cerebellum 


Fio.  211.  Diagrams  from  Monakow,  showing  the  evolution  of  the  neopallium, 
and  the  gradual  shifting  of  the  visual  sensory  tracts  from  the  mid-brain  to  the  fore- 
brain,  and  thence  to  the  occipital  cortex. 

A,  a  bonj'  fish.     B,  brain  of  a  lizard.     C.  brain  of  a  mammal  (cat). 

central  sulcus  or  fissure  of  Rolando,  the  parieto-occipital  fissure,  the 
calcarine  fissure,  the  collateral  fissure,  and  the  calloso-inarginal  fissure. 
Each  of  the  main  lobes  (or  gyri)  mentioned  above  is  further  subdivided 


420 


PHYSIOLOGY 


by  smaller  fissures.  The  extent  of  these  secondary  fissures  varies  from 
brain  to  brain,  the  higher  types  of  brain  being  richer  in  convolutions 
than  those  of  the  more  primitive  races. 

The  gradual  evolution  of  the  cerebral  cortex,  and  the  concomitant  shifting 
of  the  chief  afferent  impulses,  arising  in  the  projicient  sense-organs,  from  the 
lower  gangha  to  the  higher  educatable  cortex,  is  well  shown  in  the  diagrams 
from  Monakow  (Fig.  211,  p.  419).  In  the  lower  fishes  practically  all  the 
reactions  to  visual  impressions  are  carried  out  by  the  optic  lobes.     In  the 

higher  types  the  reflexes  through 
these  lobes  become  subordinated,  first 
to  the  more  complex  organ  of  the 
optic  thalamus  (where  representatives 
from  all  the  afferent  tracts  of  the  body 
assemble),  and  later  to  the  still  more 
complex  occipital  cortex,  when  the 
reactions  are  determined  not  only  by 
inherited  nerve-paths  but  also  by 
the  various  blocks  and  facihtations 
imprinted  on  the  nerve-paths  by  the 
experience  of  the  individual  himself. 

The  original  cavities  of  the  hemi- 
spheres form  the  lateral  ventricles, 
each  of  which,  in  the  adult  brain, 
is  prolonged  into  the  main  divisions 
of  the  hemispheres  as  the  anterior 
horn,  the  posterior  horn,  and  the 
inferior  horn.  Each  lateral  ventricle 
is  roofed  over  by  the  corpus  callosum 
and  the  adjoining  white  matter  of  the 
hemispheres.  On  opening  the  ven- 
tricle we  see  on  its  floor  the  body 
of  the  fornix,  a  flattened  tract  of  white 
matter  with  longitudinal  fibres,  which 
in  front  bifurcates  into  two  cylin- 
drical bundles  which  pass  vertically 
downwards  in  front  of  the  foramen  of 
Monro  into  the  mesial  part  of  the  sub- 
thalamic tegmentum.  Internal  to 
the  fornix  is  a  layer  of  pia  mater, 
including  the  choroid  plexus.  On 
removing  this  the  third  ventricle 
is  opened,  so  that  in  this  region  the  wall  of  the  cerebral  hemispheres,  like  the 
roof  of  the  third  ventricle,  is  Hmited  to  a  simple  layer  of  ependyma.  At  the 
margin  of  the  choroid  plexus  can  be  seen  a  part  of  the  superior  surface  of  the 
optic  thalamus,  separated,  however,  from  the  cavity  of  the  ventricle  by 
a  layer  of  ependyma.     Outside  and  in  front  of  the  optic  thalamus  are  the 


Fig.    212.     Horizontal  section  through  the 
optic  thalamus  and  corpus  striatum,  the 
'  basal  ganglia.'  (Natural  size.)  (QuAnsr.) 
vl,  lateral    ventricle,  its    anterior    cornu  ; 
cc,   corpus   callosum;    si,   septum   lucidum  ; 
af,  anterior  pillars  of  the  fornix  ;  vi,  third 
ventricle  ;    th,  thalamus  opticus  ;    st,  stria 
meduUaris ;     nc,     nucleus     caudatus,     and 
nl,  nucleus  lenticularis  of  the  corpus  stria- 
tum ;  ic,  internal  capsule ;    g,  its  angle  or 
genu ;    nc,    tail    of    the    nucleus    caudatus 
appearing  in  the    descending   cornu   of  the 
lateral  ventricle  ;    cl,  claustrum  ;   /,   island 
of  Reil. 


STRUCTURAL  ARRANGEMENTS  OF  CEREBRUM  421 

masses  of  nervous  material  constituting  the  corpus  striatum.  These  present 
two  nuclei  of  grey  matter,  known  as  the  nucleus  caudatus  and  the  nucleus 
lenticularis  (Fig.  212).  The  crusta  of  the  crura  cerebri  as  it  ascends  to  the 
cerebral  hemispheres  passes  behind  between  the  optic  thalamus  and  the 
corpus  striatimi,  and  in  front  between  the  nucleus  lenticularis  and  nucleus 
caudatus  of  the  corpus  striatum.  Outside  the  corpus  striatum  we  find 
another  mass  of  white  fibres,  known  as  the  external  capsule,  and  this  is 
separated  from  the  white  matter  of  the  cortex  cerebri  by  a  thin  layer  of  grey 
matter  known  as  the  claustrmn.  In  a  horizontal  section  through  the 
brain,  the  part  of  the  internal  capsule  which  pierces  the  corpus  striatum 
forms  an  angle  with  the  posterior  part  separating  the  optic  thalamus  from 
the  lenticular  nucleus.  The  part  where  the  two  limbs  come  in  contact  is 
known  as  the  rjenu  of  the  internal  capsule  (Fig.  212). 

THE  OLFACTORY  APPARATUS  OF  THE  BRAIN 
In  man  the  olfactory  sense  is  but  feebly  developed,  and  the  parts  of  the 
brain  connected  therewith  are  inconspicuous  in  comparison  with  those  en- 
gaged in  the  reception  of  impressions  from  the  other  two  main  projicient 
sense-organs,  namely,  sight  and  hearing.  On  this  account  it  is  not  easy  to 
make  out  the  connections  of  the  olfactory  lobe  proper,  the  rhinencephalon, 
with  the  primitive  part  of  the  cortex,  the  arch  i pall ium,  subserving  the  olfac- 
tory sense  and  probably  the  allied  sensations  derived  from  the  mouth  ca\nty. 
The  wide  connections  of  the  olfactory  sense-organs  with  the  different  parts 
of  the  brain  in  the  lower  vertebrate  are  shown  in  the  diagrammatic  figure  of 
the  brain  of  a  reptile  (Fig.  208,  p  417). 

It  is  interesting  to  note  that  the  olfactory  nerve  fibres  are  derived  from  cells  situated 
actually  on  the  surface  of  the  body.  These  aie  bilateral,  spindle-shaped  cells,  lying 
in  the  olfactory  mucous  membrane  at  the  upper  part  of  the  nasal  cavity.  The  peri- 
pheral process  is  short  and  passes  towards  the  sm'face,  wliile  the  deep  process  passes 
as  a  non-medullated  nerve-fibre  through  the  cribriform  plate  of  the  ethmoid  to  sink 
into  the  olfactory  bulb.  The  bulb,  in  man,  is  a  greyish  enlargement  at  the  anterior 
end  of  the  olfactory  tract.  In  sections  stained  by  Golgi's  method  of  impregnation  it 
may  be  seen  that  the  olfactory  fibres  terminate  in  an  arborisation  in  close  connection 
with  a  thick  end  arborisation  derived  from  a  dencbite  of  a  large  nerve-cell,  known  as 
a  mitral  cell.  The  synapses  between  these  two  sets  of  fibres  are  prominent  objects 
in  a  section  through  the  olfactory  bulb  and  form  the  '  olfactory  glomeruli '  (Fig.  213). 
The  axons  of  the  mitral  cells  pass  back  in  the  olfactory  tracts.  Each  olfactory  tract 
divides  posteriorly  into  two  roots,  the  mesial  root  wliich  curves  inw^ards  beliind  Broca's 
area  and  passes  into  the  end  of  the  callosal  gyrus,  and  the  lateral  root  which  runs 
backwards  and  over  the  outer  part  of  the  anterior  perforated  spot.  Its  fibres  pass 
into  the  uncinate  extremity  of  the  hippocampal  gj'rus.  The  small  triangular  field  of 
grey  matter  between  the  diverging  roots  of  the  olfactory  tract  is  known  as  the  olfactory 
tubercle.  The  primitive  rhinencephalon  includes  in  the  adult  human  brain  the 
olfactory  bulb  and  tract,  together  with  the  anterior  perforated  space,  the  anterior 
part  of  the  uncinate  gyrus,  the  subcallosal  gyrus,  the  septum  lucidum,  and  the  hii^ix)- 
campal  convolution.  The  two  sides  of  the  rhinencephalon  are  united  by  fibres  passing 
through  the  anterior  commissure.  Other  tracts  subserving  tliis  apparatus  include 
the  habenula  passing  from  the  fornix  to  the  ganglion  of  the  habenula,  the  fast'ieulus 
rctrollexus  passing  from  this  to  the  interpeduncular  ganglion,  and  the  corpus  mammillare 
wliich  is  connected  with  the  column  of  the  fornix  on  the  one  hand  and  throughthe  bundle 
of  Vicq  d'Azyr  with  the  thalamus  on  the  other. 


422 


PHYSIOLOGY 


THE  CHIEF  TRACTS  OF  THE  CEREBRAL  HEMISPHERES 
We  may  divide  the  tracts  of  the  upper  brain  or  cerebral  hemispheres  into 
three  classes  : 

I.  Tracts  comiecting  the  brain  with  lower  levels  of  the  central  nervous 
system. 

II.  Tracts  connecting  different  parts  of  the  cortex  of  one  hemisphere 
and  serving  as  a  means  of  association  between  these  different  parts. 

III.  Tracts   (commissural)   connecting  the  two  cerebral  hemispheres 
together. 

I.     THE  PROJECTION  FIBRES 
These  are  the  fibres  which  connect  the  cerebral  cortex  with  the  different 
lower  levels  of  the  central  nervous  system.     They  form  a  great  part  of  the 


Fig.  213.     Schema  of  course  of  olfactory  impulses.     (Ram6n  y  Cajal.) 
A,   olfactory  mucous   membrane ;     b,   olfactory  glomeruli ;     c,    mitral  cells ; 
E,  granule  cells  ;   D,  olfactory  tract ;   l,  centrifugal  fibres. 

fibres  of  the  corona  radiata  and  are  condensed  at  the  base  of  the  brain  into 
the  broad  band  of  fibres  known  as  the  internal  capsule.  A  few  of  the  fibres 
of  the  projection  system  may  gain  the  cortex  through  the  lenticular  nucleus 
and  by  the  external  capsule.  The  projection  fibres  may  be  divided  into 
two  groups  according  as  they  conduct  impulses  to  or  away  from  the  cerebral 
cortex  :  the  afferent  or  corticipetal,  and  the  efferent  or  corticifugal. 

A.     AFFERENT  TRACTS  OF  THE  CEREBRUM. 

(1)  The  thalamo-cortical.  From  all  parts  of  the  optic  thalamus  fibres 
arise  as  axons  of  the  cells  of  its  grey  matter  and  streaming  out  from  its  outer 
and  under  surfaces  pass  to  every  part  of  the  cortex.  Although  there  is  no 
division  of  them  into  distinct  groups  as  they  leave  the  thalamus,  they  are 
often  described  as  constituting  a  frontal,  a  parietal,  an  occipital,  and  a  ventral 
stalk.  The  front  fibres  pass  through  the  anterior  limb  of  the  internal  capsule 
to  reach  the  cortex  of  the  frontal  lobe,  many  of  the  fibres,  however,  termina- 
ting in  the  caudate  and  lenticular  nuclei.  The  parietal  fibres  issuing  from 
the  lateral  surface  of  the  thalamus  pass  through  the  internal  capsule  to  be 
distributed  chiefly  to  the  parietal  lobe.     The  occipital  fibres  issue  from 


STRUCTURAL  ARRANGEMENTS  OF  CEREBRUM  423 

the  outer  part  of  the  pulvinar  and  the  external  geniculate  body  and  constitute 
the  so-called  '  optic  radiation,'  passing  outwards  and  backwards  to  be 
distributed  to  the  cortex  of  the  occipital  lobe.  The  ventral  fibres  pass 
downwards  and  outwards  below  the  lenticular  nucleus  and  end  partly  in  the 
latter  nucleus  and  partly  in  the  cortex  of  the  temporal  lobe  and  of  the  insula 
or  island  of  Reil. 

(2)  The  fillet  system  of  fibres.  This  great  mass  of  ascending  fibres 
has  been  already  described  {cjj.  Fig.  197)  as  gathering  up  the  impulses 
from    the    different    sensory 

nerves  of  the  cerebro-spinal  >  o®' 

system  and  terminating  in  the 
thalamus  and  subthalamic 
region. 

(3)  The  superior  cere- 
bellar PEDUNCLE.  These 
fibres,  from  the  central 
gangha  of  the  cerebellum, 
terminate  for  the  most  part 
in  the  thalamus  and  sub- 
thalamic region.  It  is  pos- 
sible that  some  of  them  may 
pass  through  the  hinder  end 
of  the  internal  capsule,  with- 
out interruption  in  the  thala- 
mus, to  end  in  the  Rolandic 
area. 

(4)  The  optic  radiation. 
These  diverging  fibres  in  the 
back  part  of  the  corona- 
radiata  are  mixed  up  with 
fibres  which  are  partly  cortici- 
fugal.  The  corticipetal  fibres 
arise  in  the  pulvinar  and  the 
external  geniculate  body  and 
end  in  the  occipital  cortex. 

(5)  The  auditory  radiation.  These  fibres  consist  of  the  axons  of  cells 
situated  in  the  internal  geniculate  body.  They  pass  through  the  posterior 
limb  of  the  internal  capsule  under  the  lenticular  nucleus  to  end  in  the 
temporal  lobe. 


Fig.  214. 


■^      LOBE. 

Schema  of  projection  fibres  of  cortex- 
(Cunningham.) 


B.     THE  EFFERENT  PROJECTION  FIBRES. 

(1)  The  pyramidal  tract.  This  is  composed  of  fibres  which  arise  from 
the  large  Betz  cells  in  the  ascending  frontal  convolution,  the  '  motor  area.', 
They  pass  through  the  corona  radiata  into  the  internal  capsule,  where  they 
occupy  the  genu  and  the  anterior  two-thirds  of  the  posterior  limb.  Hence 
they  pass  into  the  crusta,  where  they  occupy  the  middle  two-fifths  of  this 


424 


PHYSIOLOGY 


structure,  and  are  continued  as  the  pyramids  of  the  pons  and  medulla  to 
she  upper  part  of  the  spinal  cord,  where  most  of  them  decussate  to  the  other 
tide  to  form  the  crossed  pyramidal  tracts.  Some  of  the  fibres  do  not  cross 
at  the  pyramidal  decussation,  but  are  continued  down  in  the  same  position 
in  the  anterior  columns  of  the  spinal  cord  of  the  same  side,  forming  the  direct 
or  anterior  pyramidal  tracts.  These  fibres  cross  for  the  most  part  lower  down 
in  the  cord,  so  that  the  direct  pyramidal  tract  is  not  seen  below  the  cervical 

region.  The  pyramidal  tracts  are  not 
found  in  lower  vertebrates,  and  make 
their  first  appearance  in  the  mammaha. 
Their  development  corresponds  with  the 
gradual  increase  in  the  direct  interference 
of  the  cerebral  cortex  in  the  reactions 
of  the  organism  as  a  whole  and  are  an  in- 
dex to  the  gradual  shifting  of  these  reac- 
tions from  the  inevitable  to  the  educated 
reflex.  The  fibres  of  the  pyramidal 
tract  end  at  various  levels  of  the  spinal 
cord  and  can  be  traced  to  the  lower  end 
of  the  sacral  region.  According  to 
Schafer  they  end  in  the  posterior  cornua, 
so  that  their  action  is  to  set  going  a 
reaction  which  could  otherwise  be 
elicited  by  stimulation  of  the  afferent 
fibres  entering  by  the  posterior  root  at 
the  level  of  the  cord  where  they  end. 

(2)  The    fronto-pontine    fibres. 

These   arise   from   cells  in   the  cortex 

Diagrammatic   representation  of  the  frontal  lobe,  and  pass  down  in  the 

anterior  hmb  of  the  internal  capsule 
to  gain  the  mesial  part  of  the  crusta  of 
the  crus  cerebri.  The  fibres  end  in  the  grey  matter  of  the  formatio 
reticularis  of  the  pons,  the  nucleus  pontis. 

(3)  The  temporo-pontine  fibres.  These  arise  from  the  two  upper 
temporal  convolutions,  especially  from  that  area  which  is  associated  with 
hearing.  They  pass  inwards  under  the  lenticular  nucleus  through  the  hinder 
limb  of  the  internal  capsule  to  gain  the  outer  part  of  the  crusta.  In  this 
situation  this  tract  passes  down  into  the  pons,  where  it  ends  in  the  nucleus 
pontis. 

As  part  of  these  projection  fibres  we  ought  probably  to  reckon  the  fibres 
which  take  origin  or  end  in  the  corpus  striatum.  The  afferent  fibres  of  this 
body  are  derived  chiefly  from  the  thalamus,  forming  the  thalamo-striate 
.fibres.  Other  fibres  arise  in  the  nuclei  of  the  corpus  striatum  and  pass  down 
in  the  dorsal  portion  of  the  crusta  to  end  for  the  most  part  in  the  pons,  the 
strio-pontine  fibres. 

The  relative  position  of  these  various  fibres  in  the  internal  capsule 


Fig.   215  _ 

of  the  internal  capsule,  as  seeen  in  hori 
zontal  section.     (Cunningham.) 


STRUCTURAL  ARRANGEMENTS  OF  CEREBRUM 


425 


and  ill  the   ciusta   is  shown  in  the  accompanying   diagrams    (Figs.   215 
and  21f3). 

The  fronto-pontine  and  temporo-pontine  fibres,  which  end  in  the  nucleus 
pontis,  come  there  in  relationship  with  the  fibres  forming  the  middle  peduncles 
of  the  cerebellum  and  derived  chiefly  from  the 
lateral  lobes  of  the  cerebellum.  These  fibres 
may  therefore  be  regarded  as  the  eft'erent 
side  of  the  great  cerebro-cerebellar  connections 
of  which  the  afi'erent  side  is  represented 
by  the  fibres — efferent  so  far  as  concerns 
the  cerebellum — which  pass  from  the  cere- 
bellar cortex  to  the  dentate  nucleus  and 
thence  by  a  fresh  relay  in  the  superior  cere- 
bellar peduncles  to  the  red  nucleus,  optic  thala- 
mus, and  cortex  of  the  opposite  side.  The 
development  of  these  fibres,  as  of  the  lateral 
lobes  of  the  cerebellum,  is  largely  proportional 
to  the  growth  of  the  cerebral  hemispheres.  In 
cases  where  there  has  been  congenital  atrophy 
of  one  cerebral  hemisphere  the  crusta  of  the 
same  side  and  the  lateral  lobe  of  the  cerebellum 
of  the  opposite  side  also  fail  to  develop. 


Fig.  216.     Transverse   section 
through  mid-brain   to   show 
position  of  fillet  and  pyramid. 
AQ,  anterior  corpus  quadri- 
geminum ;  dV,  descending  root 
of  fifth  nerve;  F,  fillet  (I,  lateral, 
and  m,  mesial  fillet) ;  Pyr,  pyra- 
mid ;  Fr.  fibres  from  frontal  lobe 
to  pons;  TO,  fibres  from  tem- 
poral  and  occipital    lobes    to 
pons  ;   Ne,  fibres  from  nucleus 
caudatus  to  pons ;    III,  root  of 
third  nerve  ;    S,  Sylvian  iter; 
Rn,  red  nucleus. 


II.      ASSOCIATION  FIBRES 
These  fibres  serve  to  unite  different   por- 
tions  of  the  cortex  of  the  same  hemisphere  and  may  be  classified  into 
short  and  long  association  fibres.     The  short  association  fibres  pass  round 
the  bottom  of  the  sulci  in  U-shaped  loops  connecting  adjacent  convolutions. 


Fig.  217.     Chief  association  bundles  of  the  cerebral  hemispheres.     (Cukninqham. ) 
\.  Outer  aspect  of  hemisphere.     B.  Inner  aspect  of  hemisphere. 

These  fibres  are  some  of  the  latest  to  acquire  a  medullary  sheath  and 
probably  first  become  functional  as  associated  activity  between  the  various 
portions  of  the  cortex  is  gradually  acquired  by  education. 

The  long  association  fibres  may  be  divided  into  five  groups  as  follows  : 
(a)  The  uncinate  fasciculus  passes  from  the  orbital  convolutions  of  the  frontal  lobe 
to  the  front  part  of  the  temporal  lobe  round  the  stem  of  the  Sylvian  fissure  (Fig.  217). 

14* 


426 


PHYSIOLOGY 


(h)  The  cingulum  is  closely  associated  with  those  parts  of  the  cerebral  cortex  known 
together  as  the  limbic  lobe.  In  front  it  originates  in  the  neighboiu"hood  of  the  anterior 
perforated  space,  passes  round  the  genu  of  the  corpus  callosum,  and  then  is  carried 
backwards  over  the  upper  surface  of  this  body  to  its  hinder  end,  where  it  turns  round 
and  is  distributed  to  the  hippocampal  gyrus  and  to  the  temporal  lobe. 

(c)  The  longitudinal  superior  fasciculus  lies  in  the  base  of  the  frontal  and  parietal 
lobes,  and  passing  from  before  backwards  connects  the  frontal  occipital,  and  temporal 
parts  of  the  cerebral  cortex. 

{d)  The  longitudinal  inferior  fasciculus  runs  along  the  whole  length  of  the  occipital 
and  temporal  lobes,  being  situated  behind  on  the  outer  aspect  of  the  optic  radiation. 

(e)  The  occipito-frontal  fasciculus  lies  on  the  inner  aspect  of  the  corona  radiata  in 
intimate  relation  to  the  caudate  nucleus,  and  projects  out  over  the  upper  and  outer 
aspect  of  the  lateral  ventricle  immediately  outside  the  ependyma. 

III.     THE  COMMISSURAL  FIBRES 
These  are  arranged  in  three  groups  : 

(a)  The  corpus  callosum  forms  a  great  mass  of  white  fibres  passing  trans- 
versely in  both  directions  between  the  two  hemispheres.     Its  fibres  are 


Fig.  218.     Schematic  section  through  cerebral  hemispheres,  to  show    chief    classes 
of  nerve  tracts.     (After  Ramon  y  Cj4Jal.) 
A,   corpus  callosum  ;     b,   anterior  commissure  ;    c,   pyramidal  tract ;    a,   cell 
giving  off  projection  fibre  ;    6,  cell  giving  off  commissural  fibre  ;    c,  cell  with  axon 
forming  association  fibres. 


derived  from  every  part  of  the  cerebral  cortex  with  the  exception  of  the 
olfactory  bulb  and  the  hind  and  fore  parts  of  the  temporal  lobe.  As  the 
fibres  cross  the  middle  line  they  become  gradually  scattered,  so  that  they 
tend  to  connect  wholly  dissimilar  parts  of  the  cortex  of  opposite  hemispheres. 
Each  callosal  fibre  arises  in  one  hemisphere  and  ends  by  fine  arborisations  in 
the  opposite  hemisphere.  It  may  represent  either  the  axon  of  one  of  the 
cortical  cells  or  a  collateral  from  a  fibre  of  association  or  a  collateral  from  a 
projection  fibre  (Fig.  218). 

(b)  The  anterior  commissure  is  situated  in  the  anterior  wall  of  the  third 
ventricle  in  front  of  the  two  pillars  of  the  fornix.  It  connects  together  the 
two  olfactory  lobes  and  portions  of  the  opposite  temporal  lobes.  In  lower 
vertebrates  it  is  almost  entirely  olfactory  in  function,  but  in  man  the  olfactory 


STRUCTURAL  ARRANGEMENTS  OF  CEREBRUM  427 

fibres  only  form  a  small  proportion  of  the  total  number  making  up  the 
bundle. 

(c)  The  psalterium  or  hippocampal  commissure  is  a  thin  lamina  formed 
of  transverse  fibres  filhng  up  the  small  triangular  space  on  the  under  surface 
of  the  hinder  part  of  the  corpus  callosum  formed  by  the  divergence  of  the 
posterior  pillars  of  the  fornix.  Like  the  anterior  commissure,  the  hippo- 
campal commissure  is  closely  associated  with  the  sense  of  smell.  Its  fibres 
arise  from  the  pyramidal  cells  in  the  cornu  ammonis  or  hippocampus  and  pass 
for  the  greater  part  to  the  cornu  ammonis  of  the  opposite  side. 

MINUTE  STRUCTURE  OF  THE  CEREBRAL  CORTEX 
The  cortex  of  the  cerebral  hemispheres  consists  of  a  layer  of  grey  matter 
covering  a  central  mass  of  white  fibres.  With  the  growth  in  size  of  the 
brain,  which  accompanies  the  development  of  increased  intelHgence  and 
powers  of  adaptation  the  necessary  increase  in  cortex  is  rendered  possible  by 
the  folding  of  the  surface  into  convolutions  and  fissures.  The  chief  of  these 
convolutions  have  already  been  indicated  in  the  sketch  of  the  anatomy  of  the 
brain  (Fig.  209).  ^ 

On  section  the  grey  matter  is  seen  to  consist  of  many  layers  of  nerve-cells 
embedded  in  neurogha  and  nerve  fibres,  both  medullated  and  non-medullated. 
The  nerve-cells  vary  in  size  and  shape  ;  one  kind  of  cell  is,  however,  typical 
of  this  part  of  the  central  nervous  system.  This  is  the  pijramidal  cell  (Fig. 
219),  a  cone-shaped  or  pear-shaped  cell  with  one  large  apical  dendrite  which 
runs  towards  the  surface  and  breaks  up  in  the  most  superficial  layer  into  a 
number  of  branches.  Dendrites  are  also  given  oft'  from  the  sides  and  lower 
angles  of  the  cell.  The  axon,  which  arises  from  the  axon  hillock  in  the  middle 
of  the  base  of  the  cell,  passes  downwards  into  the  white  matter,  giving  of? 
collaterals  in  its  course.  Some  of  these  axons  pass  by  the  corona  radiata  into 
the  internal  capsule  and  into  the  crura  cerebri,  including  those  which  form 
the  pyramidal  tracts  ;  others,  or  their  collaterals,  may  pass  into  the  adjacent 
regions  of  the  cortex,  or  across  by  the  corpus  callosum  into  the  opposite 
hemisphere. 

Although  varying  in  structure  at  different  parts,  it  is  generally  possible 
to  distinguish  four  or  five  layers  in  the  cortex. 

(1)  The  most  superficial  layer,  known  as  the  outer  fibre  lamina,  or 
molecular  layer,  contains  very  few  cells.  It  is  composed  generally  of  the  den- 
drites of  cells  from  the  deeper  layers.  It  contains  a  few  cells  which  are 
spindle-shaped  and  are  provided  with  several  processes  running  parallel 
to  the  surface.  These  are  sometimes  called  association  cells.  It  is  probable 
that  aft'erent  fibres,  entering  the  cortex,  pass  up  towards  the  surface  and  end 
for  a  large  part  in  this  molecular  layer. 

(2)  Below  this  is  a  layer  of  pyramidal  cells,  the  outer  cell  lamina,  which 
is  divided  by  some  observers,  e.g.  Campbell,  into  three,  viz.  : 

(a)  The  small  pyramidal  cells. 

(b)  Medium-sized  pyramidal  cells. 

(c)  Internal  layer  of  large  pwamidal  cells. 


428 


PHYSIOLOGY 


(3)  Below  the  pyramidal  layer  we  find  a  stratum  of  small  cells,  most  of 
which  are  stellate  in  form.  This  is  known  as  the  stellate  or  granule  layer, 
or  middle  cell  lamina. 

(4)  Internal  to  the  granule  layer  is  the  inner  fibre  lamina.  In  the 
motor  cortex  and  in  certain  other  parts  of  the  brain  this  contains  large 
sohtary  cells,  which  in  the  motor  area  receive  the  name  of  the  cells  of  Betz. 

(5)  Most  internal  of  all,  lying  next  to  the  white  matter,  is  the  poly- 


lit'      '  1   I         !    , 


mr..r 


Fig.  219.     Schematic  representation  of  the  neuro- fibrillar  apparatus  of  a  cortical 

pyramidal  cell.     (After  CaJal.  ) 

a,  axon  ;   dh,  dendrites. 


morfhous  layer  or  inner  cell  lamina,  composed  of  many  types  of  cells,  among 
which  spindle-shaped  cells  predominate.  Other  cells  are  also  found  resem- 
bling pyramidal  cells  of  the  more  superficial  layer,  but  directed  in  the  reverse 
direction,  so  that  their  axons  take  a  course  towards  the  surface.  These 
are  the  cells  of  Martinotti.  We  also  find  Golgi  cells  with  a  freely  branching 
axon,  which  terminates  in  the  adjacent  grey  matter. 


STRUCTURAL  ARRANGEMENTS  OF  CEREBRUM  429 

If  sections  of  the  cortex  be  stained  by  some  method  such  as  Weigert's, 
which  displays  medullated  nerve  fibres,  sheaves  of  radial  fibres  may  be 
seen  running  from  the  white  centre  towards  the  surface  and  giving  off  a  rich 


Fig.  220.     Diagrammatic  section  of  cerebral  cortex.     (From  Barker  after  Starr. 
Strong,  and  Leamino.) 
I.  inoli'cular  layer  with  a,  bi-pnlar  cell ;    II,  layer  of  small  pyramidal  cells  ; 
III,  layer  of  large  pjTamidal  cells  ;   I\',  polymorplunis  layer  :    \'.  white  matter. 


mesh  work  of  fibres  to  the  intervening  portions  of  the  grey  matter.  In  addition 
bands  of  tangential  fibres  are  seen  running  parallel  to  the  surface  in  certain 
situations,  viz.  : 


430  PHYSIOLOGY 

(a)  A  layer  of  very  fine  fibres  just  under  the  surface  of  the  cortex.  This 
layer  is  especially  marked  in  the  hippocampal  convolution  and  is  but  slightly 
developed  in  other  regions  of  the  cortex. 

(6)  A  layer  between  the  molecular  layer  and  the  layer  of  pyramidal 
cells,  known  as  the  outer  line  of  Baillarger. 


(1)  Molecvilar   or   outer 
fibre  lamina. 
0-34  mm. 


(2)  Pyramidal  or  outer 
cell  lamina. 
0-90  mm. 


(3)  Granular    layer    or 
middle  cell  lamina. 
0-22  mm. 


(4)  Inner  fibre  lamina. 
0-22  mm. 


(5)  Polymorphic  or  inner 
cell  lamina. 
0-31  mm. 


a.  Tangentiallayer. 


b:  Outer  line  of   Bail- 
larger. 


c.  Inner  line   of  Bail- 
larger. 


Fig.  221.     Motor  leg  area. 

(c)  Internal  to  the  granule  layer  is  another  zone  of  fibres,  the  inner 
line  of  Baillarger,  giving  its  name  to  the  inner  fibre  lamina. 

{d)  In  the  part  of  the  occipital  cortex,  distinguished  as  the  visuo-sensory 
area,  which  receives  fibres  of  the  optic  radiations,  a  special  layer  of  tangential 
fibres  is  observed  running  through  the  middle  of  the  granular  layer  and 
dividing  it  into  two  parts.     This  is  known  as  the  line  ofGennari  (Fig.  222). 

A  careful  study  of  the  distology  of  the  different  parts  of  the  cortex  in 
man  enables  us  to  distinguish  certain  types  of  structure  characteristic  of 
various  regions  of  the  grey  matter.  In  attempting  by  such  means  an 
histological  localisation  of  functions  we  have  to  take  into  account : 

(a)  The  thickness  of  the  cortex. 


STRUCTURAL  ARRANGEMENTS  OF  CEREBRUM 


431 


(6)  The  relative  thickness  of  the  various  layers. 

(c)  The  character  of  the  cells  found  in  the  various  layers. 

(d)  The  arrangement  and  degree  of  development  of  the  systems  of 
medullated  fibres,  both  radial  and  transverse. 

The  possibilities  in  such  a  method  are  at  once  apparent  if,  as  in  Figs.  221, 
222  and  223,  we  compare  the  structure  of  the  cortex  from,  e.g.  the  pre-central 


(:!)      (I-21 


TTTJ 


4    r 


■^  ">)^: 


(5) 
0-29 


FiLi.  222.     Visuo-sensoiy. 


Tiu.  223.     Visuo-psj-chic. 


motor  convolution,  the  visuo-sensory  area  of  the  occipital  convolution,  and 
the  '  visuo-psychic  '  area.  The  finer  differences  are  not  so  readily  perceptible 
without  careful  study  and  measurement  of  the  various  layers  and  the  elements 
constituting  them.  By  this  method  we  can  mark  out  the  cortex  into  areas, 
which  agree  closely  with  the  localisation  of  functions  as  arrived  at  by 
experimental  methods  or  by  a  study  of  the  systems  of  fibres  in  the  brain  or 
of  the  functional  defects  observed  under  pathological  conditions. 

The  localisation  arrived  at  in  this  way  is  represented  in  the  diagrams 
taken  from  Campbell  (Fig.  224).     Thus  in  the  motor  area,  the  precentrul 


432 


PHYSIOLOGY 


or  ascending  frontal  convolution,  we  find  below  the  granular  layer  the  well- 
marked  pyramidal  cells  or  Betz  cells,  which  are  larger  than  any  other  element 
in  the  cerebrum.     The  layer  of  pyramidal  cells  is  also  very  thick,  while 


Fig.  224.  Human  brain  showing  outer  (A)  and  mesial  (B)  surfaces,  and  the  situation 
of  the  chief  motor  and  sensory  areas.  The  different  shading  represents  the  extent 
of  each  of  these  areas  as  determined  by  a  study  of  the  histological  structure  of  the 
cortex.     (Campbell.) 

the  granular  layer  is  but  slightly  developed.     In  this  area  the  actual  average 
thickness  of  the  different  layers  is  as  follows  : 


Molecular  or  outer  fibre  lamina  . 
Pyramidal  or  outer  cell  lamina  . 
Granular  or  middle  cell  lamina   . 
Betz  or  inner  fibre  lamina 
Polymorphous  layer  or  inner  cell  lamina 


0-34  mm. 
0-90  mm. 
0*22  mm. 
0-22  mm. 
0"31  mm. 


STRUCTURAL  ARRANGEMENTS  OF  CEREBRUM  433 

In  the  visuo-sensory  area  the  granular  layer  is  the  thickest,  and  is 
divided  into  two  layers  by  the  band  of  tangential  fibres  forming  the  line 
of  Gennari.  In  the  association  areas,  both  those,  such  as  the  intermediate 
precentral  and  visuo- psychic,  which  are  normally  associated  with  motor 
or  sensory  processes,  as  well  as  the  higher  association  centres  of  Flechsig, 
i.e.  the  frontal,  parietal  and  temporal  lobes,  the  most  marked  feature  in  the 
section  is  the  great  development  of  and  the  large  number  of  cells  observed 
in  the  outer  cell  lamina  or  pjTamidal  cell  layer.  It  will  be  noticed,  too,  that 
the  audito-sensory  area  is  but  small  in  extent  and  lies  almost  entirely  within 
the  lips  of  the  fissure  of  Sylvius,  while  the  greater  part  of  the  superior 
temporal  convolution,  which  on  the  left  side  is  associated  with  the  auditory 
images  and  associations  necessary  for  the  comprehension  of  speech,  partakes 
of  the  character  of  an  intermediate  or  psychic  sensory  area. 

The  same  method  may  be  applied  to  a  comparison  of  the  relative  develop- 
ment of  the  cerebral  functions  in  different  types  of  animals.  A  comparison  of 
the  brain  of  the  dog,  ape,  and  man  shows  that  while  the  absolute  amount  of 
brain  substance  devoted  to  the  elementary  functions  of  movement  and 
sensation  remains  practically  the  same  throughout,  in  man  these  areas  are, 
relatively  to  the  whole  brain,  very  much  diminished  in  size,  the  greater  part 
of  the  brain  surface  being  taken  up  with  the  nervous  material  of  the  type 
which  is  connected  with  the  functions  of  association  involved  in  the  higher 
processes  of  reflection,  intelligence,  and  vohtion. 

If  we  draw  still  lower  animals  into  the  sphere  of  our  observations  we  are 
enabled  to  form  some  idea  as  to  the  relative  significance  of  the  various 
elements  of  the  cortex.  Thus  in  an  animal,  such  as  the  rabbit,  the  poly- 
morphous layer  is  three  times  the  thickness  of  the  p}Tamidal  layer  ;  whereas 
in  man,  ^v'ith  an  infinitely  greater  range  of  reaction,  it  is  only  one-third  of  the 
thickness  of  this  layer.  If  we  may  roughly  assign  a  function  to  each  of  the 
types  of  cells  found  in  the  cortex,  we  may  say  that  the  pyramidal  cell  layer 
is  generally  associative  in  functions.  The  large  pyramidal  cells  of  Betz  are 
motor  ;  the  granular  layer  is  sensory,  while  the  polymorphous  layer  presides 
over  the  lowest  cortical  functions,  such  as  those  concerned  in  the  getting  of 
food,  the  sexual  instincts,  and  so  on. 

The  description  given  above  applies  to  the  whole  of  the  neopallium. 
In  the  more  primitive  part  of  the  brain,  the  archipallium,  represented 
by  the  hippocampus,  we  find  only  two  cell  lamina}  which  are  homologous 
with  the  middle  (granule)  and  the  inner  polymorphous  cell  layers  of  the 
neopallium. 


SECTION  XVII 

THE   FUNCTIONS   OF  THE  CEREBRAL 
HEMISPHERES 

In  an  animal  possessing  cerebral  hemispheres  it  is  impossible  to  foretell 
with  certainty  what  particular  reaction  may  be  evoked  by  any  stimulus. 
The  animal  which  has  been  deprived  of  its  hemispheres  can,  as  we  have 
seen,  be  played  on  at  will,  whereas  the  intact  animal  is  an  individual  whose 
actions — to  judge  by  our  own  experience — are  guided  by  intelligence,  and 
influenced  by  motives  or  by  feehngs  of  fear,  hunger,  pain,  and  the  like.  In 
short,  its  behaviour  is  analogous  to  that  which  in  man  we  associate  with 
conscious  feehng  and  vohtion.  This  association  of  the  voKtional  manifesta- 
tions w^th  the  cerebral  hemispheres  has  long  been  assumed,  and  is  borne  out 
by  the  exact  paralleHsm  existing  between  the  degree  of  intelhgence  with 
w^hich  an  animal  is  endowed  and  the  extent  of  development  of  its  cerebral 
hemispheres.  Moreover  in  man  himself  there  is  a  proportionahty  between 
the  average  size  of  the  brain,  i.e.  of  the  cerebral  hemispheres,  and  the 
average  intelhgence  of  the  race. 

Earher  attempts  to  analyse  the  factors  entering  into  the  sphere  of 
consciousness  and  to  associate  with  these  factors  locaUsed  parts  of  the 
brain  failed,  largely  on  account  of  a  faulty  psychological  analysis  and  the 
absence  of  any  proper  experimental  groundwork  for  the  conclusions  put 
forward.  Gall,  the  founder  of  phrenology,  recognised  more  clearly  than 
previous  authors  that  the  cerebral  hemispheres  must  be  regarded  as  the 
material  basis  of  consciousness.  Impressed,  however,  by  the  fact  that  there 
was  no  proportionahty  between  the  acuteness  of  the  senses  and  the  degree 
of  development  of  the  cerebral  hemispheres,  he  considered  that  any  division 
of  fmictions  among  different  parts  of  the  hemispheres  must  relate  to  highly 
complex  psychical  conditions,  and  therefore  on  very  slender  grounds  allotted 
to  parts  of  the  brain  functions  such  as  those  of  intelhgence,  memory,  judg- 
ment, amativeness,  and  so  on.  These  conclusions  of  Gall  were  overthrown 
by  Flourens  on  both  theoretical  and  experimental  grounds.  In  the  first 
place,  Flourens  pointed  out  that  the  mental  faculty  of  man  cannot  be  divided 
up  into  a  number  of  different  independent  quahties  or  faculties,  such  as  those 
proposed  by  Gall.  In  the  second  place,  he  showed  that  in  the  pigeon 
although  loss  of  the  whole  cerebral  hemispheres  destroyed  intelligence  and, 
associative  memory  with  the  actions  founded  on  such  endowments,  removal 
of  portions  of  the  brain  caused  simply  a  lowering  of  these  functions,  and  it 

434 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES 


435 


COR 


was  a  matter  of  indifference  whether  the  brain  substance  was  taken  from  the 
anterior  or  from  the  posterior  portions  of  the  hemispheres.  Flourens  there- 
fore concluded  that  the  cerebral  hemispheres  acted  as  a  whole  as  the  seat  of 
the  will  and  intelligence.  There  is  no  doubt  that  Flourens  was  so  far  per- 
fectly correct,  since  all  parts  of  the  brain  must  co-operate  in  determining 
the  psychical  condition  of  any  individual  in  any  given  moment.  He  was, 
however,  as  later  researches  showed,  in  error  in  thinking  that  no  difference 
could  be  distinguished  between  the  parts  contributed  by  the  various  con- 
volutions of  the  brain  to  the  organic  whole  which  is  called  consciousness. 

As  we  have  seen,  histological 
evidence,  which  in  the  case  of  ^5^ 

the  cerebellum  displays  a 
marked  uniformity  throughout 
the  whole  cortex,  in  the  case 
of  the  cerebrum  reveals  strik- 
ing differences  between  its 
various  areas.  The  demarca- 
tion of  the  cerebral  cortex  into 
areas  according  to  the  histo- 
logical structure  of  their  grey 
matter  agrees  with,  and  in 
many  cases  supplements,  the 
results  procured  by  an  experi- 
mental inquiry  into  the  func- 
tions of  the  different  parts. 

That  there  is  a  localisation 
of  function  in  the  cortex  so 
far  as  concerns  the  movements 
of  the  two  sides  of  the  body 
was  known  to  Galen,  who  men- 
tions the  occurrence  of  paralysis 
on  one  side  of  the  body  as  a  re- 
sult of  lesions  in  the  brain  of  the  opposite  side.  In  1861  a  French  physician, 
Broca,  confirming  older  statements  by  Dax  and  Bouillaud,  maintained  that 
aphasia,  i.e.  loss  of  power  of  speech,  when  it  occurred  in  right-handed  people 
was  always  associated  with  a  lesion  of  the  third  frontal  convolution  of  the 
left  hemisphere,  which  has  ever  since  that  time  been  known  as  Broca's 
convolution.  Hughlings  Jackson  in  ISG-I  drew  attention  to  the  connection  of 
locaUsed  spasms  (Jacksonian  epilepsy)  with  lesions  of  certain  parts  of  the 
central  convolutions.  On  anatomical  grounds  Meynert  considered  that  the 
posterior  portions  of  the  hemispheres  were  probably  more  nearly  connected 
with  sensation,  and  the  anterior  with  the  power  of  movement ;  but  direct 
evidence  of  motor  localisation  was  first  brought  by  Fritsch  and  Hitzig  in 
1870.  These  observers  pointed  out,  in  contradiction  of  the  then  received 
idea,  that  the  grey  matter  of  the  cortex  was  excitable,  and  that  it  was 
possible  to  evoke  co-ordinated  movements  of  the  limbs  on  stimulating  the 


Fig.  225.  Upper  surface  of  dogs  brain,  showing 
results  of  excitation.  (Fritsch  and  Hitzig.) 
A,  neck  muscles  ;  -I-,  movements  of  fore  limb  ; 
=**=,  movements  of  hind  limb ;  O,  movements  of 
face;  ASG,  anterior  sigmoid  g}Tus;  PSG,  posterior 
sigmoid  gyrus  ;  COR,  coronary  fissures ;  Scr,  crucial 
sulcus. 


436 


PHYSIOLOGY 


B. 


front  part  of  the  hemispheres  in  dogs  with  weak  currents.  The  results  of 
their  experiments  are  shown  in  Fig.  225.  These  experiments  were  soon 
after  repeated  and  confirmed  by  Ferrier,  who  extended  his  observations 
to  the  monkey,  and  more  lately  by  Horsley,  Schafer,  Beevor,  Sherrington, 
and  others  in  the  higher  apes  and  man.  It  was  formerly  a  subject  of  dispute 
whether  the  movements  resulting  from  stimulation  of  the  cortex  were  due 
to  the  excitation  of  the  grey  matter  or  of  the  underlying  white  matter.  The 
following  facts  show  that  the  seat  of  the  excitation  is  in  the  grey  matter  : 

(1)  A  smaller  strength  of  current  is  required  to  excite  the  grey  matter 
than  the  underlying  white  matter,  after  removal  of  the  grey  matter. 

(2)  In  animals  poisoned  by  chloral  the  grey  matter  is  inexcitable,  though 
movements   can    still  be  aroused  on   stimulating  the  white   matter.      A 

similar  inexcitability  of  the  grey 
matter  can  be  produced  by  paint- 
ing it  with  cocaine. 

(3)  The  latent  period  elapsing 
between  the  beginning  of  the  stimu- 
lation and  the  occurrence  of  the 
movement  in  the  corresponding  limb 
is  longer  when  the  grey  matter  is 
excited  than  when  the  stimulus  is 
applied  to  the  white  matter.  The 
results  obtained  by  Fran9ois  Franck 
give  a  latent  period  of  -065  sec.  for 
the  grey  matter  and  -045  sec.  for 
the  white  matter  (Fig.  226). 


Fig.  226.      Tracings  to  show  latent  periods 
of  movements  obtained  by  stimulating : 
A,  grey  matter;  B,  underlying  white  matter 
g^of  cortex.    Time-marking 


Whether  the  stimulus  acts  directly  on 
the  pyramidal  cells  of  the''  cortex,  or 
whether,  as  seems  more  likely,  it  is  the 
endings  of  the  afferent  nerves  to  the 
cortex  which  are  really  excited  by  the 
stimulus,  we  cannot  at  present  determine. 


(F.  Franck.) 

When  we  compare  different  animals,  such  as  the  dog,  monkey,  and  man, 
we  find  there  is  a  much  finer  difierentiation  of  movements  evoked  by  stimula- 
tion of  the  cortex  in  the  higher  than  in  the  lower  type.  Whereas  in  the  dog 
the  excitable  areas  shade  into  one  another,  in  the  higher  ape  and  man  the 
areas  are  much  more  circumscribed  and  are  often  separated  from  adjoining 
areas  by  an  inexcitable  zone.  The  locahsation  of  motor  functions  in  the 
cortex  of  the  chimpanzee  is  indicated  in  the  accompanying  diagrams  by 
Sherrington  (Figs.  227,  228).  It  will  be  seen  that  the  motor  cortex  is  hmited, 
on  the  convex  side  of  the  brain,  to  the  precentral  convolution,  or  ascending 
frontal  convolution,  situated  immediately  in  front  of  the  fissure  of  Kolando. 
On  the  inner  aspect  of  the  hemispheres  only  the  corresponding  part  of  this 
convolution  gives  motor  responses  on  excitation.  We  may  say  broadly  that, 
from  above  downwards,  by  stimulation  of  the  precentral  convolution  we  get 
movements  of  the  leg,  arm,  and  face  ;   though,  as  is  shown  in  the  diagram, 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES 


437 


within  these  larger  areas  smaller  areas  can  be  distinguished  for  definite 
co-ordinated  movements  of  the  different  parts  of  the  body. 

NATURE  OF  MOVEMENTS  EXCITED.     The  movements  obtained  by 
excitation  of  these  areas  resemble  in  every  respect  the  co-ordinated  move- 

FiG.  227. 

/)/7us  &  i/agina 

Toes 
Ankle"--. 
Knee 
Hip   .., 

Shoulder 
Elbow 

Finders 
&  fhSmb 


Sulcus , . 
.  centralis 


Abdomen 
^Chest 


Ear-'  ■•'      / 
Eyelid, ■-'Closure 

Nose  °^j^  ^  Op  ening    \ 

of  jaw    l/ocal 

cords    MasticaTJon 


Sulcus  centralis 


Sulccalioso 

Svbic.parifto 
occtp. 


Fig.  228. 

SuLcCentral.      ^"u^i  Vkgina, 

Sitle./nvcencr.marg. 


Sulccalicarin. 


CSS.  del. 


Fig.  227,  outer  surface ;   Fig.  228,  inner  surface  of  brain  of  cliimpanzcc,  showing 
movements  obtained  by  excitation  of  the  motor  areas.     (Sherrington.) 


ments  observed  during  the  normal  willed  or  spontaneous  activity  of  the 
animal.  Like  the  movements  evoked  by  stinuilation  of  a  sensory  surface 
they  involve  therefore  the  reciprocal  innervation  of  antagonistic  nuiscles. 
Never  do  we  find  simultaneous  contractions  of  antagonists,  even  where  two 


438  PHYSIOLOGY 

opposing  centres  are  excited  simultaneously  ;  one  reaction  is  prepotent,  as 
is  the  case  with  cutaneous  excitation,  and  this  reaction  is  attended  and 
brought  about  by  ordered  contraction  of  certain  muscles  accompanied  by 
an  ordered  relaxation  of  their  antagonists.  Thus  the  movement  of  opening 
the  jaw,  which  can  be  excited  from  a  fairly  large  area  of  the  cortex,  involves 
a  relaxation  of  the  normal  tone  of  the  masseter  muscle.  Flexion  of  the  leg 
demands  relaxation  of  the  extensor  muscles.  As  in  the  case  of  the  spinal 
reflexes,  this  relaxation,  or  inhibition,  can  be  abolished  under  the  action  of 
strychnine,  or  the  toxin  of  tetanus.  After  administration  of  either  of  these 
it  is  impossible  to  evoke  inhibition  of  any  muscle.  Excitation  of  the  cortical 
centre  for  the  movements  of  the  jaw  causes  contraction  of  both  closers  and 
openers  of  the  jaw,  i.e.  a  strife  in  which  the  stronger  masseter  muscles 
predominate,  so  that  the  jaw  is  firmly  closed. 

The  part  played  by  muscular  relaxation  in  the  response  to  cortical  stimula- 
tion is  also  well  seen  in  the  case  of  the  eye  muscles.  Stimulation  of  the  centre 
for  eye  movements  on  the  convex  surface  of  the  frontal  lobes  on  the  right  side 
causes  '  conjugate  deviation '  of  both  eyes  to  the  left.  This  movement  involves 
contraction  of  the  right  internal  rectus  and  left  external  rectus,  and  a  simul- 
taneous inhibition  of  the  tone  of  the  right  external  rectus  and  left  internal 
rectus.  If  all  the  muscles  of  the  right  eye  be  divided  except  the  external 
rectus,  this  eye  looks  permanently  towards  the  right  side,  i.e.  a  right  external 
strabismus  or  squint  is  produced.  On  now  exciting  the  right  cortex  both 
eyes  move  to  the  left,  although  the  right  internal  rectus  is  divided.  The 
movement  of  the  right  eye  stops  at  the  middle  line,  and  is  brought  about 
simply  by  a  relaxation  of  the  tone  of  the  right  external  rectus  muscle 
(Sherrington). 

This  movement  of  both  eyes  on  stimulation  of  one  side  of  the  brain  shows 
that  the  function  of  each  hemisphere  is  not  entirely  unilateral  with  regard 
to  the  muscles  of  the  body.  As  a  rule  the  response  to  excitation  of  the  motor 
area  for  limbs  is  strictly  unilateral.  In  the  case  of  those  movements,  how- 
ever, which  are  normally  carried  out  by  co-operation  of  the  muscles  of  the 
two  sides,  such  as  the  movements  of  the  trunk,  neck,  and  eyes,  stimulation  of 
the  motor  area  in  one  hemisphere  evokes  a  movement  involving  the  muscles 
of  both  sides  of  the  body,  i.e.  the  cortical  representation  is  one  of  movement 
rather  than  one  of  muscles.  Where  an  action  is  carried  out  by  similar  con- 
tractions of  corresponding  muscles  on  the  two  sides,  the  movement  itself 
is  bilaterally  represented  in  the  cortex.  Types  of  such  reactions  are  found 
in  closure  of  the  mouth,  contraction  of  the  abdominal  muscles,  erection  or 
flexion  of  the  trunk.  It  seems  that  under  such  circumstances  there  is  a  free 
communication  between  the  lower  motor  centres  of  the  two  sides,  since  the 
bilaterahty  of  the  response  is  not  altered  by  extirpation  of  the  cortex  of 
the  opposite  hemispheres  to  that  which  is  being  stimulated. 

CORTICAL  EPILEPSY.  When  electrical  excitation,  of  any  strength 
over  the  minimum  effective  stimulation,  is  applied  to  the  motor  area  of  the 
cortex,  the  movements  evoked  tend  to  persist  for  a  short  time  beyond  the 
duration  of  the  stimulus.     On  still  further  increasing  the  strength  of  the 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES 


439 


current,  the  contraction  spreads  to  adjoining  muscles,  and  finally  may 
affect  all  parts  of  the  body,  giving  rise  to  the  phenomenon  known  as  an 
epileptic  convulsion.  The  same  effect  may  often  be  caused  by  weak  stimuli, 
if  the  irritability  of  the  cortex  be  raised  in  consequence  of  repeated  previous 
stimulation.  A  typical  fit  consists  of  two  parts.  The  first  effect  of  the  stimu- 
lation is  a  strong  tonic  contraction  ;  this  outlasts  the  stimulus  for  some 
time,  and  then  gives  way  to  a  series  of  clonic  contractions,  repeated  at  first  at 
intervals  of  from  six  to  ten  per  second,  but  gradually  getting  slower  as  the 
fit  dies  away.     The  tracing  of  such  a  contraction  is  given  in  Fig.  229. 


Fig. 


229.     Tracing  of  muscular  contractions  during  an  epileptic  convulsion  aroused 
by  strong  stimulation  of  the  motor  area.     (Hoksley  and  Schafer.) 


The  main  phenomena  of  a  fit,  due  to  irritation  of  any  portion  of  the 
motor  area,  were  described  by  Hughlings  Jackson  in  186-i,  even  before  the 
experimental  proof  of  cortical  locahsation  had  been  brought  forward  by 
Fritsch  and  Hitzig.  A  similar  condition  may  occur  in  the  human  subject 
as  a  result  of  irritative  lesions  of  this  part  of  the  cortex,  such  as  that  due  to 
the  presence  of  a  tumour  or  a  spicule  of  bone  pressing  on  the  brain.  Jackson 
showed  that  in  this  condition  the  convulsive  movements  follow  a  certain  order 
or  '  march.'  Thus  if  the  thumb  area  be  the  seat  of  stimulation,  the  fit 
begins  by  a  contraction  of  the  thumb  muscles,  then  spreads  to  the  muscles 
of  the  hand,  fore-arm  and  shoulder  muscles  of  the  same  side,  and  then  to  the 
face,  trunk,  and  leg.  If  it  begins  in  the  toes  the  order  would  be  up  the  leg  and 
down  the  arm.  The  same  '  march '  is  observed  in  artificial  stimulation  of 
the  motor  area.  If  the  convulsions  are  very  strong  they  spread  to  the 
leg  of  the  opposite  side  and  then  to  the  w^hole  body.  The  spread  to  the  other 
side  of  the  body  is  not  prevented  by  division  of  the  corpus  callosum,  nor  by 
isolating  the  centres  from  one  another,  so  that  the  sequence  seems  to  be 
maintained  through  the  mediation  of  the  sub-cortical  centres.  Complete 
excision  of  the  cortical  centre  for  any  given  movement  excludes  this  move- 
ment from  participation  in  the  fit.  In  man  this  U'^e  of  epilepsy  is,  in  the 
milder  cases  at  any  rate,  generally  unattended  with  loss  of  consciousness. 
In  animals  epileptic  convulsions  can  be  excited  by  stimulation  of  any  portion 
of  the  cortex,  though  it  is  obtained  by  a  weaker  stimulus  applied  to  the  motor 
cortex  than  to  any  other  part.  Jacksonian  epilepsy  is  often  preceded  by 
a  sensation  of  numbness  or  tingling,  the  '  aura,'  in  the  part  in  which  such 
convulsions  begin.  In  ordinary  idiopathic  epilepsy  tactile  or  visual  sensory 
aurae  may  precede  the  attack  ;  but  in  this  case  loss  of  consciousness  is  always 
a  prominent  symptom,  even  in  th(>  milder  form  of  the  disease.     Universal 


440  PHYSIOLOGY 

epileptic  con\n.ilsions  can  be  excited  in  animals  by  the  injection  of  absinthe 
into  a  vein.  Dining  the  convulsion  there  is  a  rise  of  blood  pressure  and  a 
quickening  of  the  pulse ;  the  respiration  is  very  often  stopped  during  the  tonic 
part  of  the  spasm,  so  that  the  patient  becomes  Hvid.  The  universal  con- 
dition of  excitation  affects  also  the  centres  from  which  the  secretory  nerves 
originate,  so  that  there  is  an  excessive  flow  of  saHva,  which,  in  the  idio- 
pathic case,  is  responsible  for  the  characteristic  frothing  at  the  mouth. 

EFFECTS  OF  ABLATION  OF  THE  MOTOR  CENTRES 
We  have  seen  that  a  dog  may  preserve  complete  power  of  movement 
after  a  total  ablation  of  both  cerebral  hemispheres.  We  should  not  expect 
therefore  to  find  any  lasting  paralysis  as  a  result  of  extirpation  of  portions 
of  the  brain,  such  as  the  motor  centres.  Ablation  of  the  motor  areas  in 
these  animals,  during  the  first  few  weeks  after  the  operation,  gives  rise  to 
considerable  disorders  of  movement,  the  muscles  on  the  side  of  the  body 
opposite  to  the  lesion  being  markedly  weaker  than  those  on  the  same  side. 
These  symptoms,  however,  gradually  pass  off,  so  that  after  a  time  not  only 
are  both  hmbs  employed  in  the  ordinary  automatic  movements  of  progression, 
but  the  animal  can  be  taught  new  movements  in  the  Kmb,  the  cortical  centre 
for  which  has  been  excised.  We  must  conclude  therefore  that  in  the  dog  all 
the  movements,  including  those  which  are  voluntary  and  conscious,  can  be 
carried  out  in  the  absence  of  the  motor  centres,  although  destruction  of  these 
centres  may  impair  the  accuracy  with  which  some  of  the  finer  movements  are 
regulated. 

In  the  monkey  (Macacus)  the  effect  of  ablation  is  more  marked,  corre- 
sponding to  the  greater  degree  of  locahsation  in  these  animals.  If  the  whole 
of  the  motor  area  on  the  external  surface  of  the  brain  be  excised,  e.g.  on  the 
right  side,  there  will  be  almost  complete  paralysis  of  the  left  arm  and  the  left 
side  of  the  face,  and  weakness  of  the  muscles  of  the  left  leg.  The  animal 
will  continue  to  use  the  leg  in  walking  and  in  chmbing.  If  the  lesion  extends 
to  the  medial  side  of  the  hemisphere  paralysis  of  the  leg  is  more  marked,  and 
the  muscles  of  the  left  side  of  the  trunk  are  also  affected.  Many  of  these 
symptoms  disappear  in  the  course  of  time.  In  a  monkey  in  which  Goltz  had 
destroyed  the  greater  part  of  the  left  side  of  the  cerebral  hemispheres  it  was 
found  that  the  right  arm  and  hand  could  be  still  employed  alone  for  such 
purposes  as  taking  food,  although  the  movements  were  much  more  awkward 
than  those  of  the  left  hand. 

Still  less  complete  is  the  recovery  from  lesions  of  the  motor  area  in  man. 
We  possess  now  a  considerable  number  of  typical  histories  of  cases  in  which 
part  of  the  motor  cortex  has  been  destroyed  by  disease  or  by  operation,  and 
the  seat  of  the  lesion  verified  by  post-mortem  examination.  In  all  these 
cases  there  has  been  a  loss  of  voluntary  movement  corresponding  in  distribu- 
tion to  the  seat  of  the  lesion  and  proportionate  in  its  severity  to  the  extent 
of  the  lesion.  On  the  other  hand,  equally  extensive  lesions  outside  the  as- 
cending frontal  convolution  have  been  shown  to  have  no  effect  on  voluntary 
movements.     The  loss  of  movement  is  chiefly  confined  to  those  which  we 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES  Ul 

regard  as  volitional.  Although,  for  instance,  the  arm  may  be  paralysed,  it 
can  be  still  raised  in  association  with  a  movement  involving  the  other  arm. 
A  certain  degree  of  recovery  from  the  immediate  effects  of  the  lesion  may  be 
observed,  but  the  recovery  is  never  complete. 

The  difference  in  the  reaction  of  various  animals  to  lesions  of  the  motor 
cortex  is  connected  with  the  gradual  shifting  of  functions  from  the  sphere 
of  fatal  necessary  reactions  to  the  sphere  of  educatable  adaptations  {i.e.  from 
the  lower  centres  to  the  cerebral  cortex),  which  is  a  characteristic  of  the  evolu- 
tion of  the  higher  type  of  nervous  system,  and  is  a  concomitant  of  the  in- 
creased adaptability  which  distinguishes  man  from  all  the  lower  animals.  In 
the  animal  without  hemispheres  the  motor  mechanisms  for  all  the  movements 
of  the  body  are  present  and  can  be  set  into  action  from  any  point  on  the 
sensory  surface  of  the  body.  The  first  effect  of  adding  the  cerebral  hemi- 
spheres to  this  mechanism  is  to  increase  the  range  of  reactions,  to  modify 
them  or  to  inhibit  them,  by  diverting  the  stream  of  nervous  impulses  into 
channels  which  have  to  a  large  extent  been  laid  down  in  the  cortex  by  the 
past  experience  of  the  individual.  In  the  frog  and  bird  we  notice  an  auto- 
maticity  and  a  '  conscious  '  adaptation  of  movements  to  purpose,  although 
the  hemispheres  have  no  direct  connection  with  the  motor  centres  of  the 
cord,  and  present  no  areas  which  we  can  designate  as  motor.  In  the  dog, 
although  a  portion  of  the  brain  is  in  direct  connection  with  the  spinal  motor 
centres,  and  can  therefore  initiate  movements  without  making  use  of  the 
mid-brain  motor  machinery,  these  movements  play  only  a  small  part  in  the 
motor  life  of  the  animal,  and  the  removal  of  the  corresponding  centres  takes 
away  but  little  of  the  conscious  functions  of  the  animal.  In  man  the  enor- 
mous power  of  acquisition  of  new  movements  is  rendered  possible  by  the 
shifting  of  one  motor  function  after  another  to  the  sphere  of  influence  of  the 
cerebral  hemispheres.  Almost  every  act  of  life  in  man  has  become  one 
involving  co-operation  of  the  cerebral  cortex.  For  many  years  after  birth 
man  is  helpless  and  far  inferior,  as  a  reactive  organism,  to  animals  much 
lower  in  the  scale.  Even  the  lower  motor  fmictions,  such  as  those  of  loco- 
motion or  defence,  have  to  be  painfully  learnt,  and  this  learning  implies  the 
laying  down  of  paths  (Bahmmg)  in  the  cortex.  On  this  account  the  sub- 
cortical centres  in  man  are  no  longer  complete.  Acting  in  every  instance 
of  life  as  a  subordinate  or  adjunct  to  the  cerebral  hemispheres,  they  are  unable 
to  carry  out  even  the  simpler  motor  reactions  of  the  body  after  removal 
of  those  portions  of  the  hemispheres  especially  engaged  in  the  control  of 
voluntary  movement.  The  motor  defect  therefore  which  is  brought  about 
in  man,  as  a  result  of  destruction  of  one  or  more  of  the  motor  centres,  is  to  a 
large  extent  permanent. 

If  the  lesion  in  man  be  strictly  limited  to  the  motor  areas  in  the  ascending 
frontal  convolution,  it  is  impossible  to  detect  any  loss  of  sensation  in  the 
affected  parts  of  the  body.  On  the  other  hand,  some  loss  of  sensation  is 
often  found  where  the  paralysis  is  widespread  and  occasioned  by  extensive 
lesion  in  the  neighbourhood  of  the  Rolandic  area.  Moreover,  even  in  localised 
lesions  in  man,  an  epileptic  fit  may  be  preceded  by  a  sensory  aura  in  the  part 


442  PHYSIOLOGY 

which  is  the  starting-poiut  of  the  convulsive  movements.  Much  discussion 
has  taken  place  as  to  the  exact  significance  to  be  assigned  to  these  slight 
sensory  phenomena.  By  some  observers,  e.g.  Munk,  it  has  been  thought 
that  the  motor  centres  were  the  end- stations  of  the  fibres  subserving  muscular 
sensations,  and  that  the  movements  resulting  from  their  stimulation  were 
due  to  the  revival  of  such  sensations.  Bastian  insisted  on  the  important 
part  played  in  voluntary  actions  by  afferent  impressions,  and  these  centres 
have  sometimes  been  spoken  of  as  '  kinsesthetic '  or  sensori-motor.  The 
discussion  has,  however,  now  resolved  itself  practically  into  one  of  terms. 
There  is  no  doubt  that,  when  the  lesion  is  strictly  locahsed  in  the  motor  area, 
paralysis  may  be  present  without  any  loss  of  sensation  whatsoever.  The 
paralysis  therefore  cannot  be  classed  with  the  sensori-motor  paralysis  dis- 
tinguished earlier  as  the  result  of  division  of  sensory  roots.  On  the  other 
hand,  when  we  say  that  this  part  of  the  brain  represents  a  '  centre  for 
voluntary  movements,'  we  do  not  mean  that  the  vohtional  motor  impulses 
arise  de  novo  from  the  pyramidal  cells  in  its  grey  matter.  Every  neuron  in 
the  nervous  system  is  part  of  an  arc,  and  it  is  generally  difficult  to  label  any 
given  neuron  as  definitely  sensory  or  motor.  In  a  reaction  involving  a  chain 
of  neurons  we  can  assign  the  name  of  motor  to  that  neuron  which  sends 
its  axon  to  the  muscle,  and  of  sensory  or  afferent  to  that  neuron  which 
receives  the  impulses  at  the  periphery  of  the  body.  Where  in  the  chain  we 
are  to  draw  the  dividing  fine  and  to  say  these  neurons  are  sensory  and  those 
motor,  it  is  difficult  to  decide.  The  motor  areas  in  the  cortex  give  origin  to 
the  long  fibres  of  the  pyramidal  tract,  which  passes  right  through  the  central 
nervous  system  to  the  segmental  centres  of  the  cord.  We  know  that  the 
integrity  of  these  tracts  is  essential  for  the  carrying  out  of  voluntary  move- 
ment. It  is  therefore  convenient  to  speak  of  them  as  motor  or  efferent 
tracts,  and  their  origin  as  motor  centres  ;  although  these  tracts  have  the 
same  relation  to  the  motor- cells  of  the  spinal  segment  as  have  the  afferent 
fibres  from  the  posterior  roots  by  which  similar  movements  may  be  evoked. 

On  the  other  hand,  the  activity  of  the  pyramidal  cells  of  the  cortex, 
hke  those  of  the  motor- cells  of  the  spinal  cord,  is  determined  by  the  arrival 
at  them  of  afferent  impressions.  In  the  absence  of  these  afferent  impressions 
no  spontaneous  discharge  of  motor  impulses  takes  place.  Thus  in  the  spinal 
frog  we  have  seen  that  complete  inactivity  is  brought  about  by  section  of 
all  the  posterior  roots.  In  the  same  way  paralysis  of  the  arm  is  induced 
by  section  of  all  its  posterior  roots,  although  it  can  be  shown  that  the  motor 
cortex  is  still  excitable,  and  that  the  apphcation  of  an  induced  current  to  the 
motor  centres  of  the  arm  evokes  a  movement  as  easily  as  in  the  normal 
animal.  The  motor- cells  in  the  cortical  motor  centres  are  normally  played 
upon  and  aroused  by  impressions  arriving  at  them  from  all  other  parts  of  the 
brain  and  nervous  system,  and  determined  originally  by  impressions  falhng 
on  the  surface  of  the  body. 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES  443 

THE  FUNCTIONS  OF  THE  CORPUS  STRIATUM 
The  mass  of  grey  matter  known  as  the  corpus  striatum,  which  consists 
of  the  nucleus  lenticularis  and  the  nucleus  cordatus,  is  the  basal  part  of  the 
outgrowth  from  which  each  cerebral  hemisphere  is  formed  and  in  the  lowest 
vertebrata  represents  almost  the  whole  of  the  telencephalon.  For  many 
years  the  corpus  striatum  was  classed  with  the  optic  thalamus  as  the  '  basal 
ganglia,'  and  these  two  ganglia  were  regarded  as  relay  stations  between  the 
cerebral  cortex  and  the  lower  parts  of  the  ct5ntral  nervous  system.  This  view 
was  correct  so  far  as  concerns  the  optic  thalamus,  in  which  end  all  the  afferent 
tracts  and  from  which  afferent  impressions  are  carried  on  by  fresh  relays  of 
fibres  to  the  cortex.  In  the  higher  mammals  the  motor  cortex  has  a  direct 
connection  with  the  motor  nuclei  of  the  bulb  and  spinal  cord  through 
the  pyramidal  tracts,  which  are  not  interrupted  anywhere  on  their  course. 
On  destroying  the  corpora  striata  degenerated  fibres  are  found  running  to  the 
optic  thalamus,  to  the  red  nucleus,  and  from  the  latter  to  the  posterior 
longitudinal  bundle.  On  the  other  hand  the  corpus  striatum  receives  fibres 
from  the  olfactory  tracts  and  from  the  optic  thalamus.  These  connections 
would  tend  to  show  that  the  corpus  striatum  serves  in  no  way  as  an  inter- 
mediary between  the  cortex  and  the  lower  parts  of  the  central  nervous 
system,  but  is  an  independent  mass  of  grey  matter,  receiving  impulses  from 
the  same  source  as  the  cortex  and  sending  impulses  which  may  join  in  the 
stream  of  impressions  which  play  upon  the  lower  motor  mechanisms  of  the 
bulb  and  cord. 

Isolated  excitation  of  the  caudate  and  lenticular  nuclei  has  no  visible 
effect,  provided  the  current  is  not  so  strong  as  to  spread  to  the  adjoining 
pyramidal  fibres  in  the  internal  capsule.     A  study  of  the  evolution  of  the 
central  nervous  system  in  different  classes  of  animals  points  to  a  diminishing 
importance  of  these  bodies  in  the  normal  hfe  of  the  animal.     In  the  carti- 
laginous fishes  it  probably  serves  to  a  greater  or  less  degree  the  same  functions 
in  the  determination  of  educated  reflexes  as  the  cerebral  hemispheres  in 
mammals.     In  birds  the  corpus  striatum  attains  its  greatest  relative  develop- 
ment, the  increased  powers  of  adaptation  in  these  animals  being  apparently 
procured  by  development  of  the  corpus  striatum  instead  of  as  in  mammals  by 
increased  development  of  the  palHum  or  cerebral  hemispheres.     In  the 
monkey  Kinnear  Wilson  found  no  definite  results  to  follow  destruction  of 
the  grey  matter  in  these  bodies.     The  animals  were,  however,  only  allowed 
to  survive  the  operation  of  destruction  three  weeks,  and  the  same  observer 
has  pointed  out  that  destruction  of  the  corpora  striata  in  man  may  give  rise 
to  a  morbid  condition,  characterised  by  tremor  in  the  execution  of  willed 
movements  and  increased  tonicity  of  the  muscles.     He  therefore  ascribes 
to  these  bodies,  or  rather  to  the  sensori-motor  mechanism  which  has  its  chief 
meeting-place  in  their  nuclei  of  grey  matter,  a  stead}'ing  efi'ect  on  the  motor 
system,  and  places  this  system  by  the  side  of  the  other  systems  wliich  we 
have   already   studied,    namely,    the   vestibular,    the   cerebellar,    and    the 
pyramidal  system. 


444  PHYSIOLOGY 

According  to  Meyer  and  Barbour,  the  anterior  part  of  the  corpus 
striatum  plays  an  important  part  in  the  regulation  of  body  temperature. 
In  the  experiments  a  metal  tube,  closed  at  one  end,  was  introduced  through 
the  brain  so  as  to  he  in  or  on  the  corpus  striatum.  Through  this  tube  water 
at  any  temperature  could  be  passed.  It  was  found  that  coohng  the  water 
gave  rise  to  shivering  and  increased  heat  production  in  the  body  with  a  rise 
of  body  temperature,  while  warming  the  water  had  the  reverse  effect.  He 
is  therefore  inclined  to  regard  this  part  of  the  nervous  system  as  representing 
the  chief  thermo-taxic  mechanism  of  the  body. 

THE  LOCALISATION  OF  SENSORY  FUNCTIONS  IN  THE  CORTEX 

It  was  pointed  out  by  Ferrier  that  movements  might  be  obtained  on 
electrical  excitation  of  regions  of  the  cortex  cerebri  other  than  those  we  have 
described  as  motor.  Thus  excitation  of  the  superior  temporal  convolution 
on  the  right  side  causes  the  animal  to  turn  its  head  and  eyes  to  the  left  and  to 
prick  up  its  ears.  In  the  same  way  stimulation  of  the  right  occipital  lobe 
causes  movement  of  both  eyes  and  head  to  the  left  side.  These  portions  of 
the  brain  cannot  be  regarded  as  having  a  direct  relationship  to  the  motor 
mechanisms  involved  in  the  above  movements,  since  their  ablation  leads  to 
no  defect  of  movement,  but  does,  in  many  cases,  lead  to  defect  of  sensation. 
Thus  excision  of  the  right  occipital  lobe  in  the  monkey,  though  leaving  the 
eye  movements  intact,  causes  a  loss  of  power  to  discern  objects  lying  to  the 
left  of  the  middle  hne.  The  obvious  explanation  therefore  of  the  movements, 
obtained  on  excitation  of  this  portion  of  the  cortex,  is  that  they  are  due  to 
the  revival  or  arousing  of  sensory  impressions,  that  these  portions  of  the 
cortex  represent  the  cortical  receiving-stations  for  the  impulses  from 
definite  sense-organs,  and  that  the  movements  obtained  are  simply  those 
which  are  normally  associated  with  a  corresponding  sensory  excitation. 

This  conclusion  is  borne  out  by  the  fact  that  it  requires  a  greater  strength 
of  stimulus  to  excite  movement  on  stimulation  of  the  sensory  areas  than  is 
necessary  if  the  stimulus  be  applied  to  the  Kolandic  area.  Moreover  Schafer 
has  shown  that  the  latent  period  which  intervenes  between  the  stimulus  and 
the  resulting  movement  is  considerably  longer  when  the  stimulus  is  apphed 
to  the  sensory  centre  than  when  it  is  applied  to  the  motor  centre,  suggesting 
that  more  neurons  are  interpolated  between  the  point  of  stimulus  and  the 
discharging  motor  neuron  in  the  first  case  than  in  the  latter.  Thus  in  one 
experiment  the  latent  period  between  the  stimulus  and  the  resulting  move- 
ment of  the  eyes  amounted  to  0-2  sec.  when  the  frontal  lobes  were  stimulated 
and  0-4  sec.  when  the  occipital  lobes  were  stimulated.  Finally  the  anatomi- 
cal investigation  of  the  course  of  the  fibres  in  the  white  matter  of  the  cerebral 
hemispheres  points  to  a  concentration  of  sensory  fibres  from  different  sense- 
organs  towards  certain  regions  of  the  cortex.  The  diagrams  (Figs.  230 
and  231)  show  those  portions  of  the  brain  to  which  the  endings  of  the  sensory 
tracts  of  the  central  nervous  system  are  directed. 

From  the  purely  anatomical  standpoint  we  may  designate  as  '  sensory 
areas  '  of  the  cortex  : 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES 


445 


(1)  An  area  including  both  central  convolutions,  i.e.  the  ascending  frontal 
and  the  ascending  parietal,  and  spreading  forward  into  the  frontal  lobes. 

(2)  An  area  occupying  the  hinder  portion  of  the  occipital  lobe  and  the 
greater  part  of  its  inner  surface. 


'  Tactile  *  area 


Visual 
area 


Auditory  aroa 

Fig.  230.  Outer  .side  of  right  cerebral  hemisphere,  according  to  Flechsig.  The 
dotted  surface  indicates  the  regions  where  the  majority  of  the  afferent  (sensory) 
fibres  end. 

(3)  An  area  occupying  the  superior  temporal  convolution  and  extending 
well  into  the  fissure  of  Sylvius. 

(4)  An  area  on  the  inner  side  of  the  hemisphere,  occupying  the  hippo- 

'  Tactile'  area 


Olfactory  area 
Fig.  231.     Inner  .surface  of  the  same  hemisphere.     (Fr.ECHSio.) 


campal  gyrus  and  the  margin  of  the  gyrus  fornicatus  close  to  the  corpus 
callosum. 

Let  us  see  how  far  experimental  evidence  bears  out  this  localisation. 


446 


PHYSIOLOGY 


(a)  TACTILE  AND  MOTOR  SENSIBILITY.  A  lesion  limited  to  the 
ascending  frontal  convolution  may  produce  paralysis  of  definite  movements 
or  groups  of  muscles  without  any  detectable  interference  with  sensation. 
When,  however,  in  man  a  widespread  injury,  involving  both  the  Rolandic 
area  and  the  adjacent  portions  of  the  brain,  occurs  as  the  result  of  some 
morbid  condition,  such  as  blockage  of  the  middle  cerebral  artery,  the  resulting 
hemiplegia  is  almost  always  associated  with  a  greater  or  lesser  degree  of 
hemiancBSthesia.     We  are  therefore  justified  in  locating  tactile  and  muscular 

sensibility  somewhere  in  the  region 
LE.FT  RETINA  richt  RETINA     Qf   ^]^g  ccutral  couvolutious,   and 

it  is  probable  that  while  it  may 
include  the  motor  area  its  chief 
representation  is  to  be  found  in 
the  post-central  gyrus,  i.e.  the 
ascending  parietal  convolution. 

The  sensory  aura  which  pre- 
cedes an  attack  of  Jacksonian 
epilepsy  points  to  the  motor  area 
itseif  having  some  degree  of  sen- 
sory functions,  and  it  has  been 
observed  that  faradisation  of  the 
central  convolution  in  man  may 
produce  tinghng  sensations  in  the 
part  of  the  body  which  is  the 
seat  of  the  muscular  contractions 
induced  by  stimulation.  No  pain 
is,  however,  felt  as  a  result  of  the 
stimulation.  The  impulses  which 
subserve  cutaneous  and  muscular 
sensibihty  travel  up  to  the  brain  in 
the  mesial  fillet.  This  tract  comes 
to  an  end  in  the  ventro-lateral 
portion  of  the  thalamus  and  the 
subthalamic  region.  The  new  relays  of  fibres,  which  carry  on  impulses  to 
the  cortex,  arise  in  the  thalamus  and  pass  through  the  hinder  limb  of  the 
internal  capsule  to  be  distributed  to  the  central  convolutions.  Their  area 
of  distribution  is,  however,  much  wider  than  the  area  of  origin  of  the  pyra- 
midal fibres.  We  may  therefore  conclude  that  tactile  and  muscular  sensi- 
bihty are  chiefly  subserved  by  the  central  convolutions,  including  the  motor 
area,  but  are  especially  dependent  on  the  integrity  of  the  post-central  gyrus. 
Flechsig  has  shown  that  fibres  from  the  thalamus,  which  may  probably  be 
regarded  as  continuations  of  the  fillet  system,  are  also  distributed  to  other 
portions  of  the  cortex,  i.e.  the  temporal,  the  frontal,  and  the  occipital  lobes. 
It  is  therefore  not  surprising  that  the  hemiansesthesia  produced  by  lesions 
in  the  cetral  convolutions  is  rarely  or  never  complete. 


Fig.  232.  Diagram  showing  the  probable 
relations  between  the  parts  of  the  retinse 
and  the  visual  area  of  the  cortex.    (Schafer.) 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES  447 

VISUAL  IMPRESSIONS 

Each  optic  tract,  carrying  impulses  arising  as  a  result  of  events  occurring 
in  the  opposite  field  of  vision,  ends  in  the  pulvinar  of  the  optic  thalamus,  the 
external  geniculate  body,  and  the  superior  corpora  quadrigemina.  The  last 
named  is  apparently  not  concerned  in  vision,  but  represents  a  centre  for 
the  co-ordination  of  visual  impressions  with  those  from  other  regions  of  the 
body  in  influencing  bodily  movements.  From  the  pulvinar  and  external 
geniculate  body  arises  a  sheaf  of  fibres,  which  pass  through  the  extreme  hinder 
end  of  the  posterior  limb  of  the  internal  capsule  and  diverge  in  the  centrum 
ovale  to  be  distributed  to  the  occipital  lobes,  being  here  known  as  the  optic 
radiations.  The  anatomical  connection  of  the  occipital  lobes  with  vision 
is  confirmed  by  evidence  derived  from  experiment.  Movements  of  the 
eyes  result  from  stimulation  of  almost  any  part  of  this  lobe.  If  the  upper 
surface  of  the  right  occipital  lobe  be  stimulated,  both  eyes  move  downwards 
and  towards  the  left.  Excitation  of  the  posterior  part  causes  movement 
of  the  eyes  up  and  to  the  left ;  while  between  these  two  parts  there  is  an 
intermediate  zone,  most  marked  on  the  mesial  surface,  stimulation  of  which 
evokes  a  purely  lateral  deviation  of  the  eyes  to  the  left.  It  is  therefore  con- 
cluded not  only  that  there  is  representation  of  visual  impressions  in  the 
occipital  lobes,  but  that  there  is  a  certain  amount  of  localisation  within  the 
visual  area  itself,  as  is  represented  in  the  diagram  (Fig.  232). 

These  conclusions  are  fully  borne  out  by  the  results  of  ablation.  While 
extirpation  of  the  whole  occipital  lobe  on  one  side  in  animals  causes  crossed 
hemianopia,  i.e.  has  the  same  effect  as  division  of  the  corresponding  optic 
tract,  extirpation  of  these  lobes  on  both  sides  causes  complete  bhndness. 
It  seems  that  the  fovea  centralis — the  region  of  distinct  vision — is  bilaterally 
represented,  so  that  central  vision  is  usually  retained  in  both  eyes  after 
destruction  of  one  occipital  lobe  (Fig.  233). 

The  area  connected  with  vision  seems  to  be  smaller  in  man  than  in  the 
ape,  and  in  the  ape  than  in  the  dog.  Thus  in  man  complete  blindness  has 
been  observed  as  the  result  of  localised  bilateral  lesions  of  the  internal  sur- 
faces of  the  occipital  lobes,  and  we  find  the  same  relative  limitation  of  area 
as  we  proceed  from  lower  to  higher  forms  in  the  case  of  the  other  sensory 
areas  of  the  cortex. 

THE   AUDITORY  AREA 

Anatomical  study  indicates  a  connection  of  auditory  sensations  with  the 
superior  temporal  lobe.  The  impulses,  started  by  the  arrival  of  sound  waves 
at  the  ear,  travel  by  the  cochlear  nerve  to  the  medulla.  From  the  two  audi- 
tory nuclei  a  well-marked  set  of  fibres  passes  across  to  the  opposite  side  in 
the  corpus  trapezoides,  then  turns  up  into  the  tegmentum  of  the  oppsite  side 
to  form  the  tract  known  as  the  lateral  fillet.  The  fibres  of  this  tract  end 
partly  in  the  inferior  corpora  quadrigemina,  partly  in  the  internal  geniculate 
body.  From  the  latter,  fibres  pass  into  the  internal  capsule,  and  thence  as 
'  auditory  radiations  '  directly  to  the  superior  temporal  convolution. 

In  the  monkey  stimulation  of  the  upper  two-thirds  of  this  lobe  of  the 


448 


PHYSIOLOGY 


brain  causes  pricking  of  the  opposite  ear,  dilatation  of  the  pupils,  and  rotation 
of  the  head  and  eyes  to  the  opposite  side.  It  was  stated  by  Ferrier  that 
ablation  of  the  superior  temporal  convolution  causes  deafness,  but  Schafer 
found  that,  even  after  extirpation  of  the  superior  temporal  convolutions  of 
both  sides,  monkeys  showed  signs  of  hearing  quite  distinctly,  and  of  under- 
standing the  nature  of  the  sounds  heard.  One  must  conclude  therefore  that 
the  function  of  auditory  perception  is  not  entirely  confined  to  the  temporal 
lobe,  though  its  focal  point  may  be  located  in  the  superior  temporal  con- 
volution, especially  in  that  part  which  is  seated  within  the  fissure  of  Sylvius. 


Fig.  233.     Perimeter  charts  from  right  and  left  eye,  showing  the  limitation  of  the  field  of 
vision  (right  hemianopia)  produced  by  a  lesion  of  the  left  occipital  cortex.    (Bechtekew.) 

This  conclusion  is  strengthened  by  the  results  of  clinical  evidence  in  man,  in 
whom  cerebral  lesions,  which  have  produced  disturbances  of  auditory  per- 
ception, are  found  almost  invariably  to  be  closely  associated  with  the  superior 
temporal  convolution. 

SMELL  AND  TASTE 
The  course  of  the  fibres  from  the  olfactory  lobe  may  be  used  to  throw 
light  upon  the  localisation  of  olfactory  sensation  in  the  cerebral  cortex. 
There  is  a  great  divergence  between  different  animals  in  the  degree  to  which 
the  olfactory  sense  is  developed,  and  with  this  divergence  we  find  corre- 
sponding variations  in  the  development  of  certain  portions  of  the  brain. 
In  those  species  with  highly  developed  olfactory  sense  the  following  parts 
of  the  brain  show  special  growth  : 

(1)  The  olfactory  lobe,  including  the  olfactory  bulb,  and  the  olfactory 
tract. 

(2)  The  posterior  part  and  the  inferior  surface  of  the  frontal  lobe. 

(3)  The  hippocampal  gyrus  and  the  dentate  convolution. 

(4)  A  convolution  termed  the  gyrus  supracallosus  and  forming  that  part 
of  the  gyrus  fornicatus  closely  encircling  the  corpus  callosum. 

.    (5)  The  anterior  commissure. 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES  449 

The  olfactory  lobe  is  connected  almost  exclusively  with  the  cerebral 
hemispheres  of  the  same  side.  Ferrier  found  that  electrical  excitation  of 
the  hippocampal  region  causes  contortion  of  the  lip  and  nostril  on  the  same 
side,  i.e.  a  reaction  such  as  that  actually  induced  in  these  animals  by  applica- 
tion of  an  irritative  or  pungent  odour  direct  to  the  nostril.  Ablation  ex- 
periments have  not  yielded  very  definite  evidence  on  the  question  of  localisa- 
tion of  the  olfactory  sense.  So  widespread  are  the  connections  of  the  olfac- 
tory tract  throughout  the  brain  that  it  would  be  extremely  difl&cult,  if  not 
impossible,  to  extirpate  all  those  parts  which  receive  fibres  from  this  tract. 
It  is  usual  to  regard  the  sense  of  taste  as  associated  with  that  of  smell,  but 
here  again  experiment  and  clinical  evidence  have  yielded  very  little  that  is 
definite. 

GENERAL  CHARACTERISTICS  OF  CORTICAL  MOTOR  FUNCTIONS 
The  motor  phenomena,  which  may  be  observed  as  the  result  of  artificial 
excitation  of  the  motor  and  sensory  areas  in  the  cortex,  constitute  a  very 
small  fraction  of  the  activities  which  must  be  associated  with  the  cerebral 
hemispheres.  An  animal  with  its  cerebral  hemispheres  intact  differs 
markedly  from  a  decerebrate  animal  in  the  variety  of  combined  movements 
which  it  may  exhibit,  either  spontaneously  or  in  response  to  external  stimuh. 
When,  however,  we  excite  the  motor  areas  directly,  we  obtain  movements 
which  are  practically  identical  with  those  which  we  may  elicit  from  a  bulbo- 
spinal animal  by  appropriate  peripheral  stimulation.  The  movements  thus 
excited  from  the  skin  may  be  looked  upon  as  variations  from  the  tonic  postural 
activity  of  the  musculature  of  the  body.  We  have  seen  that  from  the  end- 
organs  subserving  deep  and  muscular  sensibihty  (the  proprioceptive  system), 
as  well  as  from  the  labyrinth,  impulses  are  continually  arising  which  travel 
up  to  the  spinal  cord,  bulb,  cerebellum,  and  mid-brain,  and  excite  a  tonic 
activity  of  these  centres.  The  normal  attitude  of  the  animal  depends  on  the 
tonus  thereby  produced  in  certain  muscles.  Muscular  tone  is  indeed  a 
quality  specially  found  in  certain  groups  of  muscles.  If  the  cerebral  hemi- 
spheres be  removed,  as  by  a  section  through  the  crura  cerebri  or  in  front  of 
the  mid-brain,  this  postural  tonus  is  increased  and  the  animal  enters  into  the 
condition  of '  decerebrate  rigidity.'  Destruction  of  one  labyrinth  diminishes 
the  tone  on  the  same  side  of  the  body  ;  section  of  all  the  afferent  nerves  from 
a  hmb  abolishes  the  tone  in  that  limb,  so  that  its  posture  thereafter  depends 
entirely  on  gravity. 

The  movements  which  are  excited  in  such  animals  by  cutaneous  stimula- 
tion involve  as  a  necessary  factor  inhibition  of  the  postural  tone  as  well  as 
co-operative  inhibition  of  the  antagonistic  muscles.  In  the  same  way 
excitation  of  the  motor  area  of  the  cortex  has  as  its  most  essential  feature 
an  inhibitory  action  on  the  postural  tonus  in  addition  to  its  excitatory  action 
on  the  muscles  concerned  in  the  movement.  A  certain  antagonism  is 
evident  between  the  total  action  of  the  cerebral  hemispheres  and  that  of  the 
proprioceptive  part  of  the  central  nervous  system.  Whereas  in  the  decere- 
brate animal  there  is  increased  tonus  in  the  masseters,  in  the  neck  muscles, 

15 


450 


PHYSIOLOGY 


the  muscles  of  the  trunk,  and  the  extensor  muscles  of  the  hnibs,  stimulation 
of  the  cortex  produces  opening  of  the  mouth,  flexion  of  the  fore  hmb  or  of 
the  hind  hmb,  more  easily  than  any  other  movements.  That  an  essential 
part  of  this  action  is  inhibitory  is  shown  by  the  effects  of  exciting  the  motor 
area  of  the  cortex  after  exhibition  of  strychnine  or  during  the  local  action  of 

tetanus  toxin.    Whereas  in  the  normal 


animal  closure  of  the  jaw  and  exten- 
sion of  the  fore  Hmb  are  only  obtain- 
able from  one  or  two  points  on  the 
surface  of  the  brain,  after  the  injec- 
tion has  taken  place,  every  part  of 
the  jaw  area  gives  closing  of  the  jaw, 
every  part  of  the  arm  area  gives  ex- 
tension of  the  hmb  {cp.  Fig.  173), 

Since  the  predominant  influence  of 
the  motor  cortex  is  therefore  inhibitory 
of  the  stronger  muscles  of  the  body, 
as  well  as  of  the  tonus,  which  is  con- 
tinually and  reflexly  maintained,  it  is 
not  surprising  that  excision  of  both 
hemispheres  should  give  rise  to  de- 
cerebrate rigidity,  or  that  destruction 
or  division  of  the  chief  direct  tracts 
from  the  cortex  to  the  motor  spinal 
mechanisms,  viz.  the  pyramidal  tracts, 
should  determine  increased  tonus  and 
rigidity  of  the  limbs — the  so-called 
'  spastic  '  condition  observed  in  cere- 
bral paralyses. 

Two  separable  systems  of  motor 
innervation  appear  thus  to  control  two 
sets  of  musculature.  One  system  exhi- 
bits the  transient  phases  of  heightened 
reaction  which  constitute  reflex  move- 
ments; the  other  maintains  that  steady 
tonic  response  which  suppHes  the  muscular  tension  necessary  to  attitude. 
Hughlings  Jackson  long  ago  called  attention  to  this  contrast  between  the 
two  systems.  He  pointed  out  that  while  the  cerebrum  innervates  the  muscles 
in  the  order  of  their  action  from  the  most  voluntary  movements  (the  limbs) 
to  the  most  automatic  (trunk),  the  cerebellum,  or,  as  we  should  say  now, 
the  whole  proprioceptive  system,  innervates  them  in  the  opposite  order. 
The  cerebellum  therefore  he  regarded  as  the  centre  for  continuous  move- 
ments and  the  cerebrum  for  changing  movements.  The  increased  tone  of  the 
paralysed  muscles,  observable  after  hemiplegia,  he  ascribed  to  unbalanced 
cerebellar  influence.  While  there  is  no  doubt  that  the  cerebellum  must  play, 
and  does  play,  a  considerable  part  in  the  production  of  decerebrate  rigidity 


Fig.  234.  Diagram  (from  Mott  after  Mon- 
AKOW)  to  show  the  interaction  of  the 
different  levels  in  the  central  nervous 
system  in  the  production  of  co-ordinated 
'  volitional '  movements. 

s,  sensory  neuron  ;  b,  bulb ;  th,  thala- 
mus ;  MA,  motor  area ;  p,  pyramidal  fibre ; 
c,  cerebello-pontine  nuclei ;  vs,  vesti- 
bular neuron  (Deiters'  nucleus) 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES  451 

and  of  the  spastic  condition  of  hemiplegia,  it  is  not  the  only  element  involved  ; 
nor  is  it  essential,  since  decerebrate  rigidity  may  continue  after  extirpation 
of  the  cerebellum  and  an  exaggerated  knee-jerk  may  result  from  section  of 
the  spinal  cord  in  the  lower  cervical  region. 

HIGHER  ASSOCIATIVE  FUNCTIONS  OF  THE  CORTEX 
The  simple  and  uncomplicated  nature  of  the  movements  elicited  on 
cortical  stimulation  shows  that  we  cannot  regard  these  motor  centres  as 
responsible  for  the  whole,  or  even  the  greater  part,  of  the  motor  functions  of 
the  cortex.  They  are  in  fact  simply  the  starting-point  for  the  motor  impulses 
which  run  down  the  long  pyramidal  tracts,  but  which  result  from  the 
activities  of  the  cerebral  hemispheres  as  a  whole.  In  the  lower  mammals 
they  do  not  even  represent  the  only  starting-point,  as  is  shown  by  the  almost 
perfect  recovery  of  vohtional  motor  power  in  a  dog  deprived  of  its  motor 
cortex.  The  distinguishing  feature  of  the  response  of  an  animal  possessing 
cerebral  hemispheres  is  that  it  is  not  determined  solely  and  exclusively 
by  the  nature  and  position  of  the  peripheral  stimulation,  but  involves 
elements  connected  vdth.  the  past  experiences  of  the  animal,  and  including 
therefore  the  results  of  previous  stimulation  of  many  of  the  sense-organs, 
either  directly,  or  indirectly  as  a  result  of  reflex  movements.  The  animal's 
reactivity  is  determined  by  the  past  history  of  the  animal,  and  this  modifying 
influence  on  the  brain  must  involve  parts  connected  with  all  its  sense-organs. 
In  any  conscious  motor  act  we  may  say  therefore  that  the  brain  acts  as  a 
whole,  or  nearly  as  a  whole. 

In  endeavouring  to  arrive  at  some  idea  of  the  neural  processes  concerned 
in  volitional  movements,  i.e.  movements  of  the  intact  animal,  we  are  deahng 
with  events  which  in  ourselves  come  ^^^thin  the  sphere  of  consciousness, 
so  that  some  assistance  is  derived  by  appealing  to  our  own  mental  experiences. 
Especially  is  this  necessary  in  the  case  of  the  sensations.  It  might  be 
imagined  that  a  simple  sensation  would  ensue  as  the  result  of  local  stimula- 
tion, say  of  the  visual  centre  on  one  side.  Our  knowledge  of  the  properties 
of  the  systems  of  neurons  composing  the  central  nervous  system  would  teach 
us  that  no  excitatory  process  could  remain  confined  to  one  portion  of  the 
brain,  but  nnist  diverge  in  many  directions.  It  is  true  that  excision  of  the 
occipital  lobes  on  one  side  causes  bUndness  to  objects  in  the  opposite  half 
of  the  field  of  vision.  This  is,  however,  merely  a  result  of  localisation  of  the 
end  of  visual  fibres,  and  the  same  effect  can  be  brought  about  by  division  of 
the  right  optic  tract,  or  damage  to  the  right  half  of  both  retinte. 

On  the  other  hand,  an  appeal  to  our  own  experience  shows  that  no 
sensation  can  be  regarded  as  simple,  i.e.  as  following  merely  stimulation  of 
visual  fibres  or  visual  centres.  Thus  the  sensation  of  a  luminous  point 
has  comiected  with  it  not  only  luminositv  but  also  colour  and  intensity. 
Moreover  the  apparent  position  of  the  luminous  point  comes  into  conscious- 
ness at  the  same  time  as  the  consciousness  of  the  luminosity  itself,  and  this 
location  of  the  stinnilation  involves  muscular  impressions  from  the  eyeballs 
and  an  association  between  certain  points  on  the  retina  and  certain  corre- 


452  PHYSIOLOGY 

sponding  muscular  movements  of  the  eye  muscles,  of  the  head  and  neck,  and 
even  of  the  body  and  arm — movements  which  would  be  necessary  to  bring 
the  image  of  the  spot  on  to  the  fovea  centralis  and  to  approach  the  whole 
body  to  the  site  of  the  stimulating  object. 

As  the  visual  sensation  becomes  more  complex  the  associated  sensations 
and  experiences  which  it  evokes  become  more  numerous.  Thus  the  image 
of  a  chair  falhng  on  the  retina  excites  a  long  train  of  nervous  processes.  At 
once  we  become  aware  not  only  of  a  visual  impulse  but  of  an  object  which 
possesses  colour,  extension,  or  size  in  three  dimensions,  soHdity,  hardness, 
distance  or  position  in  space,  &c.  These  qualities  are  founded  on  past  ex- 
periences— visual,  muscular,  and  tactile.  Moreover  we  are  at  once  aware 
of  the  uses  of  the  chair,  and  of  its  name  both  spoken  and  written,  a  mental 
activity  connoting  revival  of  higher  visual  and  auditory  sensations.  The 
higher  in  the  scale  of  intelhgence,  the  greater  is  the  development  of  the 
cerebral  hemispheres  and  the  m-ore  extensive  are  the  associations  arising  in 
connection  with  any  single  sense  impression. 

Besides  the  portions  of  the  brain  which  send  out  the  motor  paths  and 
which  receive  the  endings  of  the  sensory  paths,  there  may  be  whole  regions 
taken  up  by  the  interconnecting  neurons  which  subserve  the  association  of 
the  activities  of  all  parts  of  the  cerebral  hemispheres,  and  the  higher  the 
animal  is  in  the  scale  of  intelligence  the  larger  must  be  the  relative  amount 
of  brain  substance  set  apart  for  these  functions  of  association.  This  is  very 
evident  if  we  compare  the  brain  of  three  animals,  such  as  the  dog,  the  ape, 
and  man.  Although  as  we  ascend  to  man  there  is  an  absolute  increase  in  the 
amount  of  brain  substance  involved — say  in  the  motor  areas  or  in  the  sensory 
areas — the  increase  is  very  small  as  compared  with  that  in  those  portions 
of  the  brain  which  give  no  response  on  stimulation,  and  in  man  these 
'  silent '  parts  of  the  brain  form  the  greater  part  of  the  cerebral  cortex. 
Although  every  phase  of  cerebral  activity,  every  conscious  event,  involves 
co-operation  of  a  large  number  of  distant  portions  of  the  brain  substance,  in 
most  of  them  there  will  be  some  seat  of  sense  impressions  which  "will  be 
predominant,  and  a  train  of  ideas  may  be  specially  visual,  or  auditory,  or 
tactile.  It  is  therefore  not  surprising  that  in  the  immediate  neighbourhood 
of  the  cortical  areas  which  receive  the  endings  of  the  sensory  tracts  associa- 
tion areas  are  developed  which  may  be  labelled  according  to  the  sense-organ 
with  which  they  are  most  nearly  in  relation.  Thus  we  may  speak  of  the 
visual-sensory  and  the  visual  association,  or  psychical  area,  the  auditory- 
sensory  and  the  auditory-psychical,  and  so  on.  The  hmits  of  these  areas  are 
indicated  in  Fig.  224,  p.  432. 

Conditioned  reflexes.  Until  recently,  our  study  of  the  processes  of  association 
and  therewith  all  the  higher  functions  of  the  cerebral  hemispheres  was  chiefly  carried 
out  in  man,  and  in  most  cases  by  the  introspective  method.  Even  when  carried  out 
on  other  men,  it  was  chiefly  by  using  speech  as  an  index  to  the  introspective  experi- 
ences of  those  who  were  being  investigated.  During  the  last  few  years  a  method  has 
been  introduced  by  Pawlow,  for  investigating  the  higher  cerebral  functions  by  an 
objective  method  which  is  capable  of  very  wide  application.  When  an  animal  which 
is  hungry  is  shown  food,  we  say  that  '  its  mouth  waters,'  i.e.  there  is  a  secretion  of 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES  453 

saliva;  and  if  the  animal  be  provided  with  a  salivary  fistula  the  extent  of  the  emotion 
of  appetite  may  be  gauged  in  cc.  of  saliva  flowing  from  the  fistula.  It  is  found  in 
such  an  animal  that  a  flow  of  saliva  may  be  excited,  not  only  by  the  sight  or  adminis- 
tration of  food,  but  also  by  any  other  event  which  has  become  associated  as  the  result 
of  experience  with  the  taking  of  food.  Thus  we  may  use  this  method  in  order  to  deter- 
mine the  sensitiveness  of  the  animal's  perception  of  pure  tones.  Thus  if  we  wish  to 
know  whether  the  animal  can  recognise  the  difference  between  middle  C  and  middle 
Qjt,  as  produced  by  tuning-forks,  we  can  for  some  days  or  weeks  allow  him  to  hear  both 
these  sounds  frequently  but  always  follow  up  one  of  them,  say  C,  by  giving  him  a  piece 
of  meat.  After  a  time  it  is  found  that  not  only  can  he  distinguish  between  the  two 
sounds,  but  that  he  has  a  memory  of  the  absolute  pitch,  so  that  whenever  the  note 
middle  C  is  sounded  or  any  note  differing  from  it  by  not  more  than  8  d.v.  per  second, 
there  is  a  flow  of  saliva  from  the  fistula,  whereas  the  note  C^  is  heard  without  producing 
any  response.  Such  an  acquired  reaction  is  designated  by  Pawlow,  a  '  conditioned 
reflex  '  and  the  method  has  been  applied  by  him  to  study  the  association  between  the 
most  widely  different  impressions  and  the  condition  which  we  can  regard  as  appetite 
and  which  is  associated  psychically  with  the  idea  of  food. 

THE  FUNCTION  OF  SPEECH 
The  acts  of  a  conscious  individual,  i.e.  one  possessing  cerebral  hemispheres, 
are  determined  by  his  experience.  The  Avider  the  range  of  past  sense 
impressions  which  can  be  called  up  and  taken  into  the  chain  of  processes 
involved  in  any  reaction — the  more,  that  is  to  say,  the  individual  weighs  his 
acts  in  the  light  of  past  experience — the  more  fitted  will  these  acts  be  to  his 
maintenance  amid  the  ever-changing  stresses  of  the  environment.  In  this 
guiding  of  behaviour  by  experience  man,  as  well  as  the  higher  mammals,  may 
profit  also  from  accumulated  racial  experience.  The  increased  complexity 
of  the  neural  processes  concerned  in  every  reaction  of  the  body,  and  the 
excessive  lost  time  brought  about  by  the  intercalation  of  one  neuron  after 
another  in  the  chain  of  the  excitatory  process,  would  finally  counteract  the 
advantages  derived  from  the  growth  in  complexity  of  the  brain,  were  it  not 
that,  as  a  result  of  education  or  training,  sliort  cuts  are  laid  down,  by  means 
of  which  reactions  adapted  to  the  maintenance  of  the  individual  can  be  carried 
out  immediately,  without  thought  and  without  correlated  calling  up  of 
numberless  sense  impressions.  Education  in  fact  consists  in  laying  down 
these  '  short  cuts  '  which,  as  habits,  are  the  basis  of  the  behaviour  of  the 
animal.  The  more  complex  the  central  mechanism  and  the  wider  the  range 
of  environmental  change  to  which  adaptation  is  necessary,  the  longer  must  be 
the  time  involved  in  this  process  of  road-making  within  the  cerebral  hemi- 
spheres. The  behaviour  of  man  is  therefore  a  product  of  many  years' 
training,  durijvg  which  time  he  is  in  a  state  of  subjection  and  unfit, 
from  the  absence  of  habit,  to  maintain  himself  as  a  unit  in  the  human 
connnunity.  The  neural  short  cuts  of  habit  are,  however,  only  of 
advantage  to  the  individual  in  dealing  with  those  events  which  are  of 
everyday  occurrence.  Every  novel  circumstance  must  involve  a  revival 
of  past  sense  impressions  and  a  calling  up  of  ai?tivities  of  the  most  diverse 
]wrtions  of  the  brain  in  order  to  arrive  at  the  safest  or  most  advantageous 
mode  of  action  adapted  to  the  circumstances.  Here  again  the  complexity 
of  the  process  would,  by  the  very  delay  involved,  put  a  stop  to  a  further 


454  PHYSIOLOGY 

rise  in  intellectual,  i.e.  associative,  capacities,  were  it  not  for  the  invention 
of  Speech. 

In  speech  we  have  a  symbohsm  which  acts  as  an  economy  of  thought  or  of 
cerebral  activities.  An  object,  such  as  a  table,  with  its  associated  properties 
of  colour,  consistence,  spatial  extension,  and  resistance,  with  the  connoted 
acts  associated  with  its  use,  can  now  be  evoked  as  a  word,  involving  com- 
paratively simple  auditory  and  motor  processes,  which  itself  may  be  em- 
ployed as  a  unit  of  thought  and  brought  into  connection  with  other  words, 
each  of  which  in  the  same  way  is  the  symbol  for  a  whole  series  of  sensory  and 
motor  processes.  The  training  of  the  cultivated  man  consists  in  a  constant 
extension  of  the  range  of  this  symbolism,  and  the  acquisition  of  words 
including  wider  and  wider  groups  of  neural  processes,  so  that  finally  we  arrive 
at  those  short  verbal  collections  which,  as  the  so-called  natural  laws,  sum- 
marise the  experience  not  only  of  the  individual  but  such  as  is  common  to  the 
whole  race  of  mankind.  All  science  may  in  fact  be  regarded  as  an  extension 
of  the  process  of  representation  of  neural  experience  in  symbolic  shorthand, 
which  in  the  child  begins  with  the  utterance  of  such  a  simple  word  as 
'  mamma,'  and  from  which  speech  has  arisen.  A  study  of  the  nervous 
mechanisms  involved  in  speech  is  therefore  of  interest  in  its  relations  to  the 
development  of  the  intelligence,  and  helps  us  to  reahse  more  completely  the 
conditions  which  determine  the  activity  and  functioning  of  the  cerebral 
hemispheres.  Much  light  is  thrown  upon  this  mechanism  by  the  study  of 
disorders  in  man  grouped  together  under  the  name  Aphasia. 

It  has  been  usual  to  divide  the  disorders  of  speech  known  as  aphasia  into 
various  groups,  as  follows  : 

(1)  Motor  aphasia,  or  aphasia  of  Broca.  In  this  condition,  which  was  de- 
scribed fully  by  Broca  and  referred  by  him  to  a  lesion  of  the  third  left  frontal 
convolution,  the  patient  is  miable  to  speak,  although  he  understands  what  is 
said  to  him  and  has  been  stated  to  suffer  from  no  impairment  of  his  intelUgence. 

(2)  Sensory  aphasia,  or  aphasia  of  Wernicke.  This  condition  was  con- 
nected by  Wernicke  with  the  existence  of  lesions  in  a  fairly  wide  area,  known 
as  the  area  of  Wernicke,  which  involves  the  supramarginal  and  angular  gyri 
and  the  hinder  portions  of  the  first  and  second  temporo-sphenoidal  convo- 
lutions. In  these  cases  there  may  be  hmited  power  of  speech,  but  there 
is  serious  impairment  of  the  intelligence  and  especially  of  the  power  of 
appreciation  of  spoken  words,  so  that  the  patient  does  not  understand  what 
is  said  to  him.  This  condition  may  or  may  not  be  attended  with  alexia,  loss 
of  power  to  read.  Any  impairment  of  the  motor  processes  of  speech  which 
is  present  is  due  rather  to  the  inability  of  the  patient  to  appreciate 
what  he  himself  is  saying,  so  that  there  is  here  a  species  of  sensory  paralysis 
in  the  higher  sphere  of  neural  processes. 

(3)  Anarthria.  This  is  a  condition  in  which  there  is  marked  impairment 
of  the  motor  powers  of  expression,  although  intelligence  and  appreciation 
of  speech,  both  spoken  and  written,  may  be  unaltered.  This  condition  is 
generally  associated  with  lesion  of  the  white  matter  of  the  external  capsule 
as  it  passes  round  the  lenticular  nucleus. 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES  455 

There  are,  however,  considerable  difficulties  in  the  acceptation  of  this 
traditional  classification.  Microscopic  examination  of  Broca's  convolution 
shows  a  type  of  cortex  entirely  different  from  that  part,  viz.  the  psycho- 
motor area  of  the  ascending  frontal  convolution,  which  is  concerned  \vith 
the  higher  cerebral  processes  resulting  in  movement.  Its  structure  is  in  fact 
identical  with  that  described  by  Campbell  as  the  '  intermediate  precentral 
area  '  and  regarded  as  characteristic  of  the  association  areas.  Moreover  it  is 
difficult  to  comprehend  how  a  function  such  as  speech,  with  its  enormously 
complex  mechanism,  could  be  hmited  to  so  small  a  portion  of  the  brain  as 
Broca's  convolution.  The  neural  basis  of  language  must  in  fact  be  co- 
extensive with  the  sensory  centres  (the  projection  spheres)  and  ^\^th  the 
whole  region  of  lower  association.  We  might  indeed  speak  of  auditory  and 
visual  word-centres  as  located  in  the  visuo-psychical  and  auditory  psychical 
centres.  There  is  probably,  however,  no  word,  still  less  a  collection  of  words, 
expressing  an  idea,  which  does  not  involve  the  activity  of  practically  all  parts 
of  the  cerebral  cortex.  As  Bolton  *  points  out,  "  a  word,  such  as  '  mouse,'  at 
once  sets  in  effect  processes  of  association  which  pass  to  every  projection 
sphere  with  the  solitary  exception  of  the  gustatory,  and  even  this  may  be 
aroused  in  a  person  who  has  eaten  a  fried  mouse  in  the  hope  of  thereby 
recovering  from  an  attack  of  whooping-cough." 

A  careful  examination  of  an  extensive  series  of  cases  by  Marie  has  shown, 
in  fact,  that  Broca's  aphasia  does  not  exist  as  a  result  of  lesions  of  Broca's 
convolution.  This  part  of  the  brain  may  be  destroyed  without  any  disorder 
of  speech.  The  cases  described  by  Broca  of  motor  aphasia  are  really  cases  of 
sensory  aphasia  from  lesion  of  Wernicke's  area,  combined  with  anarthria  due 
to  subcortical  injury  of  the  fibres  of  the  internal  capsule.  The  statement 
that  there  is  no  loss  of  intelhgence  in  these  cases  of  so-called  motor  aphasia 
does  not  bear  investigation.  Although  as  patients  they  may  comport 
themselves  reasonably,  as  soon  as  they  have  to  perform  any  duties  which 
have  been  learnt  by  them  in  connection  with  their  ordinary  avocations , 
they  show  their  deficiency.  They  are  incapable  of  transacting  ordinary  busi- 
ness, at  any  rate  to  the  extent  to  which  they  were  before  the  lesion.  The 
amount  of  impairment  of  intelligence  will  vary  in  different  cases  according 
to  the  extent  of  the  lesion.  Thus  softening  generally  affecting  the  occipital 
lobe  may,  with  hemianopia,  cause  '  word-blindness,"  or  alexia,  a  loss  of  power 
of  appreciating  the  meaning  of  pronounced  or  written  words.  In  most 
individuals,  and  certainly  in  the  uneducated,  this  power  may  be  cut  out 
altogether  without  iiitei'fering  considerably  with  the  mental  powers.  On 
the  other  hand,  from  babyhood  upwards  we  have  learnt  the  meaning  of  words 
and  their  grouping  by  auditory  impressions.  If  the  whole  of  the  auditory 
associations  be  destroyed  by  an  extensive  lesion  in  the  first  and  second  tem- 
poral convolutions  the  resulting  loss  of  word  appreciation,  sensory  aphasia, 
will  be  attended  with  great  diminution  of  mental  powers.  It  must  be 
remembered  tliat  the  area  of  Wernicke  is  not  a  sensory  centre,  but  a  centre 
of  association  between  the  various  sense-impressions,  especially  those  of 
*  111  his  admirable  article  iu  Hill's  "  Further  Advances  in  Physiology." 


456 


PHYSIOLOGY 


hearing  and  sight.  It  may  therefore  be  spoken  of  as  an  intellectual  centre. 
Pure  motor  aphasia  of  course  exists,  but  is  always  anarthria  and  is  due  to  a 
lesion  in  the  lenticular  zone,  i.e.  in  the  lenticular  nucleus  and  its  neighbour- 
hood, in  the  anterior  part  and  the  genu  of  the  internal  capsule,  and  possibly 
in  the  external  capsule. 

Amenta  Dementa 


Fig.  235.  Types  of  lesions  giving  rise  to  deficient  intellectual  power.  In  amentia, 
the  deficiency  is  due  to  failure  of  development ;  in  dementia,  to  atrophy  of 
the  cells  (especially  small  pyramidal)  previously  present  in  the  cortex.     (Mott.) 

It  is  important  to  make  a  distinction  between  loss  of  sanity  and  loss 
of  intellectual  powers.  The  essential  factor  of  sensory  aphasia  is  the  exist- 
ence of  intellectual  impairment,  though  in  his  behaviour  the  patient  may 
appear  perfectly  normal.  On  the  other  hand,  in  insanity  there  may  be 
perfect  retention  of  the  intellectual  processes,  which  depend  on  the  proper 
working  of  the  lower  association  centres.  The  personality  of  the  individual, 
and  therefore  finally  his  behaviour,  involves  a  further  association  on  a  higher 
plane  of  these  intellectual  processes  and  therefore  control  in  accordance  with 
the  relation,  past,  present,  or  future,  of  the  individual  to  his  environment. 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES  457 

The  prefrontal  region  is  in  all  probability  the  seat  of  this  highest  plane  of 
association.  Insanity  always  involves  alteration  of  personality  and  depends 
on  failure  of  development  or  on  disintegration  processes  (subevolution  or 
dissolution  of  this  region)  (Fig.  235).  In  monkeys  and  cats  Franz  has  found 
that  destruction  of  the  frontal  lobes  causes  a  loss  of  recently  formed  habits. 
He  concludes  from  his  experiments  that  the  fro/atal  lobes  are  the  means  by 
which  we  are  able  to  learn  and  to  form  habits,  i  e.  to  regulate  our  behaviour 
in  accordance  with  the  needs  of  our  position  in  society. 

THE  TIME  RELATIONS  OF  CENTRAL  NEURAL  REACTIONS 
In  the  spinal  animal  a  stimulus  of  any  particular  quality  and  localisation 
always  evokes  an  appropriate  reaction.  A  certain  period  of  time  necessarily 
elapses  between  the  moment  at  which  the  stimulus  is  applied  and  the  moment 
at  which  the  resulting  reaction  takes  place.  This  interval  is  spoken  of  as 
the  simple  reaction  time,  and  in  the  spinal  animal  is  entirely  independent 
of  consciousness.  Many  reactions,  even  in  the  intact  animal,  are  also,  as  we 
may  say,  involuntary  and  are  not  modified  perceptibly  by  our  consciousness 
of  their  occurrence  :  such  reflexes  as  the  withdrawal  of  the  hand  when  it 
comes  in  contact  with  a  hot  surface,  the  shutting  of  the  eyehd  when  the  con- 
junctiva is  touched,  the  drawing  up  of  the  leg  when  the  sole  of  the  foot  is 
tickled.  Not  only  are  these  carried  out  in  the  absence  of  voluntary  impulses, 
but  in  many  cases  it  is  almost,  if  not  quite,  impossible  to  check  the  reaction 
by  any  effort  of  the  will. 

When  the  leg  is  drawn  up  in  response  to  a  painful  or  nocuous  stimulus 
applied  to  the  foot,  a  certain  amount  of  time  is  involved  in  each  of  the 
following  links  in  the  chain  of  processes  which  determine  the  reaction  : 

(1)  The  conversion  in  the  peripheral  sense-organ  of  the  mechanical 
stimulus  into  a  nerve  process. 

(2)  The  passage  of  a  nerve  impulse  up  the  nerve  from  the  end  organ  to  the 
spinal  cord. 

(3)  The  passage  of  the  impulse  across  two  or  more  synapses  in  the  gi'ey 
matter  of  the  cord. 

(4)  The  passage  of  the  impulse  down  the  motor  nerve  fibres  from  the 
spinal  cord  to  the  muscles. 

(5)  The  processes  occurring  in  the  end-organs  of  the  muscle. 

(6)  The  latent  period  in  the  muscle  fibre  itself. 

With  a  weak  stimulus  No.  1  is  impossible  to  measure.  With  a  strong 
stimulus  it  may  be  so  short  as  to  be  practically  negligible.  (2),  (4),  (5), 
and  (6)  represent  (juantities  for  the  measurement  of  whicli  wo  have  all  the 
necessary  data. 

In  any  given  reflex  therefore  we  may  add  these  periods  together  and 
subtract  them  from  the  total  reaction  time  ;  we  thus  get  a  '  reduced  re- 
action time,'  which  represents  the  time  involved  in  the  passage  of  tlie  impulse 
through  the  central  nervous  system,  and  in  the  conversion  of  an  afferent 
impulse  into  an  aggregate  of  co-ordinated  motor  impulses.  It  is  found 
that  the  reduced  reaction  time  accounts  for  the  greater  part  of  the  total 

15* 


458 


PHYSIOLOGY 


reaction  time.  Since  we  have  no  reason  to  assume  that  the  rate  of  passage  of 
an  impulse  through  the  intra-spinal  course  of  a  nerve  fibre  differs  appreciably 
from  the  rate  at  ^Yhich  it  is  conducted  by  the  same  nerve  fibre  outside  the 
cord,  the  extra  delay  which  occurs  in  the  passage  of  the  impulse  through  the 
cord  must  take  place  either  in  the  nerve-cells  themselves,  or  in  the  synapses, 
through  which  the  impulse  passes  from  one  neuron  to  the  next  in  the  chain  of 
reflex  elements. 

The  rate  of  passage  of  an  impulse  through  the  nerve-cell  can  only  be 
determined  in  one  part  of  the  body,  viz.  in  the  posterior  spinal  root  gangUa, 


Fig.  236.     Arrangement  of  apparatus  for  determination  of  reaction  time. 

(Alcock  and  Ellison.) 
K,  coil ;    E,  exciting  electrodes  ;    f,  tuning-fork  ;    a,  b,  keys  ;    s,  t,  electro- 
magnetic signals  ;   d,  drum. 

since  only  in  these  is  it  possible  to  detect  the  moment  of  passage  of  an  im- 
pulse across  a  given  section  of  a  nerve  fibre  on  both  sides  of  the  ganglion- cell 
in  which  the  nerve  fibres  arise.  Experiments  on  this  point  have  been  made 
by  Steinach  and  by  Moore.  In  each  case  the  time  occupied  in  the  passage 
of  the  impulse  through  the  ganghon  was  not  appreciably  longer  than  if  the 
impulse  had  passed  through  a  corresponding  stretch  of  uninterrupted  nerve 
fibre.  We  are  therefore  justified  in  concluding  that  the  relatively  great 
delay  in  the  passage  of  an  impulse  through  the  central  nervous  system  has 
its  seat  in  the  synapses  across  which  the  impulse  has  to  pass.  This  con- 
clusion is  in  accordance  with  our  experience  on  the  latent  period  of  muscle, 
the  greater  part  of  which  is  due  to  changes  occurring  in  the  nerve-endings, 
i.e.  in  the  synapses  between  motor  nerve  and  muscle.  The  greater  the 
number  of  synapses  involved  in  any  given  reaction,  i.e.  the  greater  the  com- 
plexity of  the  reaction,  the  longer  will  be  the  period  which  elapses  between 
the  moment  of  application  of  the  stimulus  and  the  moment  at  which  the 


FUNCTIONS  OF  THE  CEREBRAL  HEMISPHERES  i59 

response  takes  place.  Especially  is  this  the  case  when  the  complex  mesh- 
work  of  neurons  of  the  cerebral  hemispheres  is  involved,  or  when  the  occur- 
rence of  the  reaction  is  associated  with  the  conscious  processes  of  sensation 
and  vohtion.  In  the  latter  case  the  determination  of  the  reaction  time  has 
the  added  interest  that  it  gives  information  as  to  the  time-relations  of  the 
psychical  processes  which  are  the  representation  in  consciousness  of  the 
physiological  changes  occurring  in  the  neurons  of  the  central  nervous 
system. 

Many  methods  are  employed  for  the  measuring  of  the  reaction  time  of  conscious 
processes.  In  most  methods  the  ai^plication  of  the  stimulus  is  arranged  so  as  to  close 
the  circuit  of  a  cm-rent  which  flows  tluough  an  electro-magnet  activating  a  lever  which 
writes  on  a  rapidly  moving  blackened  surface.  The  reaction  of  the  individual  who 
is  the  subject  of  experiment  is  arranged  so  that  the  resulting  movement  activates  a 
key  by  which  the  same  current  is  opened.  We  thus  obtain  a  tracing  on  the  blackened 
surface  showing  the  moment  of  application  of  the  stimulus  and  the  moment  at  which  the 
reaction  takes  j)lace.  Thus,  if  the  reaction  time  for  an  auchtory  stimulus  is  to  be 
determined,  the  electric  current  is  arranged  so  as  to  pass  through  : 

(1)  A  spring  contact  key  which  can  be  pressed  so  as  to  make  a  noise. 

(2)  An  electric  signal  -na-iting  on  a  rapidly  moving  surface. 

(3)  A  second  key,  which  the  subject  will  release  as  soon  as  he  hears  the  noise  of 
the  first  key  and  so  break  the  ciu-rent. 

The  recording  surface  may  be  a  drum,  a  pendulum  myograph,  or  a  spring  myograph, 
such  as  the  '  shooter  '  of  du  Bois-Reymond.  If  the  sensory  impression  is  to  be  from 
the  skin  the  current  may  be  made  to  pass  through  the  primary  coil  of  an  inductorium 
and  wires  be  taken  from  the  second  coil  to  some  part  of  the  sm-face  of  the  skin.  In 
this  case  the  signal  may  be  started  by  opening  the  circuit,  and  the  subject  of  the  experi- 
ment will  respond  by  closing  the  circuit  by  means  of  a  spring  key  directly  he  feels 
the  shock  caased  by  the  break  of  the  primary  circuit.  If  the  reaction  period  is  to  be 
determined  for  sight  a  white  piece  of  paper  may  be  placed  on  an  electro-magnet  in  the 
primary  circuit  and  the  person  will  respond  directly  he  sees  this  move.  Many  other 
instruments  have  been  devised  for  the  same  purpose. 

The  average  reaction  times  obtained  with  the  different  senses  are  as 

follows  :  Electrical 

Sight  Hearing  stimulation  of  skin 

0-186  to  0-222  sec.  0115  to  0-182  sec.  0-117  to  0-201  sec. 

The  two  figures  given  for  each  case  are  the  extremes  obtained  in  difterent 
series  of  observations. 

The  times  vary  according  to  the  condition  of  the  person  that  is  the  subject 
of  the  experiment.  They  are  lengthened  by  fatigue  ;  they  are  shortened 
up  to  a  certain  point  by  continued  practice.  Within  limits  also  they  are 
shortened  by  increase  of  the  strength  of  the  stimulus. 

DILEMMA.  When  the  subject  has  to  make'a  deliberate  choice  between 
the  parts  of  the  body  stinuilated  the  reaction  time  is  considerably  longer. 
To  show  this,  the  wires  from  the  secondary  coil  are  connected  by  a  switch 
to  two  pairs  of  electrodes  which  are  applied,  one  to  the  right  and  one  to  the 
left  half  of  the  body.  It  is  agreed  beforehand  that  the  subject  shall  react 
only  to  stimulation,  say,  of  the  right  side.  The  switch  is  removed  from 
the  observation  of  the  subject  and  the  stimulus  is  applied  irregularly  to  one 
side  or  to  the  other.      It  is   found   that   the   additional   neural  processes 


460  PHYSIOLOGY 

involved  in  determining  whether  the  stimulus  is  on  the  right  side,  and  there- 
fore should  be  followed  up  as  agreed,  adds  considerably  to  the  length  of  the 
reaction  time  (on  an  average  -066  sec).  It  is  possible  to  complicate  the 
dilemma  to  almost  any  extent.  Thus  the  experiment  may  be  so  arranged 
that  either  a  red  or  a  white  disc  appears  and  the  subject  has  to  react  with 
the  right  hand  to  the  red  disc  and  with  the  left  hand  to  the  white  disc.  In 
such  an  experiment  the  reaction  time  was  found  to  be  0-154  sec.  longer  than 
the  simple  reaction  time.  A  still  more  complex  process  would  be  involved 
in  the  experiment  in  which  a  word  was  spoken,  and  the  subject  had  to  speak 
some  other  word  which  had  some  association  with  the  word  which  formed  the 
stimulus,  e.g.  horse — mammal ;  paper — pen,  &c.  In  such  an  experiment 
the  reaction  time  was  found  to  be  as  long  as  0'7  to  0-8  sec. 

We  see  that  the  recording  of  the  time  of  occurrence  of  any  physical  event 
can  only  occur  after  a  certain  lost  time,  which  represents  the  observer's 
reaction  time  for  the  stimulus  in  question.  This  only  applies,  however, 
to  movements  carried  out  in  response  to  single  stimuli,  or  to  stimuli  repeated 
at  irregular  intervals.  When  the  stimuli  are  rhythmic  the  lost  time  only 
applies  to  the  first  one  or  two  of  the  stimuli.  The  observer  or  subject  is 
conscious  of  the  interval  elapsing  between  the  physical  event  and  his  reaction, 
and  anticipates  the  later  stimuh  so  that  his  reaction  becomes  synchronous 
with  the  stimulus.  This  synchronism  of  stimulus  and  reaction  characterises 
all  ryhthmic  movements,  such  as  dancing  or  the  playing  of  an  orchestra  in 
time  with  the  beat  of  the  conductor's  baton. 


SECTION  XVIII 

THE  NUTRITIVE   AND   VASCULAR   ARRANGEMENT 
OF  THE   CENTRAL  NERVOUS  SYSTEM 

The  brain  and  spinal  cord  are  enclosed  within  three  membranes  or  meninges, 
named  from  without  inwards,  the  dura  mater,  the  arachnoid  membrane, 
and  the  pia  mater.  The  dura  mater  consists  of  a  strong  fibrous  membrane, 
smooth  and  hned  with  endothelial  cells  on  its  inner  surface.  In  the  head 
its  outer  surface  is  closely  attached  to  the  bones  forming  the  cranium,  of 
which  it  represents  the  periosteum.  Strong  fibrous  partitions  are  sent  from 
the  dura  mater  into  the  cavity  of  the  cranium  to  support  the  chief  parts 
of  the  brain.  One  of  these,  the  falx  cerebri,  supports  the  two  cerebral  hemi- 
spheres, a  second,  the  tentorium  cerebelli,  forms  a  horizontal  division  between 
the  cerebral  hemispheres  and  the  cerebrum,  and  a  smaller  one.  the  falx 
cerebelli,  passes  a  short  distance  inwards  between  the  cerebellar  hemispheres. 
In  the  spinal  canal  the  bones  have  their  own  periosteum  and  the  dura  mater, 
which  is  closely  attached  round  the  margins  of  the  magnus,  forms  a  loose 
sheath  round  the  spinal  cord,  being  slung  up  in  the  vertebral  canal  by  the 
tubular  prolongations  which  it  sends  along  each  nerve  root  to  form  the  outer 
sheath  of  the  nerve.  The  dura  mater  in  the  cranium  may  be  separated 
with  greater  or  less  difficulty  into  two  layers,  and  between  these  two  layers 
are  found  the  venous  sinuses,  which  receive  the  whole  of  the  blood  returned 
from  the  brain.  These  venous  sinuses  are  angular  clefts,  the  chief  of  which 
lie  along  the  attached  margin  of  the  falx  cerebri  and  the  tentorium  cerebeUi. 
Most  of  the  blood  leaves  the  skull  by  the  internal  jugular  veins.  In  the 
spinal  cord  the  place  of  these  venous  sinuses  is  taken  by  a  plexus  of  thin- 
walled  veins,  imbedded  in  fat,  lying  on  the  outside  of  the  dura.  Under  the 
dura  mater  we  find  the  subdural  space,  which  is  rather  potential  than  actual. 
It  can  be  regarded  as  a  large  lymph  space  and  any  contents  are  drained 
oft'  into  the  lymph  spaces  of  the  nerve  roots  and  adjoining  tissues. 

The  arachnoid  is  a  delicate  transparent  membrane  which  covers  the  whole 
of  the  surface  of  the  brain  and  spinal  cord.  Superficially  it  is  covered  with 
endothelial  cells  which  bound  the  subdural  space.  On  its  deep  surface  it  is 
connected  with  the  pia  mater  by  fine  fibres.  It  bridges  over  the  inequalities 
in  the  surface  of  the  brain  so  that  in  various  localities  a  space  is  left  which  is 
filled  with  cerebro-spinal  fluid  and  is  known  as  the  subarachnoid  space. 
In  certain  situations  it  sends  prolongations  into  the  fissures  of  the  brain. 
Thus  a  marked  expansion  passes  by  the  transverse  fissure  between  the 

461 


462  PHYSIOLOGY 

cerebral  hemisplieres  and  the  third  ventricle,  sending  prolongations  into  the 
lateral  ventricles.  This  layer  of  connective  tissue  is  covered  on  one  surface 
by  the  ependyma  of  the  ventricles,  on  the  other  surface  by  the  ependyma 
forming  the  roof  of  the  third  ventricle.  It  carries  a  rich  plexus  of  blood 
vessels  known  as  the  choroid  plexus,  and  the  ependyma  covering  the  vascular 
fringes  which  dip  into  the  cerebral  ventricles  consist  of  clear  columnar  or 
cubical  cells,  often  spoken  of  as  the  epitheHum  of  the  choroid  plexus. 
Similar  vascular  fringes  are  found  in  the  roof  of  the  fourth  ventricle. 

The  pia  mater  is  a  layer  of  connective  tissue  which  serves  to  carry  the 
blood-supply  to  the  whole  surface  of  the  brain.  It  is  closely  apphed  to  the 
surface  and  follows  all  the  irregularities  of  the  latter,  dipping  down  into  the 
various  fissures  and  crevices  on  the  brain.  In  the  spinal  canal  the  pia  mater 
sends  out  a  series  of  processes  on  each  side  of  the  spinal  cord,  the  ligamentum 
denticulaium,  the  outer  extremities  of  which  are  attached  to  the  dura 
mater  and  serve  to  shng  the  spinal  cord  in  its  dural  sheath. 

The  brain  is  richly  supplied  w^ith  blood.  Its  chief  supply  is  derived  from 
the  two  carotids  and  the  two  vertebral  arteries.  The  vertebrals  unite  on 
the  lower  surface  of  the  bulb  to  form  the  basilar  artery,  which  divides  again 
at  the  anterior  extremity  of  the  pons  varolii  into  two  branches  which  unite 
\x\th.  the  two  carotid  arteries  to  form  the  circle  of  Willis,  so  that  the  pressure 
in  this  arterial  circle  can  be  maintained  indifferently  by  any  three  out  of  the 
four  arteries  by  which  it  is  supplied.  From  these  vessels  three  main  arteries, 
the  anterior,  middle  and  posterior  cerebral,  pass  up  to  supply  the  correspond- 
ing regions  of  the  outer  surface  of  the  brain,  while  the  inner  parts  of  the 
brain,  e.g.  the  corpus  striatum,  optic  thalamus,  &c.,  are  supplied  from 
artsries  arising  from  the  circle  of  Wilhs  and  passing  straight  into  the  sub- 
stance of  the  brain.  The  connection  between  the  vascular  supply  of  the 
different  parts  of  the  brain  is  shght  and  effected  only  by  the  capillaries  ; 
hence  obstruction  of  any  one  vessel,  such  as  the  middle  cerebral,  perma- 
nently cuts  oft'  the  blood-supply  to  the  greater  part  of  the  area  supphed  by 
it  and  the  result  is  death  and  softening  of  the  brain  substance.  The  arteries 
supplying  the  surface  of  the  brain  divide  up  into  arterioles  and  capillaries 
within  the  pia  mater,  and  the  capillaries  run  into  the  brain  substance  sur- 
rounded by  a  so-called  lymphatic  sheath,  which  apparently  communicates 
with  the  subarachnoid  space. 

In  certain  cases  of  disease  these  perivascular  sheaths  may  be  found  to 
contain  leucocytes  often  filled  with  products  of  disintegration  of  the  nervous 
tissues. 

THE  CEREBRO-SPINAL  FLUID 

The  subarachnoid  space  contains  a  thin  transparent  colourless  flviid, 
known  as  the  cerebro-spinal  fluid.  In  composition  this  fluid  resembles 
blood  plasma  minus  its  protein  constituents.  It  contains  a  mere  trace  of 
coagulable  proteins  but  it  has  the  same  molecular  concentration  as  the  blood 
plasma  and  its  salts  are  identical  with  those  of  the  blood  plasma.  It  also 
contains  other  diffusible  constituents  of  blood  plasma,  e.g.  small  traces  of 
sugar  and  of  urea.     It  may  be  collected  by  introducing  a  cannula  through  the 


THE  CENTRAL  NERVOUS  SYSTEM  463 

atlanto- occipital  membrane  into  the  ample  subarachnoid  space  lying  over 
the  fourth  ventricle.  Another  method  is  to  introduce  a  glass  cannula  through 
a  slit  in  the  sheath  of  a  nerve  root  up  into  the  subarachnoid  cavity  of  the 
spinal  canal.  In  man  it  may  be  obtained  in  small  quantities  for  examination 
by  introducing  a  hollow  needle  directly  into  the  spinal  canal  in  the  lumbar 
region  between  the  laminae  of  the  vertebrae.  On  introducing  a  cannula 
into  the  subarachnoid  space,  the  fluid  may  spurt  out,  showing  that  it  is  under 
a  certain  pressure  (about  100  nun.  H2O).  After  the  first  rush  the  fluid  begins 
to  drop  away,  at  first  rapidly,  but  becoming  slower  with  lapse  of  time.  If 
the  fluid  be  allowed  to  drain  oiS  for  some  hours,  signs  of  interference  with  the 
functions  of  the  central  nervous  system  are  evinced.  The  cerebro-spinal 
fluid  appears  to  be  formed  chiefly  in  the  neighbourhood  of  the  choroid  plexus. 
Although  its  composition  would  suggest  that  it  was  merely  a  transudation 
from  the  blood,  the  amount  formed  does  not  seem  to  run  parallel  with  the 
pressure  in  the  capillaries  of  the  brain.  Moreover,  it  has  been  shown  by 
Dixon  and  Halhburton  that  a  considerable  increase  in  the  flow  of  cerebro- 
spinal fluid  may  be  brought  about  by  injecting  an  extract  of  the  choroid 
plexus  itself.  It  has  therefore  been  concluded  that  this  fluid  is  really  a 
secretion  by  the  modified  ependyma  cells  covering  the  fringes  of  the  choroid 
plexus. 

Although  the  method  of  formation  of  the  cerebro-spinal  fluid  is  still  not 
clear,  there  is  no  question  that  its  removal  from  the  subarachnoid  space  is 
brought  about  by  simple  physical  factors.  The  subarachnoid  space  com- 
municates with  the  ventricles  by  means  of  openings  in  the  roof  of  the  fourth 
ventricle.  The  pressure  of  the  fluid  is  ordinarily  about  equal  to  the  pressm-e 
in  the  venous  sinuses  of  the  cranium.  If  salt  solution  be  injected  into  the 
subarachnoid  space,  it  escapes  with  extreme  ease  and  it  is  found  that  its 
channel  of  escape  is  into  the  veins  and  especially  into  the  venous  sinuses  of 
the  dura  mater.  Its  removal  by  these  sinuses  is  facilitated  by  the  existence 
of  pecuUar  structures,  known  as  the  Pacchionian  bodies.  Each  of  these 
bodies  is  a  bulbous  protrusion  of  the  arachnoid  membrane  into  a  blood 
sinus.  It  remains  connected  with  the  arachnoid  by  a  narrow  pedicle, 
through  which  a  continuation  of  the  sub-arachnoid  space  is  prolonged  into 
the  interior  of  the  sinus.  It  is  therefore  a  Httle  sac  of  arachnoid  membrane 
separated  from  the  blood  stream  only  by  an  invagination  of  the  endothelium 
lining  the  sinus.  Filtration  of  the  cerebro-spinal  fluid  will  occur  into  the 
venous  sinuses  whenever  the  pressure  of  the  fluid  rises  above  that  of  the 
blood  in  the  sinus.  The  fluid  can  also  escape,  but  with  greater  difticulty, 
along  the  sheaths  of  the  spinal  nerve  roots,  by  which  it  will  pass  into  the 
lymphatic  space  outside  the  spinal  canal. 

THE  NUTRITION  OF  THE  BRAIN.  The  grey  matter  of  t4u^  brain  is  very 
richly  supplied  with  blood  vessels.  Any  interference  with  the  blood  flow 
through  the  brain  rapidly  checks  the  functions  of  the  central  nervous  system 
in  consequence  of  deprivation  of  oxygen.  Although  so  susceptible  to  slight 
deprivation  of  oxygen  it  does  not  seem  that  the  brain  tissues  have  a  very  rapid 
gaseous  metabohsm  ;  that  is,  they  need  oxygen  supply  at  high  tension  but  do 


464  PHYSIOLOGY 

not  deprive  the  blood  of  any  very  large  amount  of  the  oxygen  which  it  con- 
tains. Nor  does  it  seem  probable  that  the  brain  requires  a  large  supply 
of  food  material.  It  must  be  remembered  that  in  all  parts  of  the  brain 
a  peri-vascular  lymphatic  intervenes  between  the  capillary  and  the  brain 
tissue.  Since  these  '  lymphatics '  communicate  with  the  subarachnoid 
space  they  must  contain  a  fluid  which  differs  httle  if  at  all  from  the  compo- 
sition of  the  cerebro-spinal  fluid  obtained  from  the  subarachnoid  space.  The 
nutrient  fluid  of  the  brain  is  therefore  practically  salt  solution  with  a  trace 
of  sugar  and  possible  minute  traces  of  amino  acids. 

Our  study  of  the  events  which  accompany  the  propagation  of  a  nervous 
impulse  down  a  nerve  fibre  has  prepared  us  for  the  conclusion  that  very  httle 
energy  is  involved  in  ordinary  nerve  activity.  It  is  true  that  extreme  fatigue 
causes  changes  in  the  initial  granules  of  the  nerve  cells  and  is  therefore  asso- 
ciated with  the  using  up  of  some  material  constituent.  But  even  though 
material  changes  in  the  nerve-cells  and  in  the  synapses  may  be'  larger  in 
amount  than  those  in  nerve  fibres,  they  are  probably  not  to  be  compared 
in  extent  with  those  taking  place  in  a  contracting  muscle  or  in  an  active  liver 
cell. 

THE  CEREBRAL  CIRCULATION 

In  all  higher  animals  the  brain  is  enclosed  in  a  rigid  case  formed  by  the 
bony  cranium.  In  the  child,  before  the  cranial  vault  is  fully  ossified,  part 
of  this  vault  consists  of  membrane,  known  as  the  anterior  fontanelle.  It 
is  easy  to  see  that  the  fontanelle  pulsates  with  each  heart-beat  as  well 
as  with  rise  of  venous  pressure,  such  as  that  produced  during  strong 
expiratory  efforts.  When  ossification  is  complete,  such  alterations  in  the 
volume  of  the  cranial  contents  are  impossible.  And  yet  the  pressure  in 
the  arteries  within  the  cranium  must  be  still  pulsatile,  the  rise  of  pressure  at 
each  heart-beat  must  make  the  arteries  expand,  but  room  for  this  expansion 
has  to  be  found  by  contraction  of  some  other  part  of  the  cranial  contents. 
We  find  that  each  arterial  beat  is  associated  with  a  corresponding  expulsion 
of  some  of  the  contents  of  the  veins  and  a  contraction  of  these  vessels.  If, 
for  instance,  a  cannula  be  introduced  through  the  occipital  bone  into  the 
torcular  Herophih,  the  venous  blood  is  seen  to  pulsate  and  to  be  pressed  out 
with  each  beat  of  the  heart.  If  there  is  a  rise  of  arterial  pressure,  although 
the  arteries  may  expand  somewhat  at  the  expense  of  the  veins,  there  can  be 
no  dilatation  of  the  whole  organ.  The  only  effect  of  the  rise  of  pressure 
will  be  to  cause  an  increased  pressure  fall  in  the  cranial  vascular  system,  and 
therefore  augmented  velocity  of  flow  through  the  system.  A  prolonged  rise 
of  pressure  may  cause  a  certain  amount  of  dilatation  of  the  vessels,  but  only 
at  the  expense  of  the  cerebro-spinal  fluid.  Since  this  is  only  small  in  amount, 
any  expansion  of  the  brain  due  to  vascular  causes  must  be  very  Hmited. 

BRAIN  PRESSURE.  If  by  means  of  a  trephine  an  opening  be  made  into 
the  cranial  vault,  the  brain  bulges  into  the  opening.  By  screwing  a  tube 
covered  with  a  membrane  into  the  trephine  opening,  we  can  find  the  pressure 
necessary  to  force  the  brain  back  to  its  previous  position.  This  is  known 
as  the  brain  pressure  and  is  approximately  equal,  as  might  be  expected,  to  the 


THE  CENTRAL  NERVOUS  SYSTEM  465 

cerebro-spinal  pressure  and  to  the  pressure  in  the  venous  sinuses.  It  is 
closely  dependent  on  the  latter.  Forced  expiratory  efforts,  such  as  may 
occur  in  the  convulsions  of  strychnine  poisoning,  may  raise  the  pressure  from 
30  to  50  mm.  Hg.  In  the  vertical  position  in  man  the  pressure  may  be 
slightly  negative  in  consequence  of  the  tendency  of  the  venous  blood  to  run 
downwards  towards  the  heart. 

REGULATION  OF  THE  BLOOD-SUPPLY  TO  THE  BRAIN 

No  satisfactory  evidence  has  been  brought  forward  of  the  existence  of 
vaso-motor  nerves  controlling  the  calibre  of  the  cerebral  blood  vessels.  Nor 
indeed  are  such  nerves  necessary.  The  brain,  as  the  master  tissue  of  the 
body,  controls  through  the  medullary  centres  the  circulation  through  all 
other  parts  of  the  body.  It  is  therefore  able  to  regulate  the  blood-supply 
through  its  arteries  by  allowing  less  or  more  blood  to  pass  through  other  parts 
of  the  body.  For  the  exercise  of  its  normal  functions  it  requires  a  certain 
blood-supply,  which  again  will  depend  simply  on  the  pressure  in  the  carotid 
arteries  and  circle  of  Willis.  If  this  pressure  fails,  the  functions  of  the  brain 
are  affected  and  loss  of  consciousness  rapidly  ensues.  This  is  what  occurs 
when  a  person  who  is  weak  from  long  illness  faints  on  suddenly  getting  up 
from  bed.  In  the  normal  individual  the  change  in  the  circulation  ^\'ith  altera- 
tion of  bodily  position,  which  would  be  produced  by  the  action  of  gravity, 
is  at  once  counteracted  through  the  vaso-motor  system.  The  splanchnic  area 
is  contracted  or  dilated  according  to  the  necessities  of  the  case,  but  the  pres- 
sure in  the  carotid  and  the  circulation  of  the  brain  remains  unaltered.  Even 
when  the  heart  in  consequence  of  disease  is  scarcely  able  to  carry  on  the  circu- 
lation, the  arterial  pressure  undergoes  little  or  no  alteration.  Any  other 
tissue  of  the  body,  even  the  heart  itself,  may  suffer,  but  the  brain  at  all  costs 
must  receive  its  proper  supply  of  blood. 


SECTION  XIX 
THE  VISCERAL   OR   AUTONOMIC   NERVOUS  SYSTEM 

In  the  medulla  oblongata  it  is  easy  to  differentiate  the  central  grey  matter 
connected  with  the  peripheral  nerves  into  two  categories,  viz.  splanchnic 
and  somatic.  Each  of  these  two  sets  of  nerves  possesses  both  afferent  and 
efferent  fibres.  Gaskell  has  suggested  that  the  same  arrangement  would  hold 
for  any  typical  segmental  nerve,  which  would  therefore  have  four  roots,  viz. 
two  somatic — the  motor  and  sensory  roots  distributed  to  the  skin  and 
skeletal  muscles — and  two  splanchnic  roots,  also  motor  and  sensory,  and 
composed  of  small  fibres  distributed  to  the  viscera  or  structures  which  are 
visceral  in  origin  {e.g.  developed  from  the  branchial  arches).  In  the  medulla 
the  somatic  efferent  fibres,  such  as  the  sixth  and  twelfth  nerves,  arise  from  the 
column  of  large  cells  lying  in  the  floor  of  the  fourth  ventricle  close  to  the 
middle  hue.  The  splanchnic  fibres,  e.g.  those  of  the  facial  and  vago-glosso- 
pharyngeal  nerves,  arise  from  a  column  of  cells — the  nucleus  ambiguos  and 
facial  nucleus,  lying  more  laterally  and  deeper,  below  the  surface  of  the 
ventricle.  The  motor  root  of  the  fifth  would  also  belong  to  the  same  system. 
In  the  spinal  cord  the  visceral  fibres  arise  in  the  cells  of  the  lateral  horn,  i.e. 
from  a  situation  corresponding  to  the  splanchnic  motor  nuclei  of  the  pons 
and  medulla.  Whereas,  however,  the  splanchnic  afferent  nerves,  such  as  the 
glossopharyngeal,  and  perhaps  the  sensory  nucleus  of  the  fifth,  form  a  well- 
marked  splanchnic  system  of  nuclei  in  the  medulla,  in  the  cord  the  afferent 
fibres  from  the  viscera  pass  in  with  the  other  afferent  somatic  fibres,  and  their 
immediate  connections  in  the  cord  are  as  yet  unknown. 

The  autonomic  system  of  nerves  includes  the  sympathetic  system 
(properly  so  called)  and  some  of  the  cranial  and  sacral  nerves.  The  sym- 
pathetic system  (Fig.  237)  is  composed  of  a  chain  of  gangha  lying  each  side 
of  the  vertebral  column,  there  being  as  a  rule  one  ganghon  to  each  spinal 
nerve-root.  In  the  cervical  region  these  gangha  are  condensed  into  two, 
the  superior  and  inferior  cervical  gangha,  united  by  the  cervical  sympa- 
thetic trunk ;  and  the  upper  three  or  four  thoracic  ganglia  on  each  side  are 
condensed  to  form  the  '  stellate  '  ganghon.  At  the  bottom  of  the  chain 
there  is  only  one  coccygeal  ganglion  for  the  coccygeal  vertebrae. 

In  the  abdomen  is  a  second  system  of  gangha,  in  special  connection 
with  the  abdominal  viscera,  lying  in  front  of  the  aorta  and  surrounding  the 
origins  of  the  large  arteries  to  the  ahmentary  canal.  These  are  the  semilunar 
or  solar  gangha,  the  superior  mesenteric  and  the  inferior  mesenteric  gangha. 

466 


THE  AUTONOMIC  NERVOUS  SYSTEM 


467 


Sup.cerv.  g.' 


Inf.cerv.g 


•     H 

Stellate  g/ ' 

S^mp.  chain  <^ 

Semilunar  g.^ 

Sup.mes.g.^, 

>  Head  &  Neck 


,  Abdominal 
Viscera 


Hypogastric  n     ^g^^jscn 


FT(i.  2:?7.  Diagrammatic  rciirescntation  of  the  distribution  of  the  sympathetic  system. 
'rh(>  l)laci<  lines  represent  the  mecluHated  pre-ganglionic  fibres,  .such  as  those  making 
up  the  white  rami  eoininunicantcs,  while  the  imst-ganglionic  fibres  are  printed  in  red. 
On  the  extreme  right  of  tlie  figure  is  indicated  the  general  distribution  of  the  white  rami 
arising  from  the  several  nerve-roots,  while  the  double  brackets  jjoint  to  the  nerve- 
roots  making  up  the  limb  plexuses.  H,  heart ;  .s,  .stomach  ;  i.  small  intestine  ;  c,  colon  ; 
B,  bladder. 


467 


468 


PHYSIOLOGY 


In  the  organs  themselves  we  find  a  third  system  of  ganghon-cells,  either 
scattered  or  collected  to  form  small  ganglia.  These  isolated  ganglion  cells 
as  a  rule  have  no  connection  with  the  fibres  of  the  sympathetic  system,  but, 
as  we  shall  see  later,  he  on  the  course  of  the  impulses  descending  by  other 
nerves  of  the  autonomic  system,  e.g.  the  vagus  or  the  pelvic  visceral  nerves. 
The  three  systems  of  ganglia  have  been  distinguished  as  the  lateral,  collateral, 
and  terminal  gangha. 


Fig.  238.  Diagram  of  spinal  segment  with  its  nerve 
roots,  somatic  and  visceral.  (G.  D.  Thane.) 
(The  visceral  roots  are  represented  in  red.) 

The  gangha  of  the  sympathetic  chain  are  connected  with  all  the  spinal 
nerves,  just  after  they  have  given  off  their  posterior  divisions,  by  means  of  the 
rami  communicantes.  These  rami  communicantes  are  of  two  kinds  :  white 
rami  consisting  of  small  medullated  fibres,  and  grey  rami  composed  ahnost 
exclusively  of  non- medullated  nerves.  It  has  been  shown  by  Gaskell  that 
the  white  rami  are  formed  by  fibres  which  have  their  origin  in  the  spinal  cord 
and  perhaps  in  the  posterior  root  ganglia  ;  whereas  the  grey  rami  represent 
fibres  which,  arising  in  the  sympathetic  gangha,  run  back  to  join  the  spinal 
nerves.  The  visceral  outflow  represented  by  the  white  rami  is  limited  to  a 
distinct  region  of  the  cord,  viz.  from  the  first  thoracic  to  the  third  or  fourth 
lumbar  nerve-roots  ;  whereas  the  grey  rami  pass  from  the  sympathetic 
to  all  the  spinal  nerve-roots.  It  is  found  by  experiment  that  stimulation  of  a 
hmited  number  of  white  rami  produces  all  the  effects  that  can  be  evoked  by 
stimulation  of  the  grey  rami,  showing  that  the  impulses  leaving  the  cord  pass 
upwards  and  downwards  in  the  sympathetic  system  and  are  broken  some- 
where in  their  course,  being  transferred  to  a  fresh  relay  which,  by  means  of 
non-medullated  nerves,  carries  them  on  to  their  destination. 

Finally,  in  certain  organs  of  the  body  are  to  be  found  sheets  of  nerve 
structures,  including  both  ganglion  cells  and  fibres,  which  must  be  regarded 
as  local  nerve-centres,  capable  of  carrying  out  co-ordinated  acts  in  response 
to  stimuli,  independently  of  the  central  nervous  system.  It  seems  probable 
that  these  systems  are  to  be  regarded  as  analogous  rather  to  the  diffuse  neuro- 
fibrillar system  of  an  animal,  such  as  the  medusa,  than  to  the  synaptic  ner- 
vous structures  characteristic  of  the  central  nervous  system  of  vertebrates. 


THE  AUTONOMIC  NERVOUS  SYSTEM 


^69 


In  the  latter  the  direction  and  effect  of  any  impulses  are  determined  by  the 
synapses  intervening  between  various  systems  of  neurons  and  allowing  the 
passage  of  the  impulse  only  in  one  direction.  This  law  of  forward  direction 
has  not  been  proved  to  hold  good  for  the  primitive  nerve  systems  ;  an 
impulse  apparently  spreads  equally  well  in  either  direction.  As  a  type  of  this 
peripheral  diffuse  nerve  system  may  be  cited  the  Auerbach's  and  Meissner's 
plexuses  in  the  wall  of  alimentary  canal.  How  far  we  are  to  regard  the 
nerve-nets  in  other  viscera,  such  as  the  heart  and  the  bladder,  as  conforming 
to  this  type  is  still  a  moot  point,  and  will  be  discussed  in  dealing  with  the 
origin  of  the  heart-beat. 


Posc'root  - 
Ant'  root 


—  Pre-ganglionic  fibre 


-  -Symp.  gangl. 


-..J        "     ■    ,  '  ^  ^  Post-qanqlionic  fibre 

IVIade-up    spinal  nerve ' 

Fig.  239.  Diagram  (after  Langley)  to  show  tlic  manner  in  which  a  spinal  nerve  is 
completed  by  the  entry  of  a  grey  ramus,  containing  fibres  derived  from  cells  in 
the  sympathetic  chain. 

p.pr.d,  posterior  primary  division.     (The  post-ganglionic  fibres  are  represented  red.) 

The  relationships  of  the  white  and  grey  rami  are  strikingly  illustrated 
in  the  case  of  the  pilomotor  systems  of  nerves.  These  in  the  cat  arise  from 
the  cord  by  the  anterior  roots  from  the  fourth  thoracic  to  the  third  lumbar 
inclusive.  Passing  by  the  white  rami  to  the  sympathetic  system,  they 
travel  upwards  and  downwards  and  end  by  arborisations  in  the  various 
gangha  of  the  main  chain.  From  the  cells  of  each  ganglion  a  fresh  relay  of 
fibres  starts,  which  runs  as  a  bundle  of  non-medullated  nerves  (the  grey 
ramus)  to  the  corresponding  spinal  nerve,  with  which  it  is  distributed  to 
its  peripheral  destination.  Each  grey  ramus  causes  erection  of  the  hairs 
above  one  vertebra,  whereas  stimulation  of  one  white  ramus  causes  erection 
over  three  or  four  vertebrae,  showing  a  distribution  of  the  fibres  of  the  white 
ramus  to  the  cells  in  several  successive  ganglia. 

These  pilomotor  fibres  in  the  cat  have  the  following  distribution  : 
(1)  For  the  head  and  upper  part  of  the  neck  the  fibres  arise  by  the  fourth 
to  the  seventh  thoracic  anterior  roots,  and  have  their  cell  stations  in  the 


470  PHYSIOLOGY 

superior  cervical  ganglion.  They  travel  as  small  medullated  nerve  fibres 
from  the  white  rami  up  the  sympathetic  chain,  through  the  stellate  ganghon 
and  ansa  Vieussenii  and  up  the  cervical  sympathetic. 

(2)  The  next  set  of  nerve  fibres  have  their  cell  station  in  the  stellate 
ganghon.  The  white  rami  arise  from  the  fifth  to  the  eighth  thoracic  nerves, 
while  the  grey  rami  pass  to  the  nerve-roots  from  the  third  cervical  nerve 
to  the  fourth  thoracic  nerve. 

(3)  The  remaining  nerves,  supplying  all  the  rest  of  the  body  and  tail, 
arise  by  the  white  rami  from  the  seventh  thoracic  to  the  third  or  fourth 
lumbar  nerve,  and  are  distributed  as  grey  rami  to  all  the  spinal  nerves  below 
the  fourth  thoracic. 

We  thus  see  that,  in  speaking  of  the  functions  of  a  spinal  nerve-root,  we 
must  clearly  distinguish  whether  we  mean  the  root  as  it  arises  from  the 
spinal  cord,  in  which  case  its  visceral  functions  will  include  those  of  its  white 
ramus,  or  whether  we  mean  the  made-up  or  complete  spinal  nerve  after  it  has 
received  its  grey  ramus  (Fig.  239).  In  the  latter  case  the  visceral  functions 
of  the  root  will  be  more  restricted  than  in  the  former  case,  and  will  have  a 
different  distribution.  In  stimulating  the  nerve-roots  in  the  spinal  canal 
it  is  sometimes  possible,  by  weak  stimuli,  to  display  the  functions  of  the 
corresponding  white  ramus,  and  then  by  increasing  the  stimulus  to  get 
superadded  the  effects  due  to  the  excitation  of  the  grey  ramus  in  the  made-up 
nerve,  in  consequence  of  the  spread  of  current. 

"When,  for  example,  the  eleventh  thoracic  anterior  roots  are  stimulated  in  the 
spinal  canal  with  weak  shocks,  a  fairly  long  strip  of  hairs  in  the  lumbar  region  will 
be  erected,  the  maximum  movement  of  the  hairs  being  near  the  middle  of  the  strip. 
This  marks  the  area  of  distribution  of  the  pilomotor  nerves  given  by  the  eleventh  thoracic 
nerve  to  the  sympathetic.  If  then  the  strength  of  the  shock  be  increased  to  a  certain 
point,  the  hairs  in  the  long  strip  will  of  course  be  erected  as  before,  but  in  addition 
there  will  be  energetic  erection  of  hairs  in  a  short  strip  a  little  distance  above  the  long 
strip,  and  separated  from  it  by  a  quiescent  region.  This  short  strip  is  the  same  as  that 
affected  by  stimulating  the  grey  ramus  or  the  dorsal  cutaneous  branch  of  the  eleventh 
thoracic  nerve.  It  marks  the  area  of  distribution  of  the  pilomotor  fibres  received 
by  the  spinal  nerve  from  the  sympathetic."    (Langley.) 

We  may  now  indicate  briefly  the  main  course  and  functions  of  the  fibres 
of  the  sympathetic  system. 

(1)  The  head  and  neck  are  supplied  by  fibres  leaving  the  spinal  cord 
by  the  first  five  dorsal  nerves  (chiefly  by  the  second  and  third).  They  all 
have  their  cell  station  in  the  superior  cervical  ganghon.     They  convey  : 

Vaso- constrictor  impulses  to  the  blood-vessels. 
Dilator  fibres  to  the  pupil. 

Secretory  fibres  to  the  salivary  glands  and  sweat  glands. 
Vaso-dilator  fibres  to  the  lower  lip  and  pharynx  (?). 

(2)  The  thoracic  viscera  (heart  and  lungs)  are  supplied  by  the  same  five 
nerve-roots.  The  cell  station  of  these  fibres  is,  however,  situated  in  the 
stellate  ganglion.     They  convey  : 

Accelerator  or  augmentor  impulses  to  the  heart. 

(3)  The  abdominal  viscera  receive  fibres  from  the  lower  six  dorsal  nerves 


THE  AUTONOMIC  NERVOUS  SYSTEM 


471 


and  the  upper  three  or  four  kimbar.  Most  of  these  fibres  run  through  the 
sympathetic  chain  without  making  any  connection  with  the  gangha,  and 
have  their  cell  stations  in  the  collateral  ganglia  of  the  solar  plexus,  the  semi- 
lunar and  superior  mesenteric  ganglia.  On  their  way  to  these  gangha  they 
form  the  greater  and  lesser  splanchnic  nerves.     Their  functions  are  : 

Vaso-constrictor  for  stomach  and  small  intestine,  kidney,  and  spleen. 

Probably  vaso-dilator  for  the  same  viscera. 

Inhibitory  for  both  muscular  coats  of  stomach  and  small  intestine. 

Motor  for  ileocohc  sphincter. 

(4)  The  pelvic  viscera  are  supplied  by  the  lower  dorsal  and  upper  three 
or  four  lumbar  nerve-roots.     These  fibres  also  pass  by  the  main  chain  to 


•rn  A 


rttr 


4 


Spinal  cord 


Sympathetic  chain 


Solar  ganglion 


Fig.  240.     Figure  (after  Laxgley)  to  show  the  probal>le  mode  of  connection 
of  the  fibres  of  the  splanchnic  nerve  with  nerve-cells. 

A,  usual  type,  all  the  fibres  i^assing  through  the  lateral  chain  to  end 
in  the  collateral  ganglia  of  the  solar  ])lcxus  ;  b,  alternative  condition,  in 
which  a  small  minority  of  the  fibres  have  their  cell-stations  in  the  sym- 
pathetic chain.     The  prc-ganglionic  fibres  are  black,  the  post  ganglionic  red. 

make  connections  with  the  cells  chiefly  in  the  inferior  mesenteric  gangha. 
They  convey  : 

Vaso-constrictor  impulses  to  pelvic  viscera. 

Inhibitory  fibres  to  colon  (both  coats). 

Motor  and  also  inhibitory  fibres  to  bladder. 

Motor  fibres  to  retractor  penis. 

Motor  and  inhibitory  fibres  to  uterus  and  vagina. 

(5)  The  fore  hmb  receives  nerves  from  the  white  rami  of  the  fourth 
to  the  tenth  thoracic  nerves.  All  these  fibres  are  connected  with  cells  in  the 
stellate  ganglion.     They  convey  : 

Vaso-constrictor  impulses  to  the  blood-vessels. 

Secretory  nerves  to  the  sweat  glands. 

(6)  The  hind  limb  is  supplied  by  the  nerve-roots  from  the  eleventh 


472  PHYSIOLOGY 

thoracic  to  the  third  lumbar  inclusive.  The  cell  stations  of  these  fibres 
are  situated  in  the  sixth  and  seventh  lumbar  and  first  sacral  ganglia.  They 
convey  : 

Vaso-constrictor  impulses. 

Secretory  nerves  to  the  sweat  glands. 

Every  fibre  of  the  sympathetic  system  is  thus  in  some  point  of  its  course 
interrupted  by  a  nerve-cell,  and  Langley  has  shown  that  this  is  the  only  cell- 
break  in  the  fibre,  i.e.  every  fibre  is  connected  with  one  cell  and  one  cell  only. 
This  law  apphes  not  only  to  the  sympathetic  fibres  but  also  to  the  fibres  of  the 
other  visceral  nerves.  Each  fibre  therefore  can  be  regarded  as  made  up 
of  two  sections — a  pre-ganglionic  fibre  arising  in  the  central  nervous  system 
and  passing  down  to  a  ganglion  as  a  fine  medullated  nerve  fibre,  and  a 
post-ganglionic  fibre  arising  in  this  ganglion  and  continued  generally  as  a 
non-medullated  fibre  to  its  peripheral  distribution. 

This  transference  from  one  system  to  another  involves  the  passage  across 
a  synapse  and  a  nerve-cell.  The  situation  of  this  nerve-cell  may  be  easily 
revealed  by  utilising  the  action  of  nicotine,  first  studied  by  Langley.  If 
nicotine  be  apphed  to  a  sympathetic  ganghon,  it  first  stimulates  and  then 
paralyses  any  junction  between  axon  termination  and  nerve-cell  which  may 
he  in  the  ganglion.  Intravenous  injection  of  nicotine  therefore  causes  a 
primary  general  excitation  of  all  visceral  ganglion-cells.  There  is  an  enor- 
mous rise  of  blood  pressure,  which  may  be  accompanied  by  other  sympathetic 
effects,  such  as  dilatation  of  the  pupil,  secretion  of  saliva,  erection  of  the 
hairs,  and  so  on.  This  rise  rapidly  passes  off,  and  it  is  then  found  impossible 
to  evoke  any  reflex  visceral  effects  or  any  contraction,  e.g.  of  the  blood-vessels, 
by  stimulation  of  the  spinal  cord  ;  the  passage  of  the  impulses  is  blocked  in 
every  one  of  the  visceral  ganglia.  By  observing  the  effects  of  stimulation  of 
a  nerve  before  it  enters  a  ganglion  and  then  painting  the  ganglion  with  nico- 
tine and  again  trying  the  effects  of  excitation,  it  is  easy  to  determine  whether 
the  nerve  fibres  which  were  excited  in  the  first  case  form  any  connections 
with  the  nerve-cells  of  the  ganglion.  In  the  strength  in  which  it  is  usually 
applied  nicotine  is  without  effect  on  nerve  fibres. 

THE  CRANIAL  AUTONOMIC  FIBRES 
In  the  course  of  development  the  greater  part  of  the  fibres  of  the  facial 
nerve  have  lost  their  special  visceral  functions  and  have  the  aspect  and 
functions  of  ordinary  somatic  fibres.     Visceral  fibres  are  contained  in  the 
following  cranial  nerves — the  third,  seventh,  ninth,  tenth,  and  eleventh. 

Third  nerve.  The  visceral  fibres  of  this  nerve  pass  to  the  ciliary  ganglion 
in  the  orbit  where  they  end ;  the  post-ganglionic  fibres  from  this  ganglion 
form  the  short  ciliary  nerves  which  innervate  the  sphincter  pupillse  and  the 
ciliary  muscles. 

Seventh  nerve.  The  autonomic  fibres  of  the  facial  arise  from  the  medulla 
in  the  intermediate  nerve  of  Wrisberg,  which  is  practically  the  anterior  con- 
tinuation of  the  ninth,  tenth,  and  eleventh  nerves.  From  the  seventh  nerve 
is  derived  the  chorda  tympani  nerve,  which  supplies  vaso-dilator  nerves 


THE  AUTONOMIC  NERVOUS  SYSTEM  473 

to  the  tongue,  the  submaxillary  and  sublingual  glands,  and  secretory  fibres 
to  these  glands. 

The  cell  stations  of  these  nerves  lie  peripherally,  those  of  the  sublingual 
gland  in  the  so-called  submaxillary  ganglion  ;  those  of  the  submaxillary 
gland  in  the  hilus  of  this  organ.  It  is  probable  that  the  seventh  sends  also 
pre-ganglionic  visceral  fibres  to  the  spheno-palatine  ganglion,  whence  a  fresh 
relay  of  fibres — post-ganglionic — run  with  the  branches  of  the  fifth  nerve, 
to  supply  secretory  fibres  and  possibly  vaso-dilator  fibres  to  the  mucous 
membrane  of  the  nose,  soft  palate,  and  upper  part  of  the  pharynx.  The 
glossopharyngeal  or  ninth  nerve  sends  fibres,  which  evoke  secretion  as  well  as 
vaso-dilatation  in  the  parotid  gland,  via  the  otic  ganglion.  Probably  also 
dilator  fibres  leave  this  nerve  to  supply  vessels  at  the  back  of  the  tongue. 

THE  VAGUS 

The  efferent  visceral  fibres  of  the  tenth  and  eleventh  nerves  arise  in  the 
same  column  of  cells  as  the  two  nerves  just  considered.  Most  of  the  fibres 
run  in  the  vagus.  They  include  motor  fibres  to  the  oesophagus,  stomach,  and 
small  intestines  as  far  as  the  ileocolic  sphincter  ;  inhibitory  fibres  to  the 
heart,  motor  fibres  to  the  unstriated  muscles  of  the  bronchi,  and  secretory 
fibres  to  the  gastric  glands.  The  cell  stations  of  these  fibres  are  apparently 
situated  peripherally,  the  jugular  ganghon,  and  the  ganglion  of  the  trunk 
of  the  vagus  being  in  all  likelihood  responsible  only  for  the  afferent  fibres  in 
this  nerve.  Nicotine  therefore  aboHshes  any  effect  of  stimulating  the  vagus 
in  the  neck,  though  inhibition  of  the  heart  can  still  be  produced  on  excitation 
of  the  post-ganglionic  fibres  arising  from  the  cells  in  the  sinus  venosus. 

SACRAL   AUTONOMIC  FIBRES 

These  all  run  in  the  pelvic  visceral  nerve,  also  called  nervus  en'gens. 
This  nerve  is  connected  with  a  collection  of  ganglia  lying  in  the  hypogastric 
plexus  at  the  base  of  the  bladder.     It  has  the  following  functions  : 

Dilator  to  vessels  of  the  penis  (hence  its  name  of  nervus  erigens). 

Motor  to  bladder,  colon,  and  rectum. 

Inhibitory  to  sphincter  muscle  of  bladder. 

Inhibitory  to  retractor  penis. 

It  will  be  observed  that  in  many  cases  the  viscera  get  their  nerve-supply 
from  both  sets  of  visceral  nerves,  and  that  in  such  cases  the  two  sets  of 
nerves  are  antagonistic  in  function.  It  is  impossible,  however,  to  draw  a 
sharp  line  between  the  functions  of  the  two  sets,  since  the  same  nerve  may  be 
motor  for  one  set  of  muscular  fibres  and  inhibitory  for  another  set  in  the 
same  viscus.  Thus  the  colonic  branches  of  the  inferior  mesenteric  ganglion 
are  motor  (constrictor)  for  the  blood-vessels  and  inhibitory  for  the  muscular 
walls  of  the  colon.  While  the  sympathetic  nerve-supply  is  inhibitory  for 
nearly  the  whole  intestinal  muscles,  it  produces  strong  contraction  of  the 
band  of  muscle  forming  the  ileocolic  sphincter.  In  the  bladder  there 
is  no  doubt  that  the  sympathetic  supply  includes  both  inhibitory  and 


474  PHYSIOLOGY 

motor  fibres,  the  predominating  effect  on  excitation  of  the  nerve  varying 
from  one  species  of  animal  to  another. 

FUNCTIONS  OF  THE  SYMPATHETIC   AND  PERIPHERAL 

GANGLIA 

These  gangha  consist  of  a  mass  of  nerve-cells  embedded  in  connective 
tissue,  each  cell  being  surrounded  by  a  special  capsule  of  endothehal  cells. 
The  nerve-cells,  though  in  section  resembhng  those  in  a  posterior  root 
ganghon,  differ  from  these  in  being  multipolar,  each  cell  probably  possessing 
one  axon  and  several  dendrites.  The  dendrites  end  in  httle  arborisations 
round  adjacent  cells. 

Since  the  main  nervous  system  is  characterised  by  the  possession  of 
nerve-cells,  it  was  formerly  thought  that  any  collection  of  nerve-cells  must 
partake  of  the  co-ordinating  and  reflex  functions  of  the  central  nervous 
system,  i.e.  must  act  as  local  nervous  centres.  All  efforts  have  failed,  how- 
ever, to  prove  the  existence  of  such  a  function,  and  we  must  conclude  that  the 
sole  use  of  these  ganglia  is  to  serve  as  distributing- centres.  We  may  assume 
that  one  pre-ganglionic  fibre  divides,  and  the  branches  arborise  round  several 
cells  (Fig.  240),  whence  new  fibres  arise  to  carry  the  impulse  to  the  periphery 
— an  impulse  in  the  case  of  which  there  is  no  need  for  .any  minute  localisation. 
Indeed  the  essential  part  of  a  nerve-centre  is  not  the  nerve-cells  at  all, 
but  the  presence  of  a  complex  tangle  of  fibres,  rendering  possible  the  passage 
of  impulses  in  all  directions,  the  passage  of  an  individual  impulse  being 
limited  by  reason  of  the  varying  strength  of  the  impulse  and  the  varying 
resistance  of  the  many  possible  tracts.  In  many  invertebrata  the  nervous 
system  consists  of  a  punctated  material  composed  of  a  dense  interlacement  of 
fibrils,  while  the  cells  lie  outside  the  centres  and  have  one  thick  process 
dipping  into  the  nervous  mass,  from  which  process  both  axon  and  dendrites 
arise.  In  this  case,  as  we  have  seen,  extirpation  of  the  cell  bodies  does  not 
destroy  the  capacity  of  the  remaining  fibrillar  substance  to  act  as  a  reflex 
centre.  Such  a  complex  of  fibres  is  found  in  mammals  in  the  plexuses  of 
Auerbach  and  Meissner,  which  act  as  local  nerve-centres  for  the  intestine. 
But  all  such  mechanism  is  wanting  in  the  sympathetic  ganglia,  which  con- 
tain neither  association  fibres  between  different  cells  of  a  ganglion  nor  com- 
missural fibres  between  the  cells  of  adjacent  ganglia.  All  the  fibres  in  a 
sympathetic  ganglion  have  either  entered  it  from  the  white  rami  or  are 
destined  to  leave  it  as  fibres  of  grey  rami. 

Several  reflexes  formerly  described  in  peripheral  ganglia,  as,  e.g.  the 
'  submaxillary  '  ganglion,  have  been  proved  to  be  fallacious.  There  is, 
however,  a  certain  group  of  phenomena  which  can  be  elicited  in  sympathetic 
ganglia,  and  which  have  been  termed  by  Langley  and  Anderson  pseudo- 
reflexes,  or,  better,  axon  reflexes.  If,  for  instance,  we  divide  all  the  nerves 
going  to  the  inferior  mesenteric  ganglion,  leaving  the  bladder  connected 
with  the  inferior  mesenteric  ganglion  only  by  the  hypogastric  nerves,  and 
then  after  dividing  the  left  nerve  stimulate  its  central  end,  we  obtain  a 
contraction  of  the  right  half  of  the  bladder.     This  effect  is  abohshed  by 


THE  AUTONOMIC  NERVOUS  SYSTEM 


475 


painting  the  inferior  mesenteric  ganglion  with  nicotine,  showing  that  the 
activity  of  the  cells  of  this  ganglion  is  involved  in  the  process.  It  has  been 
shown,  however,  by  Langley  and  Anderson  that  this  is  not  a  true  reflex,  but 
is  rather  analogous  to  Kiihne's  gracilis  experiment  {cf.  p.  255).  A  pre- 
ganglionic fibre  arriving  at  the  inferior  mesenteric  ganglion  branches,  one 
branch  ending  round  the  cells  of  the  ganglion,  while  the  other  bi'anch  passes 
down  in  the  left  hypogastric  nerve  to  a  cell  situated  near  the  base  of  the 
bladder  (Fig.  241).     When  therefore  we  stimulate  this  nerve  we  are  stimula- 

Sp.cord 


Inf.  mes.  g-  ^ 
Post-ganglionic  fibre 


Pre -ganglionic  fibre 
-Hypogastric  nerves 


Diagram  to  illustrate  Langley  and  Anderson's  explanation  of  the  hypo- 
gastric reflex  as  an  axon  reflex. 


Fig.  241 

The  division  of  the  axon  where  the  propagation  or  '-reflexion  '  takes  place  is  at  X 


ting  a  pre-ganglionic  fibre,  and  the  excitation  spreads  up  to  the  point  of 
junction  of  the  two  branches  and  then  down  the  other  branch  to  excite  the 
cell  in  the  inferior  mesenteric  ganglion.  We  thus  obtain  an  apparent  motor 
reflex  by  stimulation  of  a  nerve  which  is  itself  motor.  Similar  pseudo- 
reflexes  can  be  obtained  along  the  abdominal  chain  on  the  pilomotor  nerves 
but  furnish  no  groimds  for  ascribing  the  property  of  reflex  centres  to  peri- 
pheral ganglia.  On  the  other  hand,  these  axon  reflexes  are  very  similar  to 
the  spread  of  the  excitatory  process  which  occurs  in  the  diffuse  nerve  network 
of  an  animal  such  as  the  medusa.  Irreciprocity  of  conduction  would  seem 
therefore  to  be  the  most  useful  criterion  of  a  true  reflex. 


INHIBITION  IN  PERIPHERAL  GANGLIA 
The  existence  of  ganglion-cells  in  the  eour.se  of  the  nerves  to  visceral  muscles  has 
often  been  supposed  to  account  for  cerUiin  peculiarities  in  the  innervation  of  visceral, 
as  conapared  with  skeletal,  nuLscle.  Chief  among  the  differences  between  these  two 
kinds  of  muscle  i&  the  frequency  with  which  inhibition  may  be  brought  about  in  visceral 
muscle  by  stimulation  of  pcriplieral  efferent  nerves.  In  skeletal  muscle  inliibition  is 
only  known  as  the  result  of  alteration  of  the  activity  of  the  motor  centres  from  which 
it  is  supplied.  It  has  therefore  been  throught  that  the  peripheral  ganglia  of  vi.sceral 
mu-jcle  play  the  part  of  the  motor  spinal  centres  of  skeletal  muscle,  and  that  when 
wo  excite  an  inhibitory  norvo,  say  to  the  intestine,  we  are  interfering  with  and  diminishing 


476  PHYSIOLOGY 

a  tonic  state  of  activity  which  has  its  seat  in  a  peripheral  ganglion-cell  connected  with 
the  visceral  muscle. 

This  view,  which  was  first  put  forward  by  Claude  Bernard,  has  been  specially  defended 
by  Dastre  and  Morat.  These  observers  point  out  that  vaso-dilator  action  diminishes 
or  disappears  as  nerve-strands  are  stimulated  more  and  more  peripherally,  and  con- 
clude that  the  vaso-dilator  fibres  run  to  the  sympathetic  ganglion  and  inhibit  their 
tonic  action.  The  untenability  of  this  view  has  been  demonstrated  by  Langley.  Thus 
the  chorda  tj^mpani  fibres  run  to  a  local  nerve-'  centre  '  in  the  hilum  of  the  submaxillary 
gland.  On  Bernard's  theory  stimulation  of  the  fibres  peripherally  to  the  centre  should 
cause  contraction  of  the  arteries  ;  but  it  is  found  that,  after  paralysis  of  the  ganglion 
by  nicotine,  stimulation  of  the  post-ganglionic  fibres  causes  dilatation,  so  that  the 
nerve  fibres  given  o&  from  the  local  centre  are  not  vaso-constrictor  but  vaso-dilator. 
Moreover  it  can  be  shown  that  the  sympathetic  fibres  which  do  cause  constriction 
make  no  connection  with  the  cells  in  the  hilum  of  the  gland,  but  run  on  the  walls  of 
the  arteries  to  their  distribution.  These  fibres  are  connected,  not  with  cells  of  the 
submaxillary  ganglion  (the  local  nerve-centre),  but  with  cells  in  the  superior  cervical 
ganglion. 

We  must  conclude  that  the  inhibitory  nerves  in  these  visceral  structures  exert 
their  influence  directly  on  the  peripheral  tissue,  and  not  by  a  diminution  of  activity 
of  a  tonically  acting  peripheral  centre. 

AFFERENT  FIBRES  AND  THE  AUTONOMIC  SYSTEM 
(Referred  Pain) 
The  supply  of  afferent  fibres  to  the  viscera  is  very  small  in  proportion 
to  the  supply  to  the  outer  surfaces  of  the  body.  According  to  Langley,  in  a 
visceral  nerve,  such  as  the  hypogastric,  only  about  one-tenth  of  the  medul- 
lated  fibres  are  afferent,  and  the  proportion  of  afferent  fibres  in  the  splanchnic 
nerves  is  probably  not  very  different  from  this.  At  the  two  ends  of  the 
ahmentary  canal,  i.e.  at  the  mouth  and  anus,  the  afferent  visceral  fibres 
become  of  more  importance,  since  through  their  means  co-operative  somatic 
reflexes  have  to  be  excited  as  well  as  the  simple  visceral  reflexes.  Thus  in  the 
pelvic  visceral  nerve  about  one-third  of  the  fibres  are  afferent,  and  the  vagi 
contain  a  large  number  of  afferent  fibres  from  the  lungs  as  well  as  from  the 
other  viscera  innervated  by  it. 

According  to  Dogiel,  afferent  visceral  fibres  arise  from  sensory  cells  of  the  sympathetic 
ganglia  and,  passing  in  to  the  posterior  spinal  ganglia,  divide  and  form  pericellular 
endings  round  a  special  type  of  posterior  root-cells,  the  axon  from  which  divides  again 
into  a  number  of  branches  which  end  in  connection  with  typical  unipolar  cells.  Thus, 
according  to  this  observer,  a  few  afferent  sympathetic  fibres  can  stimulate  a  considerable 
number  of  posterior  root-cells.  Langley,  however,  has  not  been  able  to  obtain  any 
experimental  confirmation  of  the  origin  of  branching  afferent  fibres  from  cells  of  the 
sympathetic  system. 

It  is  probable  that  the  afferent  fibres  of  the  visceral  nerves  arise,  like 
those  of  the  somatic  system,  from  ganghon-cells  of  the  posterior  spinal 
ganglia.  Every  white  ramus  contains  afferent  fibres,  stimulation  of  which 
may  evoke  a  rise  of  blood  pressure  as  well  as  movements  of  the  skeletal 
muscles.  In  spite  of  the  supply  of  afferent  fibres  to  the  viscera,  most  of  these 
organs  are  very  insensitive  to  ordinary  stimulation  such  as  handhng  or  cut- 
ting. In  operations  on  man  for  resection  of  the  gut,  if  the  abdominal  cavity 
be  opened  under  local  or  general  anaesthesia,  cutting  and  suturing  may  be 


THE  AUTONOMIC  NERVOUS  SYSTEM  477 

conducted  without  any  anaesthetic  and  without  causing  any  pain  to  the 
patient.  On  the  other  hand,  impulses  may  arise  in  the  afferent  nerve- 
endings  of  the  viscera,  as  a  result  of  disease  or  certain  forms  of  stimulation, 
e.g.  stretching  or  compression,  which  may  reach  consciousness  and  give  rise 
to  the  sensation  of  pain.  This  pain  is  not  localised  in  the  viscera,  but 
is  referred  to  certain  parts  of  the  surface  of  the  body.  When  the  afferent 
autonomic  fibres  of  a  nerve  are  the  seat  of  pain,  the  primary  referred  pain  is  in 
the  area  of  the  cutaneous  somatic  fibres  of  the  nerve.  It  has  been  shown  by 
Mackenzie  and  by  Head  that  visceral  disease  may  cause  hyper-sensiti\aty  of 
the  corresponding  areas  of  the  skin,  and  a  method  has  been  elaborated  by 
these  observers  for  utilising  this  referred  pain  or  skin  tenderness  as  a  means 
of  locahsing  the  site  of  the  disease. 


CHAPTER   VIII 
THE  PHYSIOLOGY  OF  SENSATION 

SECTION  I 
ON  THE   RELATION   OF  SENSATION  TO  STIMULUS 

Up  to  the  present  we  have  dealt  with  the  central  nervous  system  as  a 
machine  for  the  conversion  of  afferent  into  appropriate  efferent  impulses, 
and  have  regarded  the  sense-organs  simply  as  mechanisms  by  means  of 
which  stimuli  of  various  quahty,  arising  from  events  in  the  environment 
of  the  animal,  could  give  rise  to  nerve  impulses.  We  have  seen  reason 
to  assign  these  afferent  impressions  to  various  classes,  according  to  the 
physical  character  of  the  stimulus  involved  and  according  to  the  quahty 
of  the  response.  The  nature  of  the  physiological  processes  evoked  in  the 
organism  depends  on  the  physical  nature  of  the  stimulus  and  the  locus  of  its 
incidence  on  the  surface  of  the  body.  Thus  a  nocuous  stimulus  applied  to 
the  foot  causes  flexion  of  the  leg,  whereas  steady  pressure  on  the  sole  evokes 
a  '  stepping  '  reflex  with  extension  of  the  leg.  A  beam  of  light  falhng  on  the 
eye  calls  forth  movements  involving  contractions  of  the  intrinsic  and  ex- 
trinsic ocular  muscles.  The  same  beam  of  Mght  falling  on  the  skin  is  devoid 
of  effect  unless  it  is  so  strong  as  to  burn  the  skin,  when  a  reflex  is  excited 
similar  to  that  evoked  by  a  nocuous  stimulus.  As  our  study  of  the  adaptive 
nerve  mechanisms  becomes  more  detailed,  and  especially  when  we  take 
into  account  the  activities  of  the  association  centres  in  the  cortex,  it  becomes 
more  and  more  difl&cult  to  follow  the  chain  of  processes  which  lead  to  any 
given  reaction  ;  in  order  to  advance  further  in  our  knowledge  of  the  activity 
of  the  receptor  organs,  we  have  frankly  to  abandon  the  objective  method 
which  has  served  us  in  the  study  of  all  the  other  functions  of  the  body,  and 
appeal  to  our  own  consciousness  for  information  as  to  the  effects  of  their 
excitation.  Each  one  of  us  is  aware  that  stimulation  of  an  afferent  nerve 
may  cause  a  change  in  consciousness  which  we  denote  as  a  sensation,  and  we 
attribute  to  other  living  organisms,  presenting  similar  reactions  to  ourselves, 
similar  changes  in  consciousness  in  consequence  of  like  stimuh. 

Certain  sensations  differ  one  from  the  other  to  such  an  extent  that  com- 
parison among  them  becomes  impossible.  Thus  in  the  skin  and  underlying 
parts  we  have,  as  a  result  of  stimulation,  sensations  of  touch  and  pressure, 
sensations  of  heat  and  of  cold,  and  sensations  of  pain.     The  contact  of 

478 


RELATION  OF  SENSATION  TO  STIMULUS  479 

certain  dissolved  substances  with  the  end-organs  of  the  gustatory  nerves 
excites  in  us  a  sensation  of  taste.  Other  substances  diffused  in  the  air 
and  carried  by  it  to  the  olfactory  terminations  give  as  sensations  of  smell. 
Vibrations  of  a  certain  frequency,  transmitted  by  the  air  and  by  the  auditory 
ossicles  to  the  endings  of  the  auditory  nerve,  produce  sensations  of  sound, 
while  Ught  falling  on  the  retina  evokes  visual  sensations. 

Besides  these  sensations  resulting  from  stimulation  of  the  exteroceptive 
system  of  nerves,  we  are  aware  of  the  existence  of  a  number  of  organic 
sensations — some  derived  from  the  viscera  (enteroceptive),  others  caused 
by  stimulation  of  the  proprioceptive  system.  As  examples  of  the  latter  we 
may  mention  the  muscular  sense,  by  which  we  judge  of  the  amount  of  tension 
exerted  by  a  contracting  muscle  ;  the  sense  of  position  of  the  hmbs  ;  and  the 
sense  of  position  of  the  head,  resulting  from  stimulation  of  the  labyrinthine 
organ. 

How  the  physiological  excitatory  process  in  nerve  fibres,  \\dth  its  concomi- 
tant chemical  and  electrical  phenomena,  is  able  on  arrival  at  the  brain  to 
excite  a  conscious  sensation  we  are  unable  to  decide,  or  even  to  discuss,  since 
we  are  dealing  here  with  processes  of  two  different  orders.  We  should  not 
arrive  any  nearer  to  the  solution  of  this  riddle  if  we  were  able  to  follow  out 
the  whole  of  the  events  occurring  in  the  body  as  the  result  of  the  application 
of  any  given  stimulus  to  its  surface.  We  might  under  these  circumstances 
be  able  to  predict  with  certainty  the  behaviour  of  any  animal,  if  we  knew  its 
past  history  and  the  comparative  resistance  of  every  path  in  its  central 
nervous  system  which  might  possibly  be  traversed  by  any  given  nerve 
impulse.  Such  knowledge  would  be  purely  objective  and  could  not  be  used 
to  explain  the  '  epi-phenomenon '  of  consciousness.  One  might  in  fact 
imagine  a  machine  which  would  react  hke  a  Uving  animal,  but  would  be 
perfectly  devoid  of  self-consciousness,  and  we  should  be  unable  in  such  a  case 
to  decide  whether  consciousness  were  or  were  not  present.  Each  one  of  us 
only  knows  consciousness  as  it  exists  in  himself. 

Before  therefore  we  can  employ  our  conscious  sensations  as  a  means  of 
throwing  light  on  the  conditions  of  action  of  the  receptor  organs  of  the  bodv. 
we  must  have  some  idea  as  to  how  far  our  sensations  correspond  to  the  stimuli. 
i.e.  the  physical  events  by  which  they  have  been  evoked.  Appeal  to  our 
own  experience  shows  the  existence  of  two  kinds  of  difference  between 
various  sensations.  The  greatest  difference  is  found  between  those  sensa- 
tions which  are  normally  evoked  by  different  sense-organs.  Thus  we  are  all 
aware  of  the  meaning  attached  to  such  qualities  or  such  sensations  as  sweet, 
red,  hard,  high-pitched  (of  sound),  &c.  It  would  be  absolutely  impossible 
to  compare  these  sensations  among  themselves.  We  cannot  say,  for  instance, 
that  this  sound  is  louder  than  that  colour  is  red.  Such  fundamental  differing 
quaUties  of  sense  are  spoken  of  as  the  modality  of  the  sensation. 

On  the  other  hand,  within  the  sensation  evoked  by  any  one  sense-organ 
we  find  differences  of  quality  which  are  more  comparable  among  themselves. 
Thus  we  can  compare  the  pitch  of  various  sounds,  or  the  colour  of  various 
objects  seen  with  the  eye.     We  can  even  say  that  the  bitter  taste  of  any 


480  PHYSIOLOGY 

substance  is  more  marked  than  the  sweet  taste  of  another.  The  question 
arises  how  far  these  differences  in  sensation  correspond  to  and  are  a  measure 
of  differences  in  the  physical  events  by  which  they  have  been  evoked.  A 
very  little  consideration  suffices  to  show  that  there  is  no  resemblance  between 
a  sensation  and  the  stimulus,  and  that  one  and  the  same  physical  event 
applied  to  different  sense-organs  will  evoke  absolutely  distinct  sensations ; 
while  different  modes  of  stimuh  apphed  to  one  sense-organ  will  always 
evoke  the  same  sensation.  Thus  if  light  falls  on  the  retina  it  causes  a 
sensation  of  light.  If  the  same  radiant  energy,  consisting  of  transverse 
vibrations  in  the  ether,  be  allowed  to  fall  on  the  skin,  it  either  produces  no 
sensation  at  all,  or,  if  concentrated  by  means  of  a  burning-glass,  may  give 
rise  to  a  sensation  of  warmth,  heat,  or  pain.  If  we  take  a  tuning-fork  which 
is  vibrating  100  times  per  second  and  apply  it  to  the  surface  of  the  skin,  we 
get  simply  a  sensation  of  vibration,  i.e.  a  series  of  tactile  impressions  repeated 
at  rapid  intervals.  If  the  same  tuning-fork  be  appHed  to  the  head,  its 
vibrations  are  imparted  to  the  bones  of  the  skull  and  thence  to  the  auditory 
nerve-endings  and  arouse  in  our  consciousness  a  tone-sensation  of  a  certain 
note.  The  same  thing  happens  if  the  vibrations  of  the  tuning-fork  are 
conducted  by  the  ear  to  the  auditory  nerve- endings  in  the  ordinary  way 
through  the  external  and  middle  ear.  On  the  other  hand,  a  sensation  of  light 
may  be  aroused  not  only  by  the  incidence  of  radiant  energy  of  a  certain 
wave  length  on  the  retina,  but  also  by  electrical  or  mechanical  stimulation 
of  the  retina.  If  the  eye  be  turned  inwards  and  the  finger  be  pressed  on 
the  eye  through  the  outer  canthus  of  the  lids,  a  sensation  of  hght  is  aroused 
and  we  see  a  coloured  circle  which  we  refer  to  some  spot  lying  to  the  nasal 
side  of  the  eye  stimulated.  The  character  of  the  sensation  bears  therefore  no 
resemblance  to  the  physical  events  by  which  the  sensation  is  evoked,  but 
depends  entirely  on  the  nature  of  the  sense-organ  which  is  stimulated. 
A  sensation  of  hght  may  be  produced  by  any  stimulation  of  the  retina, 
or  of  the  optic  nerve,  or  of  the  terminations  of  the  optic  nerve  in  the  brain. 
In  the  same  way  stimulation  of  an  auditory  nerve  or  its  intracranial  endings 
gives  rise  to  sensations  of  sound. 

Where  the  question  has  been  investigated  it  has  not  been  found  possible 
to  evoke  different  quahties  of  sensation  by  different  modes  of  stimulation 
of  nerve  fibres,  and  it  has  therefore  been  concluded  that  the  quality  of  any 
sensation  depends  simply  and  solely  on  the  termination  of  these  nerves 
in  the  central  nervous  system,  and  that  where  sensations  of  different  quahty 
are  produced  there  must  be  also  difference  of  nerve  fibres.  This  idea  was 
formulated  by  Miiller,  and  is  often  alluded  to  as  Miiller's  '  law  of  specific 
irritabihty.'  The  law  states  that  every  sensory  nerve  reacts  to  one  form 
of  stimulus  and  gives  rise  to  one  form  of  sensation  only,  though  if  under 
abnormal  conditions  it  be  excited  by  other  forms  of  stimuh,  the  sensation 
evoked  will  be  the  same. 

Although  the  different  forms  of  sensation  must  be  regarded  as  dependent 
on  the  integrity  of  the  brain,  and  of  its  connections  with  the  peripheral  sense- 
organs,  sensations  are  not  referred  to  the  brain,  but  are  localised  as  proceed- 


RELATION  OF  SENSATION  TO  STIMULUS  481 

ing  from  some  part  of  the  body  or  from  some  region  outside  of  the  body. 
Thus  the  sensation  of  taste  is  always  locaHsed  in  the  mouth  ;  sensation  of 
touch  at  the  skin  or  surface  of  the  body ;  while  the  sensations  of  hearing 
and  of  sight  are  '  projected,'  i.e.  are  interpreted  as  coming  from  the  en- 
vironment outside  ourselves.  Even  the  organic  sensations  of  posture  or 
fatigue  are  referred  to  the  peripheral  reacting  parts  of  the  body  and  not  to 
the  central  nervous  system.  A  sensation  therefore  cannot  be  interpreted  as 
a  reproduction  of  external  events,  but  as  a  symbol  of  these  events  evoked  by 
stimulation  of  the  sense-organs  of  the  body. 

It  is  indeed  impossible  by  a  purely  intuitive  study  of  sensations  to  arrive 
at  any  correct  idea  of  their  origin  or  of  the  factors  concerned  in  their  produc- 
tion. No  sensation  is  the  immediate  and  sole  product  of  a  stimulus  appUed 
to  the  peripheral  end  of  a  nerve  fibre,  but  the  simplest  sensation  involves 
a  judgment,  i.e.  complex  neural  activities  which  are  the  resultant  of  innumer- 
able past  and  present  streams  of  nervous  impulses  aroused  by  peripheral 
events  and  poured  into  the  central  nervous  system.  It  is  important  therefore 
not  to  regard  a  sensation  as  in  any  way  constituting  an  elementary  unit,  by 
the  aggregation  of  a  number  of  which  a  conscious  state  is  produced.  As  we 
have  seen,  the  primitive  function  of  the  whole  nervous  system  is  reaction. 
The  neural  life  of  an  animal  is  composed  of  a  series  of  reactions,  some  simple, 
some  complex,  and  becoming  ever  more  complicated  as  we  ascend  the  animal 
scale.  The  first  reactions  of  a  baby,  for  instance,  will  be  those  by  which  it 
procures  nourishment  and  satisfies  a  need.  The  earhest  event  in  its  dawning 
consciousness  will  be,  not  a  sensation  of  sweetness  or  of  colour,  but  that  of  a 
thinij  which  can  satisfy  its  needs.  It  will  have  had  to  try  many  gustatory 
experiments  before,  out  of  the  sum  of  its  material  experiences,  it  will  be  able 
to  choose  a  number  of  hke  factors  which  can  be  grouped  together  as  '  sweet.' 
Judgment  of  quahty  of  sensation  involves  a  power  of  abstraction  and  of 
classifying  similar  elements  in  different  neural  events  or  reactions  and  the 
referring  of  these  elements  to  the  external  world.  It  is  very  difficult,  how- 
ever, to  divest  ourselves  of  the  mental  standpoint  reached  as  the  result  of 
many  years'  continual  trials,  successes  and  failures,  and  constant  care  has 
to  be  exercised  if  we  are  not  to  fall  into  the  common  conception  of  the  ego, 
the  personality,  or  soul,  as  a  sort  of  sentient  god  sitting  somewhere  in  the 
brain,  or,  as  Descartes  suggested,  in  the  pineal  gland,  and  receiving  by 
means  of  one  part  or  other  of  his  servile  material  brain  a  blue  sensation 
from  the  eyes,  or  an  auditory  impression,  or  a  tactile  impression,  and  then, 
if  he  feels  so  inchned,  pressing  the  stop  in  a  pyramida  cell  to  let  out  a  volun- 
tary motor  response.  An  elementary  miit  in  psychical  life,  as  in  neural 
hfe,  must  be  a  complete  reaction.  It  is  from  the  reaction  and  not  from 
the  sensation  that  a  constructive  psychology  will  have  to  be  built  up. 
.  Although  any  given  sensation  may  be  jjroduced  by  many  forms  of 
stimulation  of  the  sense-organ,  under  normal  circumstances  each  sense-organ 
is  so  arranged  and  protected  that  it  is  only  stinnilated  by  one  kind  of  physical 
process,  i.e.  by  the  one  for  which  its  liminal  or  threshold  excitability  is  at  a 
minimum.     Thus  the  retina,  though  it  may  be  stimulated  mechanically 


482  PHYSIOLOGY 

or  electrically,  is  in  the  normal  individual  very  thoroughly  protected  from 
the  possibiHty  of  such  excitation,  so  that  all  impulses  arising  in  the  retina 
may  be  almost  certainly  referred  to  changes  in  the  light- waves  which  fall  on 
the  eye,  and  by  means  of  the  dioptric  mechanism  of  this  organ  are  thrown  in 
a  distinct  pattern  upon  the  retina.  Although  the  sensation  is  not  a  repro- 
duction of  the  stimulus,  it  is  a  symbol  of  the  stimulus,  and  can  be  used  to 
inform  us  of  events  occurring  in  the  world  around.  Like  stimuli,  falhng  on 
the  same  end- organ,  always  evoke  like  sensations,  other  conditions  being 
equal.  An  orderly  sequence  of  sensations  may  therefore  be  interpreted  as 
indicating  a  corresponding  orderly  sequence  of  physical  occurrences  in  the 
world  around  us. 


THE  QUANTITATIVE  RELATIONSHIPS  BETWEEN  STIMULUS 
AND  SENSATION 

Since  our  sensations  are  merely  symbols  of  the  physical  conditions  which 
give  rise  to  them,  it  is  important  to  inquire  how  far  they  correspond  quanti- 
tatively to  differences  in  the  energy  of  the  afferent  stimuli,  i.e.  how  alterations 
in  the  strength  of  stimulus  will  affect  the  intensity  of  the  resulting  sensation. 
Whatever  form  of  stimulus  be  appHed  and  whatever  sense-organs  be  affected, 
a  certain  minimum  intensity  of  stimulus  is  necessary  for  it  to  be  effective, 
i.e.  to  produce  a  minimum  sensation.  This  strength,  which  varies  with 
different  sense-organs,  is  spoken  of  as  the  '  liminal  intensity,'  or  '  threshold 
value  '  of  stimulus  or  sensation  respectively.  As  the  strength  of  the  stimulus 
is  increased  above  this  minimal  amount  the  resulting  sensation  also  increases. 
The  change  in  intensity  of  sensation  is  not,  however,  indefinite.  When 
the  stimulus  is  increased  to  a  certain  amount  the  resultant  sensation  becomes 
maximal,  and  a  further  increase  in  the  stimulus  evokes  no  further  increase  in 
sensation.  In  fact  fatigue  of  the  sense-organs  or  recipient  centres  of  the 
brain  rapidly  sets  in,  so  that  the  sensation  diminishes  even  with  increasing 
strength  of  stimulus.  In  each  sense-organ  we  can  measure  the  amount  of 
energy  which  must  be  applied  to  it  in  order  to  evoke  a  minimum  sensation. 
This  figure  varies  considerably  with  the  physiological  condition  of  the  animal. 
In  deahng  with  reflexes  we  have  seen  that  the  motor  result  of  stimulation  of  a 
receptor  organ  varies  in  the  same  manner.  Thus  a  minimal  stimulus  is  more 
effective  if  repeated  a  few  times  at  definite  intervals  (summation  of  stimulus)  : 
the  stimulus  which  is  subminimal  may  become  minimal  and  effective  as  a 
result  of  repetition. 

Another  factor  which  intervenes  is  that  known  as  '  adaptation  ' — a 
process  associated  to  a  certain  extent  with  the  phenomenon  of  fatigue. 
Adaptation  is  best  studied  in  the  case  of  the  eye.  Here  the  dark-adapted 
eye,  i.e.  one  that  has  been  kept  from  light  for  half  an  hour,  will  react,  and  give 
a  visual  sensation,  to  a  strength  of  stimulus  which  is  only  one-fiftieth  of  the 
minimal  stimulus  required  to  evoke  sensation  in  the  eye  that  has  been 
lately  exposed  to  light. 

Another  phenomenon  which  may  alter  the  strength  of  the  liminal  intensity 


RELATION  OF  SENSATION  TO  STIMULUS 


483 


of  stimulus  is  that  known  as  '  contrast.'  A  finger  plunged  into  mercury 
feels  a  ring  of  constriction  at  the  level  of  the  surface  of  the  mercury,  i.e. 
where  there  is  a  contrast  between  the  pressure  of  the  mercury  and  the 
absence  of  pressure  as  the  finger  emerges  into  the  air. 

The  strength  of  the  effective  stimulus  depends  also  on  the  number  of 
nerve-endings  simultaneously  excited.  Thus  when  dealing  with  tactile 
sensations,  or  sensations  of  pressure,  in  determining  the  minimal  stimuliLS 
we  must  take  into  account  the  area  stimulated,  and  we  express  the  stimulus, 
just  sufficient  to  produce  a  threshold  sensation,  as  '  weight  per  square  milli- 
metre of  surface.'  Moreover  the  rapid  '  fatigabihty '  or  adaptation  of  all 
sense-organs  makes  the  rate  at  which  the  stimulus  is  applied  of  considerable 
importance.  Thus  when  weight  was  applied  to  the  skin  of  the  ball  of  the 
thumb  at  the  rate  of  0-75  gramme  per  second  over  a  surface  of  21-2  scj.  mm., 
the  minimum  load  necessary  to  evoke  a  distinct  sensation  was  2-5  grammes. 
When,  however,  the  rate  of  application  of  the  weight  was  increased  to  5 
grammes  per  second,  distinct  sensation  was  produced  with  a  load  of  0-25 
gramme.  It  is  evident  that  the  larger  the  area  of  the  skin  stimulated 
the  greater  will  be  the  minimal  weight  required,  since  this  has  to  be  dis- 
tributed over  all  the  nerve-endings  contained  in  the  area  of  skin  which  is 
subjected  to  pressure,  and  the  larger  the  area  the  smaller  will  be  the  stimulus 
apphed  to  each  nerve-ending.  The  following  figures  were  obtained  by 
von  Frey  on  different  regions  of  the  skin  : 


stimulated  surface  21-2  mm. 2 

Volar  side  of  wrist  (Subject  K) 
Ball  of  thumb  (Subject  K) 
Volar  side  of  wTist  (Subject  F) 

Stimulated  surface  3  5  mm. 2 

Ball  of  thumb  (Subject  F) 
Tip  of  finger  (Subject  F)  . 
Volar  sid;-  of  wrist  (Subject  F) 


Rate  of  loading  17  grm.  per  second. 
Threshold  value  of  stimulus  per  mm.- 

0-024  -  0-038  grm. 

.     >0-lS9  -  0-039    „ 

.     >0-236  -  0-055    „ 

Rate  of  loading  3  grm.  per  second 
Threshold  value  of  stimulus. 

0-200  -  0-045  grm. 

0-170  -  0-028    „ 

0-640  -  0-028    „ 


It  will  be  noticed  that  when  the  excited  surface  is  small  much  gi'eater 
variations  are  found  from  spot  to  spot  in  the  size  of  the  minimum  stimulus. 
This  is  probably  connected  with  the  fact  that  the  sense-organs  for  pressure  are 
distributed  in  points  or  spots  over  the  surface  of  the  skin,  so  that  when  the 
stimulated  surface  is  small  the  threshold  value  of  the  stimulus  will  be  deter- 
mined by  the  number  of  the  tactile  spots  which  are  included  in  the  stimulated 
area.  The  minimal  effective  stimuli  in  the  case  of  the  other  senses  have  been 
determined  as  follows  : 

(a)  HEARING.  A  musical  tone  can  be  heard  when  the  variations  of 
pressure  in  the  air  ammount  to  -00000059  mm.  Hg.  with  an  amplitude  of 
vibrations  of  •(X)(X)()006G  mm.  It  has  been  calculated  that  the  intensity 
of  the  work  performed  on  the  drum  of  the  ear  by  such  a  minimal  tone  repre- 
sents an  average  of  5*1  x  10  "'•''  orgs.  In  the  case  of  noise  the  amount  of 
energy  required  to  produce  a  inininuuu  sensation  is  still  smaller.     A  distinct 


484  PHYSIOLOGY 

sound  was  heard  when  a  weight  6-7  milUgrammes  was  allowed  to  fall  a 
distance  of  1-2  mm.  on  to  an  iron  plate  at  a  distance  of  500  mm. 

(6)  VISION.  The  minimum  intensity  of  light  necessary  to  arouse  sensa- 
tion in  a  dark-adapted  eye  is,  according  to  Aubert,  equal  to  about  one 
three-hundredth  of  the  intensity  of  the  hght  reflected  from  a  piece  of  white 
paper  which  is  being  lit  by  the  hght  of  the  full  moon.  The  amount  of 
energy  involved  in  such  a  stimulus  is  much  smaller  even  than  that  deter- 
mining a  sensation  of  touch  or  hearing. 

WEBER'S  LAW 

It  is  an  interesting  question  how  far  the  strength  of  sensation  may  be 
regarded  as  an  index  to  the  strength  of  stimulus.  Although  it  is  easy  to 
measure  in  absolute  terms  the  intensity  of  a  stimulus,  i.e.  of  a  purely  physical 
process,  there  is  no  means  by  which  we  can  express  in  absolute  measure 
the  strength  of  a  sensation.  We  cannot  even  compare  the  strengths  of  two 
sensations  differing  in  quality  or  modahty ;  and  although  we  can  say  that 
such  and  such  a  hght  is  stronger  than  another  Hght,  it  is  impossible  to  say 
that  the  sensation  resulting  from  the  stronger  is  two,  three,  or  more  times 
that  of  the  weaker.  In  measuring  the  effect  on  sensation  of  increasing  the 
stimulus  we  are  therefore  reduced  to  using  the  smallest  appreciable  increase  of 
sensation  as  our  unit  of  sensation.  The  question  as  to  the  relation  between 
the  intensity  of  stimulus  and  the  intensity  of  sensation  resolves  itself  into  an 
inquiry  as  to  what  increase  in  a  given  stimulus  is  necessary  in  order  that  it 
may  evoke  an  appreciable  increase  in  sensation.  Weber's  law  states  that 
the  increase  of  stimulus  which  is  necessary  to  produce  an  appreciable 
increase  in  sensation  must  always  bear  the  same  ratio  to  the  whole  stimulus. 
Thus  if  we  found  that  we  could  just  distinguish  the  difference  between  a 
weight  of  10  oz.  and  a  weight  of  9  oz.,  it  would  not  be  sufficient  to  add  one 
ounce  to  a  weight  of  10  lb.  in  order  to  produce  a  distinct  difference  in  sensa- 
tion. In  the  latter  case  we  should  not  be  able  to  appreciate  any  difference 
until  we  had  added  a  pound,  i.e.  one-tenth  of  the  whole  stimulus  to  the 
weight.  We  can  distinguish  between  10  oz.  and  11  oz.,  or  between  10  lb. 
and  11  lb.,  but  not  between  10  lb.  and  10  lb  1  oz. 

Several  methods  have  been  proposed  for  testing  the  limits  of  the 
apphcabihty  of  this  law.     Of  these  the  most  important  are  : 

(1)  The  method  of  minimal  diflerence. 

(2)  The  method  of  average  error. 

In  the  first  method  we  find  by  trial  how  much  a  given  stimulus  must  be 
increased  in  order  to  evoke  an  appreciable  increase  of  sensation,  and  this 
determination  is  made  for  a  number  of  stimuli  of  different  intensity.  In  the 
second  method  it  is  sought  to  find  a  strength  of  stimulus  which  is  just  equal 
to  another  stimulus  of  given  intensity.  It  will  be  found  that  errors  will  be 
made  on  both  sides,  and  the  average  error  is  taken  as  representing  the 
minimum  difference,  which  is  just  sufficient  to  cause  a  distinct  difference  of 
sensation. 

In  all  sense-organs  Weber's  law  is  only  apphcable  between  hmits,  which 


RELATION  OF  SENSATION  TO  STIMULUS  485 

vary  with  each  sense-organ,  and  it  does  not  hold  either  for  very  weak  or  for 
very  strong  stimuli.  Within  these  hmits  the  ratio  which  an  increase  of 
stimulus  must  bear  to  the  whole  stimulus  to  produce  an  increase  of  sensation 
may  be  given  approximately  as  follows  for  the  different  sense-organs  : 

When  weights  are  placed  on  corresponding  points  of  two  sides  of  the 
body,  e.cj.  on  the  two  hands,  we  can  appreciate  differences  of  about  one- third ; 
if  the  contrast  be  successive,  i.e.  if  the  weights  be  placed  on  the  same  spot 
in  succession,  we  can  appreciate  differences  between  one-fourteenth  and 
one-thirtieth.  The  range  over  which  this  amount  of  accuracy  is  attained  ex- 
tends from  50  to  1000  grammes.  In  judging  of  weights  with  the  help  of 
movement  (the  method  one  ordinarily  adopts)  the  limit  of  accuracy  is  about 
one-twentieth  ;  for  sounds  the  appreciation  of  difference  amounts  to  about 
one- ninth.  The  organ  which  is  most  susceptible  to  shght  changes  of  intensity 
is  the  eye  ;  by  this  organ  we  can  appreciate  diff'erences  of  one  one-hundredth 
to  one  one-hundred-and-twentieth  in  the  total  illumination. 

FECHNER'S  LAW.  Fechner  has  endeavoured  to  give  a  mathematical  expression 
to  the  facts  described  under  Weber's  law.  According  to  Weber  the  proportion  between 
the  increase  of  stimulus  necessary  to  cause  increase  of  sensation  and  the  whole  stimulus 
is  a  constant  for  all  intensities  of  excitation.     Thus  if  C  is  a  constant 

R 

where  k  represents  the  smallest  appreciable  increase  of  sensation  evoked  by  the  minimal 
increase  of  stimulus,  R  is  the  stimulus,  and  AR  is  the  minimal  increase  of  stimulus. 

If  the  same  relation  may  be  allowed  to  hold  for  infinitesimally  small  differences  of 
sensation  and  infinitely  small  differences  of  stimulus,  this  formula  may  be  expressed 
by  the  equation  : 

dE=C^ 
R 

By  integration  we  obtain  the  expression  :  . 

E  =  C  log.  nat.  R. 

i.e.  the  sensation  is  proportional  to  the  natural  logarithm  of  the  stimulus,  which  is 
Fechner's  psycho-physical  law. 

In  view  of  the  fact,  however,  that  Weber's  law  only  holds  good  between  certain 
limits,  not  much  practical  value  can  be  attached  to  such  a  matliematical  expression. 
Moreover  Fechner's  calculation  is  based  on  the  unprovable  and  unjustifiable  assi  nip- 
tion  that,  within  the  limits  of  applicability  of  Weber's  law,  the  smallest  appreciable 
increase  in  sensation  is  always  the  same,  i.e.  that  the  increased  sensation  which  is  evoked 
by  the  addition  of  6  grammes  to  a  weight  of  100  grammes  is  identical  with  the  increased 
sensation  called  forth  by  adding  60  grammes  to  an  initial  weight  of  1000  gra,mnies. 
Such  an  assumption  does  not,  as  a  matter  of  fact,  agree  with  om-  own  exiierienee  ;  and 
it  is  probably  premature  here,  as  in  many  other  departments  of  biology,  to  attempt 
to  include  the  complex  of  variable  phenomena  presented  by  animal  function^  within 
the  Procrustean  bed  of  a  mathematical  foriiiula. 


SECTION  II 
CUTANEOUS  SENSATIONS 

The  skin,  being  the  outermost  layer  of  the  body,  represents  the  tissue  or 
organ  by  which  the  organism  is  brought  into  relationship  with  its  environ- 
ment. In  the  widest  sense  of  the  term  the  skin  is  protective.  This  function 
it  discharges  by  virtue  not  only  of  its  physical  properties  but  also  of  its  rich 
endowment  with  sense-organs,  by  means  of  which  the  intracorporeal  events 
can  be  correlated  with  those  occurring  outside  and  immediately  affecting  the 
organism. 

We  are  accustomed  to  distinguish  several  qualities  of  sensation  among 
those  having  their  origin  in  the  skin,  the  chief  of  which  are  the  sense  of  touch, 
including  that  of  discrimination,  the  sense  of  pain  and  the  sense  of  tempera- 
ture. The  very  different  quahties  of  sensation  included  under  these  three 
classes  suggest  that  there  may  be  a  special  mechanism,  or  class  of  mechanism, 
for  each  sense,  and  a  careful  investigation  of  the  sensory  quahties  of  the 
skin  surface  bears  out  this  idea.  Isolated  stimulation  of  minute  areas  on  the 
skin  does  not  excite  all  the  sensations  together,  but  only  a  sense  of  touch  or 
of  pain,  or  a  sense  of  cold  or  warmth.  We  are  therefore  justified  in  deahng 
with  each  of  these  sensations  separately. 

THE  TEMPERATURE  SENSE.  By  means  of  the  skin  we  can  appreciate 
that  a  body  coming  in  contact  with  the  skin  is  either  cold  or  warm.  If  the 
body  is  at  the  same  temperature  as  the  skin,  as  a  rule  no  sensation  of  tempera- 
ture is  excited.  It  was  formerly  thought  that  the  sensations  both  of  heat 
and  cold  were  determined  by  the  excitation  of  one  and  the  same  end-organ. 
Warming  of  this  end-organ  would  produce  a  sensation  of  warmth,  while  a 
diminution  of  its  temperature  would  produce  the  sensation  of  cold.  Careful 
investigations  by  Blix  and  Donaldson  of  the  distribution  of  the  temperature 
sense  has  shown  that  this  opinion  cannot  be  maintained.  If  a  small  surface 
warmed  to  a  few  degrees  above  the  temperature  of  the  skin  be  moved  ovei: 
any  part  of  the  surface  of  the  body,  e.g.  the  back  of  the  hand,  it  is  found  that 
the  warmth  of  the  instrument  is  not  appreciable  equally  at  all  parts  of  the 
surface  of  the  skin.  At  some  points  the  sensation  of  warmth  will  be  very 
pronounced,  but  between  these  points  the  sensation  of  warmth  may  be 
entirely  wanting  and  the  instrument  may  be  judged  to  be  of  the  same  tem- 
perature as  the  hand  itself.  In  this  way  a  series  of  '  warm  points  '  may  be 
mapped  out.  On  now  cooling  the  instrument  a  few  degrees  below  the 
temperature  of  the  surface  of  the  body  and  then  moving  it  over  the  surface  in 

486 


CUTANEOUS  SENSATIONS 


487 


the  same  way,  it  will  be  found  again  that  the  coolness  of  the  instrument  is 
only  appreciated  at  certain  points  which  can  be  regarded  as  '  cold  points  '  and 
as  containing  the  nerve-endings  by  the  excitation  of  which  the  sensation  of 
cold  is  produced.  If  the  warm  points  be  pricked  out  in  red  ink  and  the 
cold  points  in  blue  ink  it  will  be  seen  that  they  do  not  in  any  way  correspond. 

A  convenient  instrument  for  this  purpose  is  the  one  invented  by  Miescher,  con- 
sisting of  two  tubes  cemented  together  and  communicating  at  a  small  flattened  extremity, 
which  is  applied  to  the  surface  of  the  skin  ;  through  the  tubes  water  can  be  led  at  any 
desired  temperature,  which  is  read  off  by  a  thermometer  placed  within  the  tube.  Having 
mapped  out  the  warm  spots  it  may  be  shown  that  they  are  excitable  by  means  of 
mechanical  or  electrical  stimuli  and  that  the  sensation  produced  is  the  same  as  if  they 
had  been  excited  by  their  adequate  stimulus,  viz.  rise  or  fall  of  temperature. 


Cold  spots.  Heat  spots. 

Fig.  242.     Heat  and  cold  spots  on  part  of  pahn  of  right  hand. 
The  sensitive  points  are  shaded,  the  black  being  more  sensitive  than  the  lined, 
and  these  than  the  dotted  parts.     The  unshaded  areas  correspond  to  those  parts 
where  no  special  sensation  was  evoked.     (Goldscheider.) 

The  mapping  out  of  the  spots  is  rendered  difficult  by  the  irradiation 
of  the  sensation  produced  so  that  it  is  difficult  to  refer  the  sensation  of 
warmth  or  cold  definitely  to  the  point  stimulated.  An  investigation  of  the 
topography  of  these  warm  and  cold  spots  shows  that  the  apparatus  for  the 
appreciation  of  cold  is  much  more  extensively  distributed  over  the  body  than 
that  for  the  appreciation  of  warmth,  as  is  evidenced  from  the  diagram 
(Fig.  242)  giving  the  topographic  distribution  of  the  cold  and  warm  sense- 
organs  on  the  palm  of  the  hand.  The  temperature  sense  is  best  marked  in 
the  following  regions  of  the  body  :  the  nipples,  chest,  nose,  the  anterior 
surface  of  the  upper  arm  and  the  anterior  surface  of  the  fore-arm,  and  the 
surface  of  the  abdomen.  It  is  much  less  marked  on  the  exposed  parts  of  the 
body,  such  as  the  face  and  hands,  and  is  but  slight  in  the  mucous  membranes. 
Thus  it  is  possible  to  drink  hot  fluid,  such  as  tea,  at  a  temperature  which 
would  be  painful  to  the  hand,  and  still  more  to  any  other  part  of  the  body. 
The  scalp  is  also  very  insensitive  to  changes  of  temperature.  The  acuteness 
of  the  temperature  sense  varies  considerably  with  the  condition  of  the  skin 
and  with  the  previous  stimulation  of  the  sense-organs.  The  sense  is  most 
acute  at  about  ordinary  skin  temperature,  i.e.  between  27°  and  32°  C.  At 
this  temperature  the  skin  can  appreciate  a  difference  of  1°  C.  When  the 
skin  is  very  cold  or  very  hot  the  temperature  sense  is  not  nearly  so  delicate. 


488  PHYSIOLOGY 

This  sense  presents  the  phenomenon  of  adaptation  in  a  marked  degree. 
It  is  a  famihar  experience  that  on  coming  from  the  external  air  on  a  cold  day 
into  a  warm  room  a  sensation  of  warmth  is  experienced  all  over  the  body. 
In  a  few  minutes  this  sensation  wears  ofi.  On  now  leaving  the  room  to  go 
outside  again,  the  sensation  of  cold  is  at  once  appreciated,  to  disappear  in  its 
turn  after  a  few  minutes.  The  effect  of  adaptation  is  still  better  shown  by 
the  experiment  of  taking  three  basins  of  water  a,  h,  and  c  :  a  contains  cold 
water,  h  tepid  water,  c  hot  water.  The  left  hand  is  immersed  in  the  cold 
water  and  the  right  hand  in  the  hot  water  for  a  few  minutes.  On  now  placing 
both  hands  into  the  basin  of  tepid  water  it  feels  hot  to  the  left  hand  and  cold 
to  the  right  hand.  Such  experiences  as  this  led  Weber  to  the  conclusion 
that  the  essential  stimulus  for  the  temperature  sense  was  not  the  actual 
temperature  to  which  the  sense-organs  were  subjected,  but  the  fact  of  a 
change  of  temperature.  He  imagined  that  while  the  temperature  sense- 
organs  were  being  warmed  a  sensation  of  warmth  was  produced,  and  when 
their  temperature  was  being  lowered,  a  sensation  of  cold.  Such  a  theory 
would  not,  however,  account  for  the  fact  that,  above  a  certain  tempera- 
ture, water  may  feel  warm  and  the  feehng  may  continue  so  long  as  the  skin 
continues  to  be  stimulated.  On  a  cold  day  the  air  may  feel  cold  to  the  face 
and  the  feeling  may  last  the  whole  time  that  the  face  is  exposed.  Moreover 
we  have  in  the  temperature  sense  conditions  which  remind  one  of  the  after 
images  which  occur  in  the  eye  and  v/hich  will  form  the  subject  of  a  later 
section.  If  a  penny  be  pressed  on  the  forehead  and  then  removed  the  sensa- 
tion of  cold  lasts  some  httle  time  after  the  penny  has  been  removed.  In  this 
case  a  sensation  of  cold  is  produced  although  the  end-organs  are  being 
gradually  warmed  up  after  the  removal  of  the  penny.  In  order  to  account 
for  these  facts  Hering,  at  a  time  when  the  differentiation  of  hot  and  cold 
spots  had  not  yet  been  effected,  suggested  that  the  temperature  sense-organs 
could  be  regarded  as  having  a  zero-point  at  which  no  sensation  was  produced. 
If  their  temperature  was  raised  above  this  point  a  sensation  of  warmth  was 
produced  and  vice  versa.  The  zero-point,  however,  was  not  a  fixed  one,  but 
could  move  upwards  to  a  certain  extent  on  prolonged  exposure  to  high 
temperature,  or  downwards  on  prolonged  exposure  to  a  low  temperature. 
In  the  light  of  the  researches  of  Blix  and  Goldscheider  we  should  have  to 
apply  Hering's  theory  of  a  zero-point  to  each  of  the  temperature  end-organs 
separately. 

A  cold  pencil  passed  over  a  warm  spot  evokes  no  sensation  whatsoever. 
If,  however,  a  pencil  considerably  warmer  than  the  skin  be  passed  over  a  cold 
spot  this  may  be  excited,  so  that  the  paradoxical  result  is  produced  of  a 
sensation  of  cold  as  the  result  of  stimulation  with  a  warm  body.  It  is  a 
familiar  fact  that  the  immediate  effect  of  entering  a  hot  bath  is  very  much 
the  same  as  that  of  entering  a  cold  bath,  viz.  a  rise  of  blood  pressure  and 
contraction  of  the  unstriated  muscles  of  the  skin  and  hair  follicles  with  the 
production  of  '  goose  skin.'  It  has  been  suggested  that  the  distinctive 
quality  of  a  sensation  of  hot  as  compared  with  that  of  warm  is  due  to  the 
simultaneous  stimulation  of  warm  spots  and  cold  spots.     When  testing  the 


CUTANEOUS  SENSATIONS  489 

distribution  of  the  temperature  sense  it  is  found  that  the  sense  of  cold  is 
evoked  more  promptly  than  that  of  warmth.  This  is  interpreted  as  showing 
that  the  end- organs  for  the  warm  sense  are  situated  more  deeply  than  those 
for  cold.     We  have  no  evidence  as  to  the  histological  identity  of  these  organs. 

THE  SENSE  OF  TOUCH 

By  means  of  the  sense  of  touch  we  arrive  at  a  conclusion  a^  to  the  qualities, 
such  as  shape,  texture,  hardness,  &c.,  of  the  bodies  with  which  the  skin 
is  in  contact.  In  this  judgment,  however,  very  many  other  sensations 
are  involved  besides  those  which  can  be  regarded  as  strictly  tactile.  Thus 
the  hardness  of  an  object  signifies  its  resistance  to  deformation,  besides 
its  power  of  deforming  the  skin  surface  with  which  it  is  in  contact ;  the 
former  quahty,  i.e.  of  resistance,  is  one  which  involves  the  muscular  sense, 
since  we  judge  of  it  by  the  extent  to  which  we  can  move  our  muscles  without 
causing  any  alteration  of  the  surface  of  the  body. 

The  tactile  sensibihty  of  the  skin  as  a  whole,  like  its  temperature  sensi- 
bility, is  due  to  the  presence  in  it  of  a  number  of  touch  spots,  i.e.  small 
areas  which  are  extremely  sensitive,  separated  by  areas  almost  or  entirely 
insensitive  to  pressure.  The  tactile  sensibihty  of  any  part  is  proportional 
to  the  nmnber  of  such  touch  spots  present.  If  the  calf  of  the  leg  be  shaved 
and  then  tested  by  pressing  on  it  mth  a  fine  bristle  or  hair  it  "will  be  found 
that  the  minimal  stimulation  used  evokes  sensation  only  at  certain  definite 
points,  the  '  touch  spots.'  In  a  square  centimetre  of  such  skin  there  may 
be  about  fifteen  touch  spots.  On  thrusting  a  fine  needle  into  one  of  these 
spots  a  sharply  locahsed  sensation  of  pressure  is  produced  unaccompanied 
by  any  painful  quality  and  often  described  as  having  a  '  shotty  '  character, 
as  of  a  little  hard  object  embedded  in  the  skin  and  there  pressed  upon. 
These  touch  spots  are  arranged  chiefly  around  the  hairs,  lying  usually 
on  the  side  from  which  the  hair  slopes.  They  vary  in  number  according 
to  the  part  of  the  body  which  is  the  subject  of  investigation.  Thus  the 
dorsal  surface  of  the  finger  contains  about  seven  times  as  many  touch  spots 
as  an  equal  area  between  the  shoulders.  In  some  regions,  such  as  the 
skin  over  subcutaneous  surfaces  of  bone,  as  much  as  one  centimetre  may 
intervene  between  two  neighbouring  touch  spots.  They  have  no  relation 
to  the  warm  and  cold  spots  ;  they  are  entirely  absent  from  tlio  cornea, 
the  glans  penis,  and  the  conjunctiva  of  the  upper  lid. 

The  adequate  stimulus  for  these  tactile  nerve-endings  is  not  so  much 
pressure  as  deformation  of  surface.  It  appears  to  matter  little  whether 
the  surface  be  deformed  by  pulling  it  or  by  pushing  an  instrument  into  it. 
The  ineffectiveness  of  mere  pressure  is  shown  by  dipping  the  finger  into  a 
vessel  of  mercury.  The  sensation  of  pressure  is  only  noted  at  the  point 
where  the  finger  passes  through  the  siirface  of  the  mercury,  and  this  is  the 
only  part  where  there  is  an  actual  deformation  of  the  skin,  due  to  the  sudden 
passage  from  the  pressure  of  the  mercury  to  tlie  negligible  pressure  of  the 
outside  air.  The  tactile  apparatus  is  smarter  in  its  response  than  any  other 
of  the  sense-organs.     On  this  account  stimuli  are  still  percei\'ed  as  discrete, 

16* 


490 


PHYSIOLOGY 


when  they  are  repeated  at  a  rhythm  which  would  result  in  complete  fusion 
in  the  case  of  any  of  the  other  sense-organs.  Thus  if  a  bristle  be  attached 
to  a  tuning-fork  and  allowed  to  press  on  the  skin,  the  vibrations  of  the 
fork  are  perceived  by  the  ear  as  a  continuous  sound  and  by  the  skin 
as  a  series  of  discofitinuous  taps.  Faradic  currents  when  applied  to  the 
skin  can  be  perceived  as  separate  when  repeated  at  the  rate  of  130  per 
second.  The  sensations  evoked  by  placing  the  finger  against  the  edge  of  a 
cog-wheel  do  not  become  continuous  until  the  wheel  is  revolving  at  such  a 
rate  that  the  stimulation  on  the  skin  by  the  serrations  occurs  at  a  greater 
rate  than  5C0  or  600  per  second.  The  tactile  apparatus  resembles  all  the 
other  skin  sense-organs  in  showing  adaptation.  A  stimulus  after  continuing 
for  some  time  may  become  ineffective.  We  are  usually  entirely  unaware 
of  the  stimulation  of  our  skin  by  the  pressure  of  the  clothes,  and  even 
an  unwonted  stimulation,  such  as  that  of  the  mucous  membrane  of  the 
mouth   by   a   plate   carrying   artificial   teeth,  though  almost  unbearable 


3 


Fig.  243.     Hair  mounted  on  a  wooden  handle,  and  used 
by  von  Frey  for  testing  tactile  sensibility. 


during  the  first  day,  rapidly  becomes  less,  and  in  a  few  days  it  is  not 
perceived  at  all. 

In  order  to  test  the  sensitiveness  of  touch  we  may  use  the  method  in- 
troduced by  Hensen,  viz.  the  bending  of  a  glass-wool  fibre.  We  could 
determine  the  pressure  at  which  any  given  fibre  will  bend,  and  if  we  find 
by  trial  the  fibre  which  just  evokes  sensation  when  pressed  on  the  skin, 
we  know  exactly  the  force  which  we  are  applying  to  the  skin.  Von  Frey 
employed  hairs  of  difierent  thickness  for  the  same  purpose  (Fig.  243).  The 
following  represents  the  minimal  excitabihty  of  the  surface  of  different 
parts  of  the  body  when  tested  in  this  way. 


Tongue  and  nose  . 

Lips    . 

Finger-tip  and  forehead 

Back  of  finger 

Palm,  arm,  thigh 

Fore-arm 

Back  of  hand 

Calf,  shoulder 

Abdomen     . 

Outside  of  thigh  , 

Shin  and  sole 

Back  of  fore-arm . 

Loins 


Gim.    per  sq.  mm, 

2 

2-5 

3 

5 

7 

8 
12 
16 
26 
26 
28 
33 
48 


CUTANEOUS  SENSATIONS  401 

The  sensitiveness  of  the  sense-organs  in  the  skin  is  probably  much 
greater  than  that  of  the  nerve-trunks  themselves.  Thus  Tigerstedt  found 
that  the  minimal  mechanical  stimulus  necessary  to  excite  the  exposed 
nerve  amounted  to  0'2  grm.  moving  at  140  mm.  per  second.  For  the  touch 
spots  von  Frey  found  that  0*2  grm.  moving  at  0*17  mm.  a  second  is  an 
adequate  stimulus. 

In  testing  the  sensibiUty  of  any  surface  it  is  important  to  remember 
that  the  hairs  themselves  form  very  effective  tactile  organs.  The  touch 
spots  are  distributed  in  greatest  profusion  around  hair  follicles,  and  there 
is  a  rich  plexus  of  nerve  fibres  round  the  root  of  each  hair.  A  shght  touch 
appHed  to  the  hair  acts  on  these  as  on  the  long  end  of  a  lever,  the  hair  being 
pivoted  at  the  surface  of  the  skin,  so  that  pressure  on  the  hair  is  transmitted, 
increased  five  or  more  times  in  force,  to  the  hair  foUicle  and  the  surromiding 
nerve-endings.  The  actual  sensibility  of  any  part  is  therefore  much  dimin- 
ished by  removal  of  the  hairs.  On  9  sq.  mm.  of  the  skin,  from  which  the 
hairs  had  been  shaved,  the  minimal  stimulus  necessary  to  evoke  a  tactile 
sensation  was  found  to  be  36  mg.,  whereas  on  the  same  surface  before  it  was 
shaved  2  mg.  was  effective. 

WEBER'S  LAW.  The  smallest  increment  or  decrement  of  stimulus 
which  determines  a  perceptible  difference  of  sensation  must,  according 
to  Weber's  law,  always  bear  the  same  ratio  to  the  whole  stimulus.  In 
measuring  such  differences  it  is  best  to  apply  the  stimulus  successively  to 
the  same  surface  of  the  skin  rather  than  simultaneously  to  adjoining  areas. 
The  time  interval  between  two  successive  stimuli  should  not  be  more  than 
five  seconds  and  the  duration  of  the  stimuli  should  be  equal.  Weber  found 
that  in  the  terminal  phalanx  of  the  finger  the  minimal  perceptible  difierence 
was  about  one-thirtieth,  but  the  ratio  was  not  the  same  for  all  regions  of 
the  skin  nor  for  all  individuals.  The  following  represents  the  liminal 
difference  in  various  skin  regions  : 

Forehead,  lips,  and  cheeks  .  .  .       l/30th  to  l/40th 

Back  of  fore-arm,  of  leg,  and  of  thigh  ;  ^ 

back  of  hand,  and  first  and  second  -  1/lOth  to  l/20th 

phalanx  of  finger,  &c.  .  .J 

All  parts  of  the  foot,  surface  of  leg,  and 

thigh  .....       more  than  1 /10th 

THE  SPATIAL  QUALITY  OF  TOUCH.  DISCRIMINATION.  If  any 
part  of  the  skin  be  stimulated  the  subject  of  the  experiment  can  tell  at  once 
the  exact  situation  of  the  excited  spot.  If  two  points  be  stinuilatod  simul- 
taneously excitation  is  perceived  as  double,  i.e.  as  proceeding  from  two 
points,  provided  the  distance  between  the  points  exceeds  a  certain  amount, 
varying  in  different  parts  of  the  body.  The  power  of  discrimination,  i.e. 
of  judging  whether  a  stimulus  is  single  or  double,  can  be  tested  by  arming 
the  points  of  a  pair  of  compasses  with  small  pieces  of  cork  and  then  seeing 
how  far  apart  the  points  must  be  when  pressed  on  the  skin  in  order  that  the 


492 


PHYSIOLOGY 


stimulus  may  be  perceived  as  double.     The  following  Table  represents  this 
distance  for  various  regions  of  the  body  : 


Distance  in  mm. 

Skin  region 

mm 

Tip  of  tongue        .          .          . 

11 

Volar  surface  of  finger  tip      . 

2-3 

Dorsum  of  third  phalanx 

6-8 

Palm  of  hand        ..... 

11-3 

Back  of  hand        .          .          .          . 

31-6 

Back  of  neck        ..... 

54-0 

Middle  of  back,  upper  arm,  and  thigh 

67-1 

When  touch  spots  are  sought  out  for  stimulation  with  the  points  of  a 
compass,  the  distance  at  which  the  excitation  is  perceived  as  double  is 
much  diminished,  as  is  shown  by  the  following  Table  of  distances  for  the 
touch  spots  in  millimetres  : 


Skin  region 

Distance  of  touch  spots 

Volar  side  of  finger  tips 

0-1 

Palm  of  hand 

0-1 

Fore-arm  (flexor  side)    . 

.         .         0-5 

Upper  arm  .... 

0-6 

Back  ..... 

0-4 

The  compass  points  are  perceived  to  lie  apart  with  a  special  distinctness 
when  they  are  appUed  to  touch  spots  lying  on  difierent  lines  which  radiate 
from  the  hair  folhcles.  The  figures  given  in  the  first  Table  have  no  relation 
to  touch  spots,  but  show  the  average  distance  over  which  an  excitation 
can  be  perceived  as  double. 

The  delicacy  of  discrimination  of  any  part  is  largely  associated  with 
its  mobihty.  Thus  in  the  arm  the  dehcacy  increases  continuously  from 
the  shoulder  to  the  finger-tip.  If  the  localising  power  for  touch  on  the 
shoulder  be  taken  as  100,  that  of  the  finger-tips  will  be  represented  by  2582. 
In  the  same  way  there  is  a  continuous  decrease  of  the  distances  of  discrimina- 
tion as  we  pass  along  the  cheek  from  the  ear  to  the  hp,  i.e.  from  the  non- 
mobile  to  the  mobile  part.  The  power  of  discrimination  is  increased  to  a 
certain  extent  by  practice  and  largely  diminished  by  fatigue.  Any  factor 
which  diminishes  the  tactile  sensibility  of  the  part,  such  as  cold,  will  also 
diminish  the  power  of  discrimination. 

The  fact  that  we  can  localise  the  point  of  stimulation  shows  that  every 
factile  sensation  derived  from  the  surface  of  the  body,  besides  the  qualities 
of  intensity  and  extensity,  has  also  associated  with  it  a  characteristic  quality 
dependent  on  its  position.  This  localised  quality  of  a  tactile  sensation  was 
called  by  Lotze  '  local  sign.'  Among  psychologists  there  has  been  much 
discussion  as  to  how  far  this  '  local  sign  '  is  an  inborn  attribute  of  the  sensa- 
tion of  every  point  on  the  body  surface,  or  how  far  it  is  acquired  by  ex- 
perience and  based  on  memory  of  movements  and  muscular  impressions. 
In  the  retina  we  have  a  sense-organ  which,  like  the  skin,  possesses  local 
sign,  but  in  far  higher  degree,  the  power  of  discrimination  of  the  retina 
being  three  thousand  times  as  great  as  that  of  the  most  sensitive  part  of 


CUTANEOUS  SENSATIONS  493 

the  skin.  Cases  of  congenital  cataract  occur  in  which  the  subjects  have 
been  bhnd  from  birth.  By  extraction  of  the  cataract  we  can  give  such 
persons  the  power  of  sight.  It  is  found  that  at  first  there  is  no  power  of 
locaUsing  visual  impressions.  The  '  local  sign '  is  only  developed  in  re- 
sponse to  experience,  by  comparing  simultaneous  visual,  tactile,  and  motor 
sensations.  By  analogy  we  might  ascribe  the  local  sign  of  cutaneous 
sensations  to  a  similar  causation.  Our  study  of  the  spinal  animal  has 
indeed  given  us  a  physical  or  histological  conception  of  local  sign.  We 
know  that  stimulation  of  any  part  of  the  body  evokes  an  appropriate  reaction, 
the  nature  of  which  is  determined  by  the  central  connections  of  the  entering 
nerve  fibres.  A  fibre  entering  at  one  segment  must  therefore  come  into 
relation  with  a  different  set  of  motor  cells  from  those  which  are  set  into 
action  by  a  fibre  entering  one  segment  lower  down.  Every  nerve  fibre 
from  the  skin  will  therefore  have  an  appropriate  complex  of  motor  paths 
in  functional  connection  with  its  central  endings,  and  when  the  activity  of 
these  reflex  paths  comes  to  be  represented  in  consciousness  it  is  evident 
that  the  sensation  derived  from  each  point  must  differ  from  that  derived 
from  any  other  point  of  the  skin  by  virtue  of  the  differing  motor  events 
actually  or  potentially  excited  from  the  two  points.  In  ascribing  therefore 
'  local  sign  '  to  coincident  muscular  sensations,  and  to  the  memory  and 
experience  of  past  movements,  we  are  giving  but  an  imperfect  explanation  ; 
since  the  difference  between  the  sensations  from  different  parts,  which  are 
at  the  bottom  of  our  powers  of  locaHsation,  has  its  origin  in  the  structure 
of  the  central  nervous  system  itself  and  is  present  from  the  very  beginning 
of  the  evolution  of  a  reactive  nervous  system. 

PROJECTION  OF  TOUCH.  Since  the  alterations  in  the  surface  of  the  skin 
which  give  rise  to  tactile  sensations  are  habitually  caused  by  contact  with 
external  objects,  we  come  to  regard  the  sensations  themselves,  not  as 
changes  in  the  skin,  but  as  quahties  of  the  object  which  touch  the  skin,  i.e. 
we  project  the  sensation.  The  projection  is,  however,  not  so  great  as  in 
the  case  of  visual  sensations.  Cutaneous  sensations  we  always  consider 
as  quahties  of  an  object  immediately  aff'ecting  and  altering  the  condition 
of  ourselves,  whereas  the  visual  sensations  are  referred  at  once  to  objects 
lying  right  away  from  ourselves,  so  that  we  are  not  aware  that  any  change 
has  taken  place  in  our  bodies  as  a  result  of  the  entering  of  rays  of  fight  into 
the  eye. 

It  is  remarkable  to  what  extent  projection  of  touch  sensation  may 
occur.  Thus  a  surgeon  actually  lengthens  his  fingers  by  using  a  probe. 
When  he  is  probing  for  dead  bone  he  feels  the  grating  of  the  bone,  not  at 
his  finger- tips,  but  he  projects  the  sensation  to  the  end  of  the  probe.  In 
the  same  way  tactile  sensations  evoked  by  the  contact  of  bodies  with  the 
insentient  endings  of  hair  are  referred  to  the  ends  of  the  hairs  rather  than 
to  the  hair  follicles  where  the  nerve  impulses  actually  come  into  being. 

The  dependence  of  local  sign  on  habitual  experience  is  well  shown 
by  the  various  tactile  illusions,  such  as  the  well-known  experiment  of 
Aristotle.     If  we  cross  the  first  and  middle  fingers  and  bring  them  in  this 


494  PHYSIOLOGY 

position  in  contact  with  a  pea,  if  the  eyes  are  shut,  we  should  at  once  say 
that  two  peas  lay  under  the  fingers.  This  is  especially  marked  if  the  pea 
be  rolled  between  the  fingers.  The  two  sides  of  the  fingers  which  come  in 
contact  with  the  pea  usually  touch  two  different  objects,  and  these  parts 
of  the  skin  would  have  to  be  re-educated,  i.e.  their  local  sign  would  have  to 
be  changed  in  accordance  with  the  changed  conditions,  before  the  pea 
would  be  perceived  in  its  true  state  as  single. 

THE  PAIN  SENSE 

When  the  pressure  of  a  hard  object  on  the  skin  is  increased  beyond  that 
necessary  to  evoke  a  tactile  sensation,  at  a  certain  pressure  the  quahty 
of  sensation  changes  and  it  becomes  painful.  For  the  evolution  of  the 
race  as  well  as  for  the  preservation  of  the  individual  this  pain  sense  is  all- 
important  ;  it  is  the  expression  in  consciousness  of  the  reflexes  of  self- 
preservation  which  can  be  evoked  in  the  spinal  animal  by  stimuh  which  are 
nocuous,  i.e.  calculated  to  do  actual  damage  to  the  tissues  of  the  body.  Thus 
when  a  sharp  point  is  pressed  on  the  skin  the  sensation  becomes  painful  just 
before  the  pressure  is  sufficient  to  cause  penetration.  The  so-called  trophic 
lesions  which  occur  in  parts  devoid  of  sensation  are  determined  for  the 
most  part  by  the  lack  of  the  pain  sense  and  the  consequent  failure  of  the 
preservative  reflexes  of  the  part.  It  is  remarkable  that  pain  may  result 
from  changes  in  organs  which  are  devoid  of  ordinary  sensibility.  Thus 
the  intestine  may  be  cut,  sewn,  or  handled  without  arousing  any  sensation 
whatsoever.  A  strong  contraction  of  the  muscular  wall  or  increased  dis- 
tension of  the  gut  will,  however,  evoke  a  griping  pain.  In  the  same  way 
the  ureters,  which  are  devoid  of  sensation,  can  give  rise  to  excruciating 
agony  when  they  are  contracted  firmly  on  a  retained  calculus. 

We  are  accustomed  to  distinguish  many  difierent  quahties  of  pain, 
but  on  analysis  it  will  be  found  that  these  quahties  depend  on  the  nature 
of  the  sense-organ  which  is  simultaneously  stimulated.  Thus  a  burning 
pain  denotes  simultaneous  stimulation  of  the  pain  sense  and  of  the 
nerve- endings  to  the  warm  spots.  A  throbbing  pain  results  when  the 
vessels  of  the  part  are  dilated  and  the  part  is  tense  with  effused  lymph, 
so  that  each  pulse  of  the  vessels  causes  an  exacerbation  of  the  painful  stimula- 
tion and  perhaps  also  stimulation  of  the  tactile  end-organs. 

The  sense  of  pain  has  often  been  ascribed  to  over-maximal  stimula- 
tion of  any  form  of  sensory  nerve.  Although  it  is  true  that  over-stimulation 
of  the  auditory  or  optic  nerve  by  a  loud  sound  or  a  bright  hght  may  be 
extremely  unpleasant,  the  sensations  evoked  do  not  partake  of  the  characters 
of  painful  sensations  such  as  would  be  produced  by  pricking  or  burning  the 
skin.  Moreover  a  careful  investigation  of  the  sensory  points  on  the  skin 
brings  out  the  fact  that  there  are  besides  the  tactile  and  temperature  spots, 
other  spots  from  which  only  painful  sensations  can  be  evoked.  We  have 
seen  already  that  over-stimulation  of  a  touch  spot  does  not,  as  a  matter  of 
fact,  cause  pain.  The  pain  spots  which  are  distributed  among  the  touch  and 
temperature  spots  are  insensitive  to  a  low  grade  of  stimulus.     As  the 


CUTANEOUS  SENSATIONS  495 

strength  of  the  stimuhis  is  increased  a  point  is  suddenly  reached  at  which 
the  sensation  evoked  is  painful.  Moreover  in  parts  of  the  body  tactile  and 
temperature  sense  are  entirely  wanting,  though  painful  impressions  can  be 
easily  evoked.  The  best  example  of  this  is  seen  in  the  cornea,  minimal 
stimulation  of  which  evokes  pain,  but  nothing  which  can  be  regarded  as 
a  tactile  sensation.  The  specific  quahty  of  pain  sensation  is  shown  more- 
over by  the  fact  that  in  many  cases  of  disease  the  sense  of  pain  may  be 
abolished  without  the  sense  of  touch.  Such  a  patient  is  said  to  suffer 
from  analgesia,  but  not  anaesthesia.  When  pricked  on  an  analgesic  part 
the  patient  can  say  that  he  is  pricked,  but  has  no  objection  to  any  amount 
of  repetition  of  the  stimulus,  since  the  sensation  is  entirely  devoid  of  painful 
character. 

THE  WORK  OF  HEAD  ON  CUTANEOUS  SENSIBILITY 
In  a  Ions  series  of  researches  on  man  Head  has  shown  that  three  different 
classes  of  sensations  may  be  evoked  by  stimuh  appUed  to  the  surface  of 
the  body.  In  order  to  study  the  functions  of  the  afferent  nerves  Head 
has  investigated  not  only  the  condition  of  patients,  the  subjects  of  accidental 
division  of  cutaneous  or  other  nerves,  but  also  (in  conjunction  with  Rivers) 
the  effects  of  nerve  section  on  himself.  In  the  first  place,  it  is  necessary  to 
differentiate  deep  sensibihty  from  cutaneous  sensibiHty  proper.  After 
desensitisation  of  any  given  area  of  the  skin  it  is  still  possible  in  this  area 
to  appreciate  deep  pressure  and  pain,  and  the  locaHsation  of  the  situation 
of  the  pressure  is  fairly  accurately  carried  out.  On  the  other  hand,  the 
sensations  of  Hght  touch,  as  well  as  of  temperature  and  the  pain  evoked 
by  a  light  pin  prick,  are  absent.  The  sensations  of  pressure,  as  well  as  of 
deep  pain  or  pressure  pain,  are  therefore  carried  by  the  nerves  of  deep 
sensibility.  These  nerves  are  not  the  cutaneous  nerves,  but  are  derived 
from  the  sensory  elements  in  the  muscular  nerves.  To  the  fingers,  for  instance, 
they  run  in  the  tendons  of  the  muscles.  Simultaneous  division,  as  by  a 
circular- saw  cut,  of  the  cutaneous  nerves  and  tendons  to  the  fingers  will 
abolish  deep  as  well  as  superficial  sensibility.  Deep  sensibility  must  there- 
fore be  classified,  anatomically  at  any  rate,  with  the  '  organic  sensations  ' 
of  muscular  effort  and  of  position,  which  will  be  dealt  with  in  a  subsequent 
section. 

Cutaneous  sensibility  proper  Head  divides  into  two  categories,  namely, 
protopathic  and  epicritic  sensibility.  These  two  forms  of  sensibility  may 
be  studied  separately  on  an  area  of  skin,  which  has  been  desensitised  by 
section  of  its  cutaneous  nerves,  during  the  process  of  regeneration  of  these 
nerves. 

PROTOPATHIC  SENSIBILITY  returns  to  the  skin  at  an  interval  of 
seven  to  twenty-six  weeks  after  the  nerve  section.  At  this  time  it  is 
possible  to  appreciate  in  the  area  under  investigation  the  sensation  of  pain, 
and  to  recognise  roughness  of  an  object  rubbed  on  the  skin.  Localisation 
is  still  somewhat  diffuse  and  inaccurate,  so  that  the  sensation  evoked  by 
stimulation  of  the  protopathic  area  may  be  referred  to  some  adjoining  normal 


496  PHYSIOLOGY 

part  of  the  skin.  The  temperature  sense  is  also  present,  but  of  a  low  grade. 
Thus  heat  over  38°  C.  and  cold  under  24°  C.  can  be  appreciated  as  such, 
but  the  intervening  temperatures  produce  no  sensation.  Sensations  evoked 
in  the  protopathic  area  are  strongly  endowed  with  what  may  be  termed 
'  affective  '  character.  Thus  painful  stimulation  is  much  more  unpleasant 
when  apphed  to  this  area  than  would  a  similar  stimulation  be  when  apphed 
to  a  normal  area  of  skin. 

In  contradistinction  to  the  deep  sensibihty  which  is  diffuse,  protopathic 
sensibihty  is  distributed  in  spots,  so  that  heat  and  cold  spots,  for  instance, 
may  be  distinguished  as  on  the  normal  skin.  It  is  interesting  that  the 
glans  penis  is  normally  provided  only  with  protopathic  sensibihty. 

EPICRITIC  SENSIBILITY  does  not  return  to  the  desensitised  area 
until  one  to  two  years  have  elapsed  since  the  division  of  the  nerves.  With 
its  return  the  affective  character  of  the  protopathic  sensations  at  once 
disappears  and  is  replaced  by  an  accurate  discrimination  of  the  nature  and 
extent  of  the  stimulus  ;  the  tactile  sense  proper,  i.e.  the  appreciation  of  the 
Hghtest  touch  apphed  to  the  skin  and  its  accurate  locahsation,  belonging 
entirely  to  the  epicritic  sensations.  The  power  of  discriminating  the 
distance  between  two  points  applied  to  the  skin  simultaneously  is  also  a 
function  of  the  epicritic  sensibihty. 

With  the  discriminating  tactile  sense  returns  also  the  power  of  appre- 
ciating fine  differences  of  temperature,  i.e.  differences  between  26°  and 
37°  C. 

This  classification  may  be  summed  as  follows  : 

Deep  sensibility      .  .  .  including  J  Pressure  sense 

\^  Pressure  pain 

(Skin  pain 
Heat  over  38°  C. 
Cold  under  24°  C. 

Tactile  sense  proper 
Pain  localisation 
Discrimination 
Heat  and  cold  between 
26°  and  37°  C. 


Epicritic  sensibility 
(accurately  localised) 


Head  and  Thompson  have  shown  that  on  entering  the  cord  these  various 
sensations  imdergo  a  new  grouping.  Thus  the  pain  impulses,  which  arise 
in  and  are  carried  by  the  muscular  nerves,  the  nerves  of  deep  sensibihty, 
unite  with  those  which  run  in  the  protopathic  system,  so  that  a  lesion  of  the 
cord  which  abolishes  the  sense  of  pain  will  abohsh  all  forms  of  pain,  whether 
arising  from  the  skin  or  from  the  underlying  tissues.  In  the  same  way  all 
temperature  sensations,  whether  the  fine  ones  of  the  epicritic  system  or  the 
coarser  ones  of  the  protopathic  system,  run  together  in  the  cord.  If  the 
heat  sense  is  affected  by  a  lesion  of  the  cord  all  forms  and  all  degrees  of  the 
sensation  are  affected  in  like  measure,  and  the  same  applies  to  the  sensations 
of  cold. 


CUTANEOUS  SENSATIONS  497 

THE  HISTOLOGICAL  CHARACTER  OF  THE  ELEMENTS 
INVOLVED  IN  CUTANEOUS  SENSATIONS 

A  very  large  number  of  different  forms  of  sensory  nerve-endings  have 
been  described  in  relation  to  the  skin.  Their  exact  allocation  among  the 
different  cutaneous  senses  presents  considerable  difficulties. 

As  regards  touch,  two  kinds  of  elements  are  probably  involved.  In 
the  first  place,  the  most  sensitive  tactile  apparatus  are  the  follicles  of  the 
short  hairs.  Around  these  follicles  we  find  a  sheaf  of  nerve  fibres,  some 
of  which  end  in  the  hair  papilla  and  others  form  a  ring  near  the  level  of 
the  openings  of  the  sebaceous  glands.  The  other  tactile  end- organ  is 
Meissner's  corpuscle.  The  distribution  of  these  in  the  skin  is  not,  however, 
dissimilar  to  that  of  the  power  of  discrimination,  with  which  they  may  be 
specially  comiected.  Other  end-organs  which  are  supposed  to  be  stimulated 
by  changes  of  pressure,  and  therefore  to  be  tactile,  are  the  organs  of  Ruffini 
which  occur  in  the  papillae  of  the  palm  and  fingers,  and,  lying  more  deeply, 
the  elastic  tissue  spindles  as  well  as  the  Golgi  corpuscles  and  the  Pacinian 
corpuscles  in  the  subcutaneous  tissue. 

As  regards  pain,  we  known  that  in  the  cornea,  which  possesses  only 
the  pain  sense,  the  sensory  nerve- endings  are  in  the  form  of  branches  of 
axis  cylinders  among  the  epithehal  cells.  Similar  free  nerve-endings  occur 
in  the  epidermis  all  over  the  body,  and  it  is  therefore  imagined  that  these 
have  the  special  function  of  subserving  the  pain  sense.  We  have  at  present 
no  evidence  as  to  the  histological  character  of  the  organs  by  which  the 
sensations  of  heat  and  cold  are  aroused. 


SECTION  III 

SENSATIONS  OF  SMELL   AND  TASTE 

Every  living  organism  shows  a  susceptibility,  i.e.  a  power  of  reaction, 
to  chemical  stimuli.  Thus  the  plasmodium  of  myxomycetes,  placed  on  a 
strip  of  filter-paper  of  which  one  end  is  immersed  in  an  infusion  of  dead 
leaves  and  the  other  in  distilled  water,  will  crawl  along  the  paper  towards 
the  infusion  of  leaves.  If  the  infusion  of  dead  leaves  be  replaced  by  a 
weak  solution  of  quinine,  the  plasmodium  will  be  repelled  and  will  travel 
along  towards  the  vessel  of  water.  These  movements  of  attraction  and 
repulsion  are  spoken  of  as  positive  and  negative  chemiotaxis  respectively. 
A  similar  chemical  sensibility  accounts  for  the  clustering  of  aerobic  bacteria 
towards  the  surface  of  a  fluid,  i.e.  where  the  density  of  oxygen  is  greater, 
or  around  chlorophyll-containing  algse  which  are  giving  off  oxygen  in  the 
sunlight.  The  aggregation  of  leucocytes  round  microbes  or  other  foreign 
particles  in  the  tissues  is  also  determined  by  their  chemiotactic  sensibihty. 
Chemiotaxis  then  represents  the  faculty  by  means  of  which  these  minute 
organisms  are  able  to  adapt  themselves  to  chemical  changes  in  their  environ- 
ment and  to  react  to  chemical  substances  at  a  considerable  distance  from 
themselves.  If  we  could  endow  these  elementary  organisms  with  con- 
sciousness and  with  a  sense  of  their  surroundings,  we  should  have  to  say 
that  they  became  aware  of  the  presence  of  some  harmful  or  attractive 
material  at  some  distance  from  themselves.  The  sensation  they  received 
from  these  distant  objects  would  be  therefore  a  projected  sensation. 

On  the  other  hand,  a  chemical  sensibihty  of  the  body  surface  or  part 
of  it  furnishes  the  criterion  by  which  particles  are  accepted  and  ingested 
as  food  or  rejected  as  useless  or  harmful.  Consciousness  in  this  case  would 
be  of  something  affecting  and  in  contact  with  some  part  of  the  organism 
itself.  The  sensation  would  not  be  projected  further  than  the  periphery  of 
the  body. 

These  two  kinds  of  chemical  sense — the  projected  and  the  surface 
sense — are  found  throughout  almost  all  classes  of  the  animal  kingdom, 
and  in  the  higher  animals  at  least  are  known  as  the  senses  of  smell  and 
taste.  The  former  sense  in  many  animals  attains  a  high  degree  of  com- 
plexity and  is  prepotent  in  determining  the  behaviour  of  an  animal  in 
response  to  the  changes  in  its  surroundings.  In  the  elasmobranch  fishes 
the  olfactory  lobes  form  the  greater  part  of  the  higher  brain,  and  extirpation 
of  them  produces  a  loss  of  spontaneity  and  of  delayed  reactions  similar  to 

498 


SENSATIONS  OF  SMELL  AND  TASTE 


499 


.•Sfi> 


If4^- 


that  which  can  be  brought  about  in  higher  types  by  extirpation  of  the  whole 
of  the  cerebral  hemispheres. 

The  sense  of  taste,  on  the  other  hand,  is  only  used  for  sampling  the  nature 
of  substances  taken  into  the  mouth  and  determining  their  ingestion  or  re- 
jection. It  is  therefore  much  simpler  in  its  extent  and  more  susceptible  of 
analysis. 

THE  SENSE  OF  TASTE 

The  end-organs  which  subserve  the  function  of  taste  are  represented 
by  the  taste-buds.  These  are  oval  bodies  (Fig.  244)  embedded  in  the 
stratified  epithelium,  which  occur  scattered  over  the  tongue,  a  few  being 
also  found  on  the  hard  palate,  the  anterior  pillars  of  the  fauces,  the  tonsils, 
the  back  of  the  pharynx,  the  larynx,  and  the 
inner  surface  of  the  cheek.  On  the  tongue  they 
are  found  chiefly  in  the  grooves  around  the 
circumvallate  papillae  of  man,  and  in  the  grooves 
of  the  papillse  foliatse  of  rabbits.  A  few  are  also 
present  on  many  of  the  fungiform  papillae.  They 
consist  of  medullary  and  cortical  parts,  the  former 
being  composed  of  columnar  or  sustentacular 
cells,  the  latter  of  thin  fusiform  cells,  the  taste- 
cells  proper.  The  nerve  fibres  concerned  with 
taste  end  in  arborisations  among  these  taste- 
cells.  The  peripheral  end  of  the  fusiform  cell 
projects  as  a  delicate  process  through  the  orifice 
of  the  taste-bud,  so  that  it  can  come  in  contact 
with  the  fluids  contained  in  the  cavity  of  the 
mouth.  A  sapid  substance,  to  stimulate  these 
organs,  must  be  in  solution  ;  hence  quinine  in 
powder  is  almost  tasteless,  owing  to  its  shght 
solubility  in  neutral  or  alkaline  fluids. 

The  number  of  difl'erent  tastes  is  very  hmited. 
We  distinguish  four  primitive  taste  sensations,  viz.  sweet,  sour,  bitter, 
and  salt,  some  authors  adding  to  this  an  alkaline  taste  and  a  metallic  taste. 
Many  substances  owe  their  distinctive  character  when  taken  into  the  mouth 
to  the  fact  that  they  stimulate  not  only  the  taste-nerves  but  also  the  nerve- 
endings  of  common  sensation.  Thus  acids,  when  in  weak  solution,  have 
an  astringent  character  besides  their  sour  taste,  and  if  strong  produce  a 
burning  sensation.  The  primitive  taste  sensations  can  affect  one  another 
if  excited  simultaneously.  With  weak  stimulation  one  taste  may  practically 
annul  another.  Thus  a  dilute  solution  of  sugar  is  rendered  almost  taste- 
less by  the  addition  to  it  of  a  few  grains  of  common  salt.  If  the  primitive 
taste  sensations  are  more  strongly  excited  we  get  a  mixed  sensation,  in 
which  the  components  can  still  be  distingushed.  Thus,  adding  sugar 
to  lemon  juice  not  only  diminishes  its  acidity  but  produces  a  mixed  sensa- 
tion, the  quality  of  which  is  pleasant  and  in  which  the  components,  sour  and 
sweet,  can  be  easily  distinguished.     We  get  no  such  fusing  of  sensations 


Fig.  244.  Two  taste-buds 
from  the  tongue, 
e,  Stratified  epithelium  ; 
p,  opening  or  pore  of  taste- 
bud  ;  s,  gustatory  cells; 
st,  sustentacular  cells. 

(KOLLIKER.) 


500  PHYSIOLOGY 

as  in  the  eye,  where  a  sensation  of  white  Kght  may  result  from  stimulation  of 
the  retina  by  two  complementary  colours.  Stimulation  of  one  kind  of  taste- 
organ  heightens  the  sensibihty  of  the  other  taste- organs.  Thus  after  the 
apphcation  of  salt,  distilled  water  may  taste  sweet. 

That  these  primitive  taste  sensations  are  served  by  different  nerve- 
endings  is  shown  by  the  following  facts 

(a)  The  tongue  is  not  equally  sensitive  at  all  points  to  all  four  tastes. 
Thus  the  back  of  the  tongue  is  more  sensitive  to  bitter,  while  the  tip  and 
sides  of  the  tongue  react  more  easily  to  sweet  and  sour  substances.  A  differ- 
ence may  be  detected  between  even  the  circum vallate  papillse  themselves  ; 
a  mixtui'e  of  quinine  and  sugar  appUed  to  one  papiUa  may  excite  chiefly 
a  bitter  taste,  while  with  an  adjacent  papilla  a  sweet  taste  may  predominate. 

(6)  By  certain  drugs  we  can  depress  the  sensibihty  of  the  taste-organs, 
and  we  then  find  that  the  various  tastes  are  affected  to  different  degrees. 
Thus  on  painting  the  tongue  with  cocaine  the  first  effect  is  a  diminution 
of  tactile  and  pain  sensibihty,  so  that  the  application  of  acid  evokes  a  very 
sour  taste  without  any  of  the  astringent  or  stinging  sensations  normally 
aroused  by  the  contact  with  the  acid.  After  this  point  the  taste  sensations 
are  also  abohshed.  The  bitter  sensation  disappears  first,  then  the  sweet, 
and  then  the  sour,  while  the  taste  of  salt  appears  to  remain  unaffected.  On 
the  other  hand,  if  the  leaves  of  Gymnema  sylvestre  be  chewed,  the  sensations 
of  bitter  and  sweet  are  abohshed,  leaving  intact  the  acid  and  salt  tastes, 
and  also  the  general  sensibility  of  the  mucous  membrane. 

There  is  no  doubt  that  the  stimulating  effect  of  any  chemical  substance 
on  the  taste-nerves  has  relation  to  its  chemical  constitution.  Thus  a  sour 
taste  is  determined  by  the  presence  of  H  ions ;  the  alkaUne  taste  by  that 
of  OH  ions.  The  fact  that  certain  acids,  e.g.  acetic,  have  a  stronger  sour 
taste  than  would  correspond  to  their  dissociation,  i.e.  to  the  number  of  H 
ions  present,  is  due  to  the  fact  that  these  acids  penetrate  more  easily  into 
the  gustatory  cells  than  the  mineral  acids  with  a  larger  dissociation  co- 
efficient. All  the  a-amino-acids  have  a  sweet  taste.  On  the  other  hand, 
the  polypeptides  produced  by  the  combination  of  these  amino-acids,  as 
well  as  the  peptones  derived  from  the  hydrolysis  of  proteins,  have  a  bitter 
taste.  Most  of  the  alcohols  and  sugars  have  a  sweet  taste,  while  the  metalhc 
derivatives  of  these  substances  are  bitter.  We  do  not  yet  understand  the 
law  which  determines  whether  any  given  substance  shall  have  a  taste  at 
all,  and  what  its  taste  should  be. 

The  nerves  of  taste  are  the  glossopharyngeal,  which  suppKes  the  back 
part  of  the  tongue,  and  the  lingual  branch  of  the  fifth  nerve  and  the  chorda 
tympani,  which  supply  the  front  part.  All  these  fibres  are  probably  con- 
nected with  a  continuous  column  of  grey  matter  in  the  brain  stem,  which 
represents  the  splanchnic  afferent  nucleus  of  the  fifth  nerve,  the  nervus 
intermedins,  and  the  glossopharyngeal.  Some  authors  have  stated  that 
all  the  taste  fibres  of  the  fifth  nerve  are  derived  from  the  glossopharyngeal 
by  the  communication  through  the  tympanic  plexus  and  the  chorda  tympani 
nerve,  while  Gowers  has  recorded  a  case  of  complete  unilateral  loss  of  taste 


SENSATIONS  OF  SMELL  AND  TASTE 


501 


in  which  there  was  a  lesion  destroying  the  fifth  nerve,  the  glossopharyngeal 
being  intact.  It  seems  possible  that  the  actual  region  of  the  taste-nerve 
may  vary,  the  fibres  running  to  the  splanchnic  column  of  grey  matter 
being  contained  sometimes  in  the  fifth,  sometimes  in  the  glossopharyngeal, 
and  sometimes  in  both. 

Most  of  our  so-called  tastes  should  rather  be  designated  flavours,  and 
are  dependent,  not  on  the  gustatory  nerves,  biit  on  the  sense  of  smell. 


Gasserid^n  Ganglion 


Fig.  245.     Diagram  showing  origin  and  course  of  the  nerve  fibres  of  taste. 

When  the  olfactory  sense  is  destroyed  very  httle  difference  is  to  be  perceived 
between  an  onion  and  an  apple.  The  epicure  with  a  fine  palate  has  really 
educated  his  sense  of  smell  and  would  be  but  httle  satisfied  with  the  simple 
sensations  derived  from  his  four  sets  of  gustatory  end- organs. 


THE  SENSE  OF  SMELL 
The  psychical  analysis  of  olfactory  sensations  is  rendered  difficult 
by  the  fact  that  this  sense  in  man  plays  but  a  small  part  in  his  usual  adapta- 
tions. We  have  thus  to  deal  with  a  sense  which  is  in  many  respects  vestigial. 
We  see  traces  of  great  complexity  in  its  possibilities  of  performance,  but 
are  baffled  in  our  endeavours  to  reduce  the  whole  of  the  phenomena  to  the 
simpler  factors  of  which  they  are  composed.  Moreover,  like  all  vestigial  func- 
tions, the  extent  to  which  the  sense  is  developed  varies  from  one  individual  to 
anotlier.  Many,  for  instance,  are  unable  to  appreciate  the  smell  of  vanilla, 
of  hydrocyanic  acid,  or  of  violets.  On  the  other  hand,  in  animals,  such  as 
the  dog,  the  olfactory  sense  seems  to  play  a  great  part  in  determining 
behaviour,  and  the  nervous  associations,  which  are  the  physiological  basis 
of  ideas,  must  in  these  animals  be  largely  connected  ^^^til  olfactory  im- 
pressions. Another  factor  which  diminishes  the  importance  of  olfactory 
sensations  in  man  is  the  ease  with  which  the  sense-organ  becomes  fatigued. 
It  often  happens  that  the  inmates  of  a  room  are  perfectly  comfortable 


502  PHYSIOLOGY 

and  may  perceive  no  fault  in  the  ventilation,  although  a  new-comer  from 
the  outside  at  once  remarks  that  the  air  is  foul. 

The  organ  of  smell  is  situated  at  the  upper  part  of  the  nasal  cavities. 
Here  the  mucous  membrane  covering  the  superior  and  middle  turbinate 
bones  and  the  corresponding  part  of  the  septum  is  different  from  that 
covering  the  rest  of  the  nasal  passages.  Over  the  lower  parts  of  the  nasal 
cavities  the  mucous  membrane  is  of  the  ordinary  respiratory  type,  and 
is  composed  of  cihated  columnar  epithehum  containing  a  number  of  goblet- 
cells.  In  the  olfactory  part  the  epithehum  is  much  thicker,  of  a  yellow 
colour,  and  apparently  composed  of  a  layer  of  columnar  cells  resting  on 
several  layers  of  nuclei.  These  nuclei  belong  to  the  olfactory  cells  proper, 
true  spindle-shaped  nerve-cells  with  one  process  extending  towards  the 
mucus  covering  the  free  surface,  while  the  other  is  continued  along  channels 
in  the  bone,  and  through  the  cribriform  plate  as  one  of  the  non-medullated 
olfactory  nerve  fibres.  These  nerve  fibres  dip  into  the  olfactory  lobes, 
where  they  terminate  by  a  much-branched  arborisation  or  end  basket  in 
the  so-called  olfactory  glomeruh,  in  close  connection  with  a  similarly 
branched  dendrite  of  the  large  '  mitral '  cells  of  the  olfactory  lobe.  The 
axons  from  these  latter  carry  the  olfactory  impulse  towards  the  rest  of  the 
brain.  In  the  connective  tissue  basis  (dermis)  of  the  mucous  membrane 
are  a  number  of  small  mucous  or  serous  glands  (Bowman's  glands)  whose 
office  it  is  to  keep  the  surface  of  the  membrane  constantly  moist. 

In  ordinary  respiration  the  stream  of  air  never  passes  higher  than  the 
anterior  inferior  border  of  the  superior  turbinate  bone,  so  that  it  does  not 
come  in  contact  with  the  olfactory  mucous  membrane.  The  sensations 
of  smell  which  are  aroused  during  ordinary  respiration  depend  on  diffusion 
from  the  respiratory  air  into  the  still  air  of  the  upper  olfactory  portion 
of  the  nasal  cavity.  The  direction  of  olfactory  attention  is  achieved  by 
sniffing  ;  in  this  act  the  nostrils  are  dilated  and  the  direction  of  the  anterior 
part  of  the  nasal  respiratory  chamber  altered,  so  that  the  stream  of  entering 
air  is  directed  towards  the  upper  olfactory  portion  of  the  cavity. 

The  fact  that  we  are  able  to  perceive  smells  when  breathing  normally 
shows  that  the  odorous  substance  must  be  diffusible,  i.e.  gaseous  in  form. 
The  amount  of  substance  necessary  to  excite  sensation  is  extremely  minute. 
Thus  -01  mg.  of  mercaptan  diffused  in  230  cubic  metres  of  air  is  still  distinctly 
perceptible.  In  this  case  a  htre  of  air  would  contain  only  -00000004  mg. 
of  the  substance,  and  the  amount  actually  in  contact  with  the  olfactory 
epithehum  would  be  still  smaller.  It  is  possible,  however,  to  show  the 
presence  of  these  odorous  substances  in  air  by  physical  means.  Tyndall 
pointed  out  that  air  containing  a  small  proportion  of  odorous  substances 
absorbed  radiant  heat  to  a  much  greater  degree  than  did  pure  air.  Thus 
in  one  experiment  air  containing  patchouli  absorbed  radiant  heat  thirty- 
two  times  as  strongly  as  the  pure  air.  Most  odorous  substances  possess 
large  molecules  and  have  therefore  high  vapour  densities.  On  this  account 
the  smell  tends  to  hang  about  objects,  the  rate  of  diffusion  of  the  vapour 
being  only  small. 


SENSATIONS  OF  SMELL  AND  TASTE  503 

Since  the  endings  of  the  olfactory  cells  are  bathed  in  fluid,  it  is  evident 
that  the  odorous  substances  must  be  dissolved  by  this  fluid  before  they  can 
excite  the  olfactory  nerve  fibres,  and  in  the  case  of  aquatic  animals  we  know 
that  the  projected  chemical  sense,  which  we  call  smell,  can  only  be  aroused 
by  substances  in  solution.  It  is  difficult  to  show  in  man  that  the  nerve- 
endings  can  be  excited  by  solutions.  Most  of  the  experiments  have  been 
made  with  solutions  which  had  an  injurious  effect  upon  the  oKactory 
epithelium.  According  to  Arousohn  it  is  possible  to  excite  sensations 
of  smell  if  the  nasal  cavity  be  filled  with  normal  sahne  fluid,  containing 
a  very  small  proportion  of  the  odorous  substance.  To  this  experiment 
it  has  been  objected  that  it  is  almost  impossible  to  fill  the  nasal  cavities 
without  leaving  some  air  spaces  so  that  the  olfactory  sensation  obtained 
might  have  been  due  to  stimulation  of  the  olfactory  cells  in  such  a  space. 
There  is,  however,  no  a  -priori  reason  to  deny  the  probabihty  of  Aronsohn's 
conclusions. 

Many  olfactory  stimuh  owe  their  pecuhar  character  to  the  simultaneous 
stimulation  of  other  kinds  of  nerve- endings.     Thus  a  pungent  smell,  as  that 
of    ammonia,    chlorine,     &c.,    involves 
stimulation  of   the   nerves  of  common 
sensibiUty,  i.e.  the  fifth  nerve,  besides 
stimulation  of  the  olfactory  nerve. 

No  satisfactory  classification  of 
smells  has  yet  been  made.  The  follow- 
ing facts  tend  to  show  that  there  are 
a  number   of   primitive  sensations   of 

smell,   as  of  other  sensations  :  Fig.  246.     Zwaardemaker's 

[a)  Certain  individuals,  whose  olfac-  olfactometer. 

tory  sense  is  in  other  respects  normal, ' 
have  no  power  of  distinguishing  some 
odours. 

(6)  The  olfactory  sense  is  easily  fatigued.  If  it  be  fatigued  so  as  to  be 
absolutely  insensitive  for  one  kind  of  smell,  it  is  still  normally  excitable  for 
other  smells. 

(c)  It  is  possible  by  mixing  odoriferous  substances  in  certain  proportions 
to  annul  their  eft'ect  on  the  olfactory  organ.  Thus  4  grm.  of  iodoform 
in  200  grm.  of  Peruvian  balsam  is  almost  odourless,  and  the  same  neutralisa- 
tion of  odours  is  obtained  if  the  odour  of  each  substance  be  allowed  to  act 
separately  on  each  side  by  tubes  inserted  into  each  nostril. 

For  this  purpose  we  may  use  the  in3trument  invented  by  Zwaardeinaker,  called 
the  olfactometer.  This  consists  of  a  porous  cylinder  into  which  is  inserted  a  tube. 
The  porous  cylinder  is  first  immersed  in  the  fluid  whose  porous  qualities  are  to  be 
tested,  and  when  it  is  thoroughly  soaked  it  is  taken  out,  dried  outside  by  a  cloth,  and 
indde  by  drawing  air  through  it  for  a  short  time.  One  end  of  the  bent  tube  is  then 
inserted  into  the  cylinder,  which  it  must  accurately  lit,  while  the  other  end  is  placed 
in  one  nostril.  The  small  wooden  screen  shown  in  Fig.  246  serves  to  shut  off  the  smell 
of  the  fluid  from  the  other  nostril.  When  the  observer  breathes  through  the  bent 
tuba  the  amount  of  vapour  taken  up  from  the  cylinder  will  depend  on  the  amount 


504  PHYSIOLOGY 

of  surface  exposed,  and  therefore  can  be  diminished  or  increased  by  pusliing  the  bent 
tube  further  in,  or  by  drawing  it  out.  If  the  tube  is  pushed  in  so  far  that  the  smell 
is  only  just  perceptible  the  length  of  the  tube  may  be  measured  and  taken  as  the  liminal 
intensity  of  stimulus  for  the  given  substances,  in  its  action  on  the  olfactory  nerve- 
endings.  This  unit  was  called  by  the  inventor  of  the  instrument  an  '  olfactie.'  By 
this  means  it  is  possible  to  make  quantitative  estimations  of  the  olfactory  sense  on  one 
individual  and  to  compare  them  with  observations  made  on  other  individuals.  By 
using  two  such  instruments  it  is  possible  to  present  different  smells  to  the  two  nostrils. 
One  obtains  in  this  way  combination  effects  which  can  be  compared  to  the  phenomenon 
which  we  shall  study  later  in  dealing  with  binocular  contrast. 


SECTION  IV 

AUDITORY  SENSATIONS 

By  means  of  our  auditory  sensations  we  are  made  aware  of  such  changes 
in  our  environments  as  are  capable  of  giving  rise  to  a  disturbance  which  can 
be  propagated  through  the  surrounding  elastic  medium,  the  air,  to  our 
ears.  Any  sudden  jar  given  to  a  sohd  body  sets  up  vibrations  which  are 
propagated  to  the  surrounding  air  as  sound  waves,  i.e.  a  series  of  acts  of 
condensation  and  rarefaction  spreading  out  from  the  centre  of  disturbance, 
like  the  waves  which  are  caused  on  the  surface  of  a  pond  by  throwing  a  stone 
into  its  middle.  With  a  dehcate  tambour  we  can  record  these  changes  of 
pressure  and  convert  them,  by  means  of  a  lever  writing  on  a  blackened  sur- 
face, into  movements  at  right  angles  to  the  direction  of  movement  of  the 
surface.  The  ampHtude  of  vibration  of  the  membrane  will  be  proportional 
to  the  amount  of  compression  and  expansion  occurring  at  each  wave. 
These  waves  travel  through  the  air  at  the  rate  of  1100  feet  per  second, 
their  wave  length  varying  with  the  number  of  vibrations  per  second.  It  is 
of  course  possible  to  get  vibrations  of  almost  any  number  per  second.  Only 
when  the  number  of  vibrations  fall  within  distinct  limits  are  they  effective 
in  producing  a  sensation  of  sound.  Before  we  can  discuss  the  physiological 
mechanism  of  hearing  we  must  have  a  clear  idea  of  the  character  of  the 
physical  change — the  stimulus — which  is  effective  in  evoking  an  auditory 
sensation  and  determining  its  quality. 

Sounds  may  be  divided  into  noises  and  musical  tones.  If  the  vibrations 
or  series  of  vibrations  arriving  at  the  ear  are  irregular  in  character,  such 
as  those  produced  by  striking  the  table  or  the  floor  with  a  stick,  we  speak 
of  the  resultant  sensation  as  a  noise.  If,  on  the  other  hand,  the  vibrations 
follow  one  another  at  a  regular  sequence  and  possess  a  rhythm — if,  for 
instance,  a  series  of  vibrations  be  imparted  to  the  air  by  a  tuning-fork  vibra- 
ting at  100  times  per  second — the  effect  on  consciousness  is  that  of  a  musical 
tone.  Of  course  there  is  no  hard-and-fast  line  between  the  two  kinds 
of  sound  ;  even  when  the  prevalent  impression  is  that  of  a  noise  it  is  often 
possible  to  pick  out  some  series  of  vibrations  which  predominate  among  the 
irregular  ones  with  which  they  are  accompanied.  When  we  strike  a  single 
stick  with  a  hammer  the  effect  is  that  of  a  noise.  If,  however,  we  take  a  series 
of  sticks  of  different  lengths  and  strike  them  in  succession,  it  will  be  noticed 
that  the  sound  produced  by  each  stick  corresponds  to  a  distinct  note,  and 
tmies  may  be  played  on  such  a  collection  of  sticks.     On  the  other  hand, 

505 


506  PHYSIOLOGY 

the  tone  of  a  musical  instrument  may  be  so  harsh  that  there  is  very  httle 
difference  between  it  and  a  noise. 

In  a  musical  tone  we  can  distinguish  various  characters  or  quahties  : 

(1)  The  loudness  of  a  tone  is  determined  by  the  amplitude  of  the  vibra- 
tions of  which  it  is  composed.  If  a  violin  string  be  bowed  forcibly  the 
excursion  of  its  string  at  each  vibration  is  greater  than  when  it  is  bowed 
gently,  and  the  amphtude  of  the  corresponding  alternating  waves  of  sound 
varies  in  proportion  to  that  of  the  vibrating  body  by  which  they  are  started. 
By  attaching  a  pointed  shp  of  paper  to  the  end  of  a  tuning-fork  and  so  record- 
ing its  vibrations  on  a  blackened  surface,  it  is  easy  to  see  the  connection 
which  exists  between  the  amphtude  of  vibrations  and  the  loudness  of  the 
sound  produced  by  the  vibrating  fork. 

(2)  The  pitch  of  a  musical  tone  depends  on  the  frequency  of  the  vibrations 
of  which  it  is  composed.  By  means  of  a  siren  we  can  determine  the  number 
of  vibrations  corresponding  to  each  note.  As  the  speed  of  revolution  of  the 
siren  is  increased,  and  therefore  the  number  of  interruptions  per  second  of 
the  stream  of  air  passing  through  the  holes  in  its  disc,  the  note  appears  to  us 
to  rise  continuously.  If  w^e  take  two  tuning-forks,  one  vibrating  at  100  times 
per  second  and  the  other  vibrating  200  times  per  second,  the  pitch  of  the 
latter  is  observed  to  be  considerably  higher  than  that  of  the  former.  In 
fact  it  forms  the  octave.  If  the  number  of  vibrations  is  less  than  about 
thirty  per  second  no  musical  tone  is  produced,  the  individual  vibrations 
being  perceived  as  a  series  of  pulses  in  the  surrounding  air,  and  it  is  only 
when  we  increase  the  number  to  aboutf  orty  per  second  that  we  are  able  to 
appreciate  the  pitch  of  the  note  produced.  As  the  number  of  vibrations 
per  second  is  increased  the  note  rises  steadily  without  break  till  we  arrive  at 
40,000  to  50,000  vibrations  per  second.  Above  this  number  of  vibrations 
the  human  ear  is  incapable  of  perceiving  any  note  at  all,  though  it  is  probable 
that  small  animals  can  perceive  notes  still  higher  in  the  scale.  In  music 
neither  the  lowest  nor  the  highest  tones  are  used.  The  lowest  tones  of  the 
large  organs,  that  of  the  sixty- four  foot  pipe,  is  16  vibrations  per  second,  and 
one  can  hardly  speak  of  its  effect  as  that  of  a  musical  tone.  The  highest 
notes  employed  in  music  are  a4  and  c5  with  3520  and  4224  vibrations  per 
second  on  the  piano,  and  d5  with  4752  vibrations  on  the  piccolo  flute.  In 
music  therefore  we  only  employ  between  40  and  4700  vibrations  per  second, 
i.e.  about  seven  octaves.  The  manner  of  construction  of  the  musical  scale 
will  be  dealt  with  later. 

(3)  Timbre  or  quality  of  musical  sounds. 

When  the  same  note  is  sounded  on  different  instruments,  i.e.  tuning-fork, 
violin,  piano,  trumpet,  human  voice,  every  person,  whether  he  has  an 
educated  musical  ear  or  not,  can  say  at  once  what  kind  of  instrument  is 
being  used.  This  fact  shows  that  the  sound  wave  produced  by  these 
instruments  must  differ,  altogether  apart  from  any  differences  in  amplitude 
or  in  number  of  vibrations  per  second,  and  if  the  sound  waves  produced 
by  these  instruments  be  recorded  an  actual  difference  is  found  in  the 
shape  of  the  curve. 


AUDITORY  SENSATIONS  507 

If  a  stretched  wire  be  plucked  so  as  to  set  it  into  transverse  vibrations  it 
will  give  out  a  certain  note,  dependent  on  its  length,  its  thickness,  and  the 
tension  to  which  it  is  subjected.  If  its  length  be  halved  it  will  give  out  a 
note  which  is  of  double  the  number  of  vibrations  per  second.  If  only  one- 
third  of  the  wire  be  set  into  vibrations  the  sound  wave  produced  will  have 
three  times  the  number  of  vibrations  of  that  of  the  whole  string.  When  the 
string  is  free  to  vibrate  as  a  whole  the  segments  of  it  tend  to  vibrate  even 
while  the  whole  string  is  vibrating.  If  therefore  we  take  the  note  given  out 
by  the  whole  string,  the  '  fundamental  tone,'  as  corresponding  to  132  vibra- 
tions per  second,  there  will  also  be  a  series  of  notes  superadded  to  the  funda- 
mental tone  with  vibrations  per  second  in  the  ratio  of  1,  2,  3,  4,  5,  and  6,  &c. 
Thus  if  the  fundamental  tone  be  c,  the  overtones,  or  harmonics,  will  be 
produced  as  is  shown  below  : 


123456789  10 

Vibrations  per  Second 

132   2  X  132   3  >;  132   4  x  132   5  X  132   6  x  132   7  x  132   8  x  132   9  x  132   10  x  132 

Nearly  all  musical  instruments,  as  well  as  the  apparatus  for  producing 
the  human  voice,  resemble  a  stretched  wire  in  giving  out  overtones  in 
addition  to  the  fundamental  tones,  and  the  difference  in  the  quality  of 
various  instruments  is  chiefly  determined  by  the  varying  predominance 
of  the  different  overtones.  In  some  the  higher  overtones  may  be  most 
marked,  in  others  only  the  lower  overtones.  The  tuning-fork  is  practically 
the  only  instrument  the  note  of  which  is  pure,  i.e.  free  from  harmonics  or 
overtones.  It  must  be  remembered  that  these  different  tones  arrive  at  the 
external  ear  simultaneously.  We  do  not  have  some  particles  of  air  vibrating 
at  one  rate  and  other  particles  at  another  rate,  but  all  the  simple  vibrations 
of  which  the  component  tone  is  composed  are  combined  together  to  form  a 
compound  wave,  the  shape  of  which  differs  according  to  the  constituent 
vibrations  of  which  it  is  made  up. 

Thus  in  the  diagram  (Fig.  247)  the  wave  shown  by  the  continuous  line 
is  compounded  of  the  series  of  simple  vibrations  represented  by  the  different 
dotted  lines.  The  components  of  such  a  compound  curve  can  be  detected 
if  the  sound  be  analysed  by  allowing  it  to  act  on  resonators,  i.e.  on  instruments 
which  can  be  set  into  vibration  by  certain  simple  tones  of  which  the  com- 
ponent tone  is  made  up.  The  stretched  strings  of  a  piano  may  be  used  as 
a  battery  of  such  resonators.  If  the  dampers  of  the  strings  be  raised,  by 
depressing  the  loud  pedal,  and  a  note  be  then  sounded  into  the  piano,  it  may 
be  noticed  that  the  piano  gives  back  the  sound,  and  on  attaching  pieces  of 
straw  to  the  various  strings  it  will  be  seen  that  only  certain  straws  vibrate, 
i.e.  those  on  the  strings  which  are  vibrating  to  the  fundamental  tone  or 
overtones  contained  in  the  sound  received  by  the  piano.     For  the  analysis 


508 


PHYSIOLOGY 


of  sounds  the  resonators  devised  by  Helmholtz  are  generally  employed. 
Ttese  consist  of  hollow  vessels,  with  an  opening  at  one  end,  made  of  different 


Fig.  247.     d,  a  compound  sound  wave,  which  may  be  analysed  into  a,  the 
fundamental  tone,  and  h  and  t,  the  first  and  second  overtones.     (Hensen.) 

sizes,  so  that  each  will  resound  only  to  a  definite  number  of  vibrations  per 
second. 

BEATS  AND  DISSONANCE.  The  overtones  of  any  sound,  at  any  rate 
the  lower  ones,  are  at  considerable  distance  from  one  another  on  the  musical 
scale,  and  therefore  differ  considerably  in  the  number  of  vibrations  of  which 
they  are  composed.  If  two  tuning-forks  be  sounded,  the  vibrations  of  which 
differ  only  by  one  or  two  per  second,  the  phenomenon  known  as  '  beats  '  is 
produced.  This  is  due  to  the  summation  or  interference  of  the  waves  from 
the  two  tuning-forks.  Supposing  we  have  tuning-forks  vibrating  one  at  100 
and  the  other  at  101  times  a  second,  and  they  start  vibrating  together. 
At  first  the  waves  of  compression  started  by  each  fork  will  coincide,  so  that 
the  total  compression  of  the  air  at  each  beat  will  be  the  compound  effect  of 
the  compression  produced  by  the  two  forks.  The  two  forks  therefore  will 
reinforce  one  another.  After  the  lapse  of  half  a  second  the  tuning-forks  will 
be  at  different  phases  of  their  excursion.  The  101  fork  will  be  moving  in  one 
direction  while  the  100  fork  is  moving  in  the  other,  so  that  the  compression 
produced  by  one  fork  coincides  with  the  expansion  of  the  air  produced  by 
the  moving  backwards  of  the  other  fork.  The  sound  produced  by  one  fork 
is  therefore  diminished  by  the  sound  produced  by  the  other  fork,  and  the 
total  sound  is  less  than  either  of  the  two  forks.  At  the  end  of  one  second, 
the  phases  of  the  two  forks  once  more  corresponding,  we  shall  get  the  sound 
increased  in  loudness  ;  thus  there  is  an  alternate  waxing  and  waning  of  the 
sound  which  recurs  once  a  second  and  is  spoken  of  as  a  '  beat.' 

The  number  of  beats  per  second  may  be  used  to  determine  the  differences 
in  the  vibration  frequencies  of  two  forks.  Thus  two  forks  vibrating  one  at 
100  and  the  other  at  110  will  give  ten  beats  per  second.  As  the  number  of 
beats  increases  the  effect  produced  on  the  ear  becomes  more  arid  more  dis- 


AUDITORY  SENSATIONS 


509 


agreeable,  just  as  the  rapid  alternation  of  illumination  produced  by  a  flicker- 
ing light  is  disagreeable  to  the  eye.  This  objectionable  character  of  the 
sound  is  most  marked  when  the  beats  recur  at  about  thirty-three  times  per 
second  ;  the  individual  beats  are  not  then  distinguished,  but  we  speak  of  the 
sound  as  discordant  or  dissonant. 

CONSONANCE.  The  opposite  condition  of  consonance  or  harmony  in- 
volves therefore,  in  the  first  place,  an  absence  of  beats,  i.e.  of  rhythmic 
oscillations  of  ampUtude  of  sound  waves  which  reach  the  ear.  The  con- 
stituent tones  and  overtones  must  be  capable  of  being  combined  into  a 
compound  wave  of  regular  amplitude  and  rhythm.  In  the  most  complete 
consonance  the  component  notes  are  identical  as  concerns  at  any  rate  the 
gi'eater  number  of  their  overtones.  The  most  complete  consonance  is 
attained  when  the  two  notes  which  are  sounded  together  are  identical. 
Almost  as  complete  is  the  consonance  obtained  when  a  note  is  sounded 
together  w^th  its  octave.  The  other  consonant  intervals  which  are  employed 
in  music  are  as  follows  : 


1  :2 

Octave 

2:  .3 

Fifth 

.3  :  4 

Fourth 

4:  5 

Major  third 

5:  6 

Minor  third 

5:  8 

Minor  sixth 

3:  5 

Major  sixth 

It  will  be  noticed  that  in  all  these  consonant  combinations  the  vibration 
frequencies  of  the  notes  are  in  proportion  to  small  whole  numbers.  If  we 
put  down  not  only  the  fundamental  tones  of  these  notes  but  also  their  over- 
tones, we  shall  see  that  there  is  considerable  identity  as  regards  the  latter. 
In  the  case  of  the  octave  the  two  are  almost  identical,  the  only  difference 
being  the  ground  tone  of  the  lower  note,  and  the  identity  diminishes  as  we 
pass  from  the  octave  through  the  thirds  to  the  sixths.  The  overtones  which 
are  identical  are  shown  by  black  type  : 


Fand '.mental  tone 
Octave  1:2. 

Fifth  2:3. 


Overtone 

I    1   .     2  .     3  .    4  .     5  .    6  .     7  .    8  .     9  .  10 

12                4                6  8  10 

(    2    .     4   .     6    .     8    .   10   .  12  .   14   .    IG  .  18    .  20 


3 


6  9  12  15  18 


^       ,,   0     *               I    3   .  6   .     9   .  12    .    15   .  18    .   21    .  24   .   27    .   30 

^^^''^^'■^■■^-          ■[       ^        8            12            IG      20  24  28 

Major  thid  4:5    .'    *   "  §    •    12    ■    16    .    20   .  24   .   28    .    32    .    3a    .40 

•*                            (        5  10        15             20  25       30       35             40 

Minor  third  5:G      '    ^    '    '^^    '    ^\-    ^^    "   -'    '  ^^    '    '"'^    ■   ^0    .   45    .   50 

t       G  12        18        24  30            36       42       48 

rajorsixth3:5    .(    ^    "  «   "     9   •    1^   •   15    •  IS    .   21    .    24   .   27   .  30 

•'                ^  •  '    •  i       5                 10             15  20  25           30 


510 


PHYSIOLOGY 


Fundamental  tone 
Second  8  :  9 


Seventh  8  :  15 


Overtone 
r  8   .   16   .  24   .  32   .  40   .    48   .  56  .  64  .  72   .  80 
•\       9        18       27       36       45        54       63  72 

/    8    .   16   .  24   .   32    .  40   .    48    .   56   .   64   .  72   .   80 
•\     15  30  45  60  75  90 


In  the  second  and  seventh,  which  are  discordant,  it  is  only  the  eighth 
overtones  which  are  identical,  while  the  fundamental  tones  will,  as  a  rule,  be 
so  close  together  that  beats  will  be  produced  of  a  number  calculated  to  give 
dissonance.  Since  the  phenomenon  of  beats  depends  on  the  absolute  number 
of  vibrations  per  second  they  are  more  easily  produced  by  two  notes  near 
together  at  the  lower  end  of  the  scale  than  at  the  upper  end.  Thus  the  dis- 
sonance is  quite  perceptible  in  a  major  third  at  the  lower  end  of  the  piano, 
but  disappears  at  the  upper  part,  since  here  the  beats  produced  are  so  rapid 
that  they  become  imperceptible. 

The  various  notes  used  in  music  are  obtained  by  employing  the  consonant 
intervals  which  we  have  given  above.  The  major  chord  is  composed  of  the 
fundamental  tone,  the  major  third  and  the  fifth.  If  we  take  '  c '  as  the 
fundamental  tone,  the  notes  of  the  chord  are  c,  e,  g,  with  vibration  fre- 
quencies corresponding  to  1,  |^,  |,  i.e.  4,  5,  6,  the  major  chord  from  g  i^  g,  h, 
d,  i.e.  three  notes  with  vibration  frequencies  corresponding  to  -|,  ^^-,  ^,  i.e. 
4,  5,  6.  The  major  chord  from  the  fourth,  /,  is  /,  a,  c,  with  the  vibration 
frequencies  ^,  ^,  ^-,  i.e.  4,  5,  6.     The  C  major  scale  is  therefore  as  follows  : 


c 

D 

E 

F 

G 

A  B 

C 

1 

9 

5 

4 

3 

5  15 

2 

8 

4 

3 

2 

3  8 

Different  instruments  are  tuned  to  one  normal  note,  i.e.  to  A  with  440 
vibrations  per  second  (this  note  varies  somewhat  in  different  countries). 
Taking  this  as  the  normal,  the  vibration  frequencies  of  the  various  notes 
used  in  music  are  given  in  the  following  Table  : 


Notes 

Vibrations  per  second 

c  .    . 

33 

66 

132 

264 

528 

1056 

2112 

D 

37-125 

74-25 

148-5 

297 

594 

1188 

2376 

E 

41-25 

82-5 

165 

330 

660 

1320 

2640 

F 

44 

88 

176 

352 

704 

1408 

2816 

G 

49-5 

99 

198 

396 

792 

1584 

3168 

A 

55 

110 

220 

440 

880 

1760 

3520 

B 

61-875 

123-75 

247-5 

495 

990 

1980 

3960 

COMBINATION  TONES.  If  two  tuning-forks,  with  an  interval  of  one-fifth 
between  them,  are  sounded  together,  we  may  hear  a  weak  lower  tone,  the 
pitch  of  which  is  an  octave  below  that  of  the  lower  fork.  This  is  known  as 
a  '  combination  tone.'     The  combination  tones  are  divided  into  two  classes  : 


AUDITORY  SENSATIONS  511 

(1)  '  difference  tones/  in  which  the  frequency  is  the  difference  of  the  frequen- 
cies of  the  generating  tones  ;  (2)  '  summation  tones,'  which  have  a  pitch 
corresponding  to  the  sum  of  the  vibrations  of  the  tone  of  which  they  are 
composed.  By  means  of  appropriate  resonators  these  tones  can  be  rein- 
forced, showing  that  they  have  an  objective  existence  and  are  not  produced 
in  the  ear  itself. 

Not  only  can  the  ear  appreciate  difierences  between  different  musical 
instruments,  dependent  on  the  varpng  overtones  present  in  the  sound  pro- 
duced by  each  instrument,  but,  when  a  number  of  these  instruments  are 
sounded  simultaneously,  the  ear  can  pick  out  from  the  compound  sound  the 
notes  due  to  the  individual  instrument,  and  a  person  with  a  trained  ear  can 
with  ease  name  notes  composing  any  chord  struck  on  an  instrument  such  as 
the  piano.  This  power  of  analysis,  which  is  possessed  by  the  ear,  or  at  any 
rate  by  the  auditory  apparatus,  may  be  stated  in  the  form  of  the  law,  known 
as  Ohm's  law,  which  is  as  follows  : 

"  Every  motion  of  the  air  which  corresponds  to  a  composite  mass  of 
musical  tones  is  capable  of  being  analysed  into  a  sum  of  simple  pendular  vibra- 
tions, and  to  each  single  vibration  corresponds  a  simple  tone,  sensible  to  the 
ear  and  having  a  pitch  determined  by  the  periodic  time  of  the  corresponding 
motion  of  the  air." 

THE  PHYSIOLOGY  OF  HEARING 

The  organ  of  the  ear  may  be  considered  as  consisting  of  an  accessory  part 
and  an  essential  part.  The  latter  is  formed  by  the  terminal  expansion  of  the 
auditory  nerve.  The  accessory  part  is  constructed  so  as  to  bring  the  waves 
of  sound  to  act  on  the  end  organs.  The  ear  is  divided  anatomically  into  three 
parts — the  external  ear,  consisting  of  the  pinna  with  the  external  auditory 
meatus  ;  the  middle  ear,  consisting  of  the  tympanic  cavity  ;  and  the  internal 
ear,  consisting  of  the  osseous  and  membranous  labyrinths  with  the  terminal 
branches  of  the  auditory  nerve. 

The  external  ear  in  the  lower  animals  is  fashioned  so  as  to  collect  sound 
waves  from  different  directions.  To  this  end  it  is  provided  with  muscles  and 
in  many  cases  is  very  movable.  In  such  animals  the  immediate  response  to 
a  slight  sound  is  a  pricking  up  of  the  ears  and  a  direction  of  their  orifices 
towards  the  source  of  sound,  a  reflex  direction  of  attention  which  in  man  is 
replaced  by  a  conjugate  deviation  of  the  two  eyes  towards  the  side  from 
which  the  sovmd  comes.  The  collecting  fmiction  of  the  pinna  in  man  is 
rudimentary ;  in  fact  a  man  can  hear  almost  as  well  with  his  ear  cut  off 
as  normally. 

The  form  of  the  pimia  in  man  may  have  a  slight  inttuenoe  in  the  judgment  of  the 
direction  from  which  sounds  iiroceed.  It  has  been  noticed  that  a  compound  tone 
changes  slightly  in  quality  as  its  position  in  relation  to  the  ear  is  altered.  This  is 
partly  due  to  the  fact  that  the  auricle  may  reflect  a  fundamental  tone  more  strongly 
than  the  partial  or  the  converse.  According  to  Rayleigh  this  difference  in  quality  is 
determined  chiefly  by  the  fact  that  diffraction  of  the  sound  waves  occurs  as  they  piss 
round  the  head  to  the  ear  remote  from  the  source  of  the  sound,  so  that  the  partial 
tones  reach  the  two  ears  in  different  degrees  of  intensity  anil  determine  a  difference 
in  quality  of  the  sound  as  heard  b^^  the  two  cars. 


512  PHYSIOLOGY 

The  external  auditory  meatus  in  man  is  about  one  inch  long  and  directed 
forwards,  inwards,  and  sHghtly  upwards.  Its  general  function,  other  than 
as  a  mere  conductor  of  the  sound  vaves,  is  to  protect  the  dehcate  vibrating 
menibrana  tijmpani  which  closes  its  inner  end.  Opening  on  the  skin  of  the 
meatus  are  special  sebaceous  glands  which  secrete  a  yellow  wax  {cerumen) 
with  bitter  taste  and  peculiar  odour.  The  wax  not  only  protects  the  cuticle 
of  the  ear  and  the  membrana  tympani  from  drpng,  but,  together  with  the 
hairs  at  the  orifice  of  the  meatus,  serves  to  repel  insects  and  prevent  their 
entering.  B}^  the  length  of  the  meatus  moreover  the  drum  is  protected  from 
draughts  and  its  temperature  is  maintained  constant. 


Fig.  248.     Diagrammatic  view  of  auditory  organ.     (Aiter  Schafer.) 
1,  auditory  nerve  ;  2,  internal  auditory  meatus  ;  3,  utricle  ;  5,  saccule  ;  6,  canalis 
media  of  cochlea  ;    9,  vestibule  containing  perilymph  ;    12,  stapes ;    13,  fenestra 
rotunda  ;    19,  incus  ;   18,  malleus  ;   17,  membrana  tympani ;    16,  external  auditory 
meatus  ;   14,  pinna  of  external  ear  ;  23,  Eustachian  tube. 

The  sound  waves  which  pass  down  the  external  meatus  impinge  on  the 
drum  of  the  ear  and  set  this  into  vibration.  The  vibrations  are  thence 
transmitted  by  a  chain  of  three  small  bones,  the  auditory  ossicles,  across  the 
cavity  of  the  tympanum  to  the  fluid  which  bathes  the  terminations  of  the 
auditory  nerve  in  the  internal  ear.  Since  the  drum  of  the  ear  has  to  pick 
up  and  transmit  vibrations  of  every  frequency,  and  to  reproduce  accurately 
in  its  movement  the  finest  variations  of  pressure  in  the  course  of  the  wave, 
it  is  essential  that  it  should  be  devoid  of  any  periodicity,  i.e.  a  tendency  to 
vibrate  at  a  certain  frequency.  If  such  periodicity  were  present  the  ear 
would  pick  out  and  magnify  some  particular  overtone  present  in  the  com- 
pound tones  reaching  the  ear  and  magnify  it  to  the  exclusion  of  the  other 


AUDITORY  SEXSATIONS  513 

overtones.  The  perfect  aperiodicity  of  the  tympanic  membrane  is  secured 
by  its  structure  and  attachments.  The  membrane  is  composed  of  a  thin 
layer  of  fibrous  tissue  covered  externally  with  skin  and  internally  by  the 
mucous  membrane  of  the  tympanum.  To  its  inner  surface  is  attached  the 
handle  of  the  malleus,  the  first  of  the  auditory  ossicles,  along  its  whole  length. 
This  attachment  of  an  elastic  membrane  to  a  mass  of  bone  would  itself  tend 
to  damp  any  vibrations  of  the  membrane.  By  the  attachment  of  the 
tendon  of  the  tensor  tympani  muscle  to  the  inner  surface  of  the  handle  of  the 
malleus  the  middle  of  the  membrane  is  drawTi  inwards,  so  that  it  forms  a  cone 
whose  walls  are  convex  outwardly.  The  membrane  is  built  up  of  circular 
and  radial  fibres,  the  circular  being  best  marked  towards  the  periphery. 
By  the  dragging  inwards  of  its  central  part  it  follows  that  the  tension  of  its 
constituent  fibres  varies  from  point  to  point  so  that  each  bit  of  the  membrane 
would  have  a  different  periodicity,  and  the  membrane  as  a  whole  is  aperiodic. 
By  exposing  the  tympanum  from  above  it  is  possible  with  a  micro- 
scope to  observe  the  actual  movements  of  the  handle  of  the  malleus  when 
sound  waves  fall  on  the  tympanic  membrane.  The  maximum  movements  at 
the  apex  of  the  cone  maybe  taken  as  about  '04  mm.,  but  sounds  are  easily 
audible  which  would  produce  movements  of  the  tympanic  membrane  quite 
imperceptible  under  this  method  of  examination.  On  the  inner  side  of 
the  tympanic  membrane  is  the  tympanic  cavity,  which  is  connected  in  front 
with  the  pharynx  by  means  of  the  Eustachian  tube.  This  is  opened  by  each 
movement  of  swallo\\4ng,  so  that  the  pressure  in  the  tympanum  is  kept  equal 
to  that  of  the  outside  air.  When  the  Eustachian  tube  is  blocked  or  diseased 
the  air  in  the  tympanum  is  gradually  absorbed  and  the  patient  becomes  deaf 
on  that  side.  Stretching  across  the  tympanum,  from  the  membrana  tympani 
to  the  outer  wall  of  the  internal  ear,  is  a  chain  of  ossicles,  which  are  named 
respectively  the  malleus,  the  incus,  and  the  stapes.  These  ossicles  are 
articulated  together,  so  that  a  movement  inwards  of  the  malleus  causes  a 
movement  inwards  of  the  base  of  the  stapes.  The  malleus,  or  hammer  bone, 
consists  of  a  thickened  head,  from  which  two  processes  nm,  \"iz.  the  manu- 
brium, which  is  attached  to  the  tympanic  membrane,  and  the  processus 
gracilis,  by  which  it  is  anchored  to  the  walls  of  the  tpnpanic  cavity.  By 
means  of  three  ligaments  it  is  so  fixed  that  it  is  capable  only  of  rotating 
around  a  horizontal  axis,  which  passes  through  the  anterior  hgament,  the 
head  of  the  malleus,  the  body  of  the  incus,  and  the  short  process  of  the  incus 
When  the  manubrium  is  pushed  inwards,  a  part  of  the  malleus  above  this 
axis  must  move  outwards.  The  incus,  sometimes  known  as  the  anvil  bone, 
is  articulated  with  both  the  stapes  and  the  malleus,  and  a  ligament  passes 
from  its  short  process  to  the  posterior  wall  of  the  tympanic  cavity.  The 
posterior  surface  of  the  rounded  head  of  the  malleus  fits  into  the  saddle- 
shaped  cavity  on  the  anterior  surface  of  the  incus,  while  the  tip  of  the  long 
process  of  the  incus  is  articulated  with  the  stapes.  Movement  inwards  or 
outwards  of  the  head  of  the  malleus  causes  rotation  of  the  incus  round  an 
axis  which  passes  from  the  tip  of  the  short  process  through  its  body.  Thus 
when  the  handle  of  the  malleus  moves  inwards  the  greater  part  of  the  body  of 

17 


514  PHYSIOLOGY 

the  incus  and  of  the  head  of  the  malleus  move  outwards  together,  while  the 
long  process  of  the  incus  moves  inwards.  The  stapes,  or  stirrup  bone,  is  fixed 
in  the  fenestra  ovalis  of  the  internal  ear,  in  the  inner  surface  of  the  tympanum, 
by  the  annular  Mgament.  It  is  placed  almost  at  right  angles  to  the  long 
process  of  the  incus,  and  therefore  is  pressed  into  the  foramen  ovale  when  this 
process  moves  inwards.  The  breaking  up  of  the  connection  between  the 
tympanic  membrane  and  the  foramen  ovale  into  three  bones,  connected  by 
joints,  must  tend  to  prevent  any  propagation  of  sound  by  direct  continuity  of 
substance.  The  vibrations  of  the  membrane  result  in  actual  movements  of 
the  whole  bones,  which  represent  a  chain  of  levers  reproducing  exactly  the 
movements  of  the  membrane.  In  the  transmission  of  a  sound  wave  from  the 
membrana  tympani  to  the  labyrinth  there  is  a  change  in  the  amount  of  force 
as  well  as  in  the  amphtude  of  the  movement.  The  three  bones  can  be 
regarded  as  forming  a  lever  with  two  arms,  one  of  which  is  the  manubrium 
of  the  malleus,  and  the  other  the  long  process  of  the  incus.  The  length  of 
the  former  is  to  that  of  the  latter  as  3  to  2,  so  that  the  movements  transmitted 
from  the  tympanic  membrane  to  the  base  of  the  stapes  are  diminished  in  the 
proportion  of  3  to  2  and  have  their  force  increased  in  the  proportion  of  2  to  3, 
Moreover,  as  the  drum  of  the  ear  has  an  area  which  is  about  twenty  times  that 
of  the  foramen  ovale,  the  energy  of  its  movements  is  concentrated  on  an  area 
twenty  times  smaller.  Hence  the  pressure  of  a  sound  wave  acting  on  the 
tympanic  membrane  is  increased  thirty-fold  (  ^  x  20)  when  it  acts  on  the 
base  of  the  stapes. 

The  computation  of  the  actual  energy,  involved  in  the  movement  of 
these  structures  by  sound  waves,  which  are  just  perceptible  to  the  ear,  yield 
striking  results  as  to  the  extreme  sensitiveness  and  efficiency  of  this  apparatus. 
Lord  Rayleigh  has  estimated  that  the  amplitude  of  the  movement  of  an 
aerial  particle  involved  in  the  propagation  of  sound  at  the  limits  of  audibility 
is  less  than  one  ten-milhonth  of  a  centimetre.  By  other  methods  it  has  been 
calculated  that  the  ear  is  affected  by  vibrations  of  molecules  of  the  air  not 
greater  than  -0004  mm.,  which  is  equal  to  0-1  of  the  wave  length  of  green 
light.  These  results  show  that  the  amounts  of  energy,  required  to  influence 
the  eye  and  the  ear  respectively,  are  of  the  same  order  of  magnitude. 

Two  muscles  are  found  in  the  tympanum,  viz.  the  tensor  tympani  and  the 
stapedius  muscles.  When  the  tensor  tympani  contracts  it  draws  the  handle 
of  the  malleus  inwards  and  so  increases  the  tension  of  the  tympanic  mem- 
brane. Direct  observation  has  shown  that  a  contraction  of  this  muscle 
occurs  whenever  sounds  fall  on  the  membrane,  and  that  this  reflex  contraction 
is  bilateral  even  when  the  stimulation  of  the  ear  is  unilateral.  The  stapedius 
muscle  tilts  the  base  of  the  stapes  and  at  the  same  time  draws  it  shghtly 
outwards,  so  relaxing  the  tympanic  membrane.  It  acts  therefore  as  an 
antagonist  to  the  tensor  tympani.  It  is  not  yet  known  what  exact  part 
this  muscle  plays  in  audition. 

THE  END-ORGANS  OF  HEARING 

The  movements  of  the  stapes  are  communicated  to  a  fluid,  the  perilymph, 
and  by  this  to  the  endolymph,  which  immediately  bathes  the  end-organ  of 


AUDITORY  SENSATIONS  515 

hearing.  The  internal  ear  consists  essentially  of  a  membranous  sac,  formed 
originally  by  an  involution  of  the  epithehum  covering  the  surface  of  the 
embryo.  In  the  course  of  development  the  sac,  which  is  filled  with  the 
endolymph,  becomes  much  modified  in  shape,  forming  from  before  back- 
wards the  scala  media  of  the  cochlea,  the  saccule,  the  utricle,  and  the  three 
semicircular  canals.  At  certain  parts  of  its  inner  surface  thickenings  of  the 
epithehum  occur,  which  become  connected  ^vith  the  terminations  of  the 
eighth  nerve.     The  membranous  labyrinth  hes  inside  a  bony  case,  the  osseous 


Flu.  249.      The  membranous  labyrinth. 
CM,    canalis    or  scala   media    of    the 
cochlea ;  5,  saccule  ;  «,  utricle ;  sc,  semi- 
circular canals. 


Fig.  250. 


Vertical  section  through  the 
cochlea. 


labyrinth,  from  which  it  is  separated  by  the  perilymph.  The  osseous  laby- 
rinth is  formed  from  before  backwards  by  the  cochlea,  the  vestibule,  and  the 
semicircular  canals. 

The  utricle,  the  saccule,  and  the  semicircular  canals  are  concerned  with 
the  functions  of  equihbration.  At  present  we  have  only  to  deal  with  the 
structure  of  the  cochlea  and  the  end-organs  contained  in  the  scala  media.  The 
cochlea  is  a  spiral  tube  of  bone  20  to  30  mm.  long,  divided  by  the  scala  media 
into  two  parts,  viz.  scala  vestibuh  and  scala  tympani,  which  are  continuous  at 
the  apex  of  the  spiral  (hehcotrema).  The  essential  part  of  the  organ  of  hear- 
ing is  contained  in  the  scala  media.  The  sound  waves  falling  on  the  ear  and 
striking  the  membrana  tympani  are  transmitted  with  diminished  amplitude 
but  increased  force  by  the  chain  of  ossicles  to  the  fenestra  ovahs  ;  through 
these  they  are  communicated  to  the  perilymph  which  fills  the  vestibule.  The 
vibrations  travel  from  the  vestibule  to  the  scala  vestibuli.  Every  rise  of 
pressure  in  this  canal  will  cause  an  actual  movement  of  fluid  and  will  push 
the  scala  media  towards  the  scala  tympani.  The  increased  pressure  thus 
communicated  to  the  scala  tympani  causes  a  bulging  of  the  membrane 
closing  the  foramen  rotundum.  Movement  inwards  of  the  stapes  causes 
therefore  a  movement  outwards  of  this  membrane  and  vice  versa,  and  the 
wave  of  pressure  in  passing  from  one  aperture  to  the  other  must  be 
connnunicated  to  the  scala  media  with  all  the  sensitive  structures  which  it 
contains. 

The  scala  media  is  triangular  in  cross-section,  ha\ang  its  apex  at  the 
spiral  lamina  and  its  base  at  the  outer  wall  of  the  cochlea.  It  is  separated  by 
the  membrane  of  Reissner  from  the  scala  vestibuli  and  by  the  basilar  mem- 
brane from  the  scala  tympani.  The  basilar  membrane  is  composed  of  a 
number  of  elastic  fibres,  which  pass  in  a  radial  direction  from  the  spiral 


516  PHYSIOLOGY 

lamina  to  the  spiral  crest  on  the  outer  wall  of  the  cochlea.  The  length  of 
these  fibres  increases  from  0'041  mm.  at  the  base  of  the  cochlea  to  0495  mm. 
at  the  helicotrema. 


n      sp.i 


Fig.  251.     Vertical  section  of  the  first  turn  of  the  human  cochlea.     (G.    Retzius.) 
s.v,  scala  vestibuli ;  s.t,  scala  tympani ;    d.c,  canal  or  duct  of  the  cochlea  ;  sf.l,  spiral 
lamina  ;  7i,  nerve  fibres  ;  l.sp,  spiral  ligament ;  sir.w,  stria  vascularis;  s.Sf,  spiral  sulcus  ; 
R,  section  of  Reissner's  membrane  ;  I,  limbus  laminae  spiralis  ;  m.t,  membrana  tectoria  ; 
iC,  tunnel  of  Corti ;   6.m,  basilar  membrane  ;   li.i,  h.e,  internal  and  external  hair-cells. 

The  end-organ  of  the  auditory  nerve  is  represented  by  the  organ  of  Corti, 
which  rests  on  the  basilar  membrane  (Fig.  252).     It  consists  of  a  double 


m.t 


B.M 


Fig.  252.     Section  through  the  end-organ  of.  the  auditory  nerve  in  the  cochlea 

(organ  of  Corti). 
BM,  basilar  membrane  ;    c,  canal  of  Corti ;   rc,  rods  of  Corti ;   ih  and  oh,  inner 
and  outer  hair-cells  ;   so,  sustentacular  cells  ;   An,  auditory  nerve  ;   mt,  membrana 
tectoria. 

row  of  stiff  cells,  the  inner  and  outer  rods  of  Corti,  which  run  throughout  the 
whole  length  of  the  scala  media  and  are  surrounded  by  sense  epithelium,  the 
hair-ce]]s.  On  the  inner  side  of  the  rods  of  Corti  there  is  a  single  row,  on  the 
outer  side  three  rows  of  hair-cells.  Between  the  hair-cells  are  the  sustenta- 
cular cells,  or  cells  of  Deiters,  the  peripheral   processes  from  which  join 


AUDITORY  SENSATIONS  517 

together  so  as  to  form  a  reticulate  membrane  over  the  hair-cells,  the  hairs 
themselves  projecting  through  orifices  in  the  membrane.  Resting  on  the 
upper  surface  of  the  membrana  reticularis  is  the  membrana  tectoria.  To  this 
membrane  is  often  ascribed  a  damping  effect  on  the  vibrations  of  the  struc- 
tures below.  Any  movement  of  the  basilar  membrane  would  be  transmitted 
to  the  rods  of  C'orti,  and  by  these  to  the  overlying  hair-cells.  With  every 
vibration  these  would  move  in  the  line  of  their  long  axis  so  that  their  hairs 
would  move  up  and  down  in  the  membrana  reticularis  and  possibly  strike 
against  the  under  surface  of  the  membrana  tectoria.  The  fibres  of  the 
auditory  nerve  pass  up  through  the  column  of  the  cochlea,  through  the 
bipolar  gangUon-cells  which  form  the  spiral  ganghon,  and  then  out  along 
grooves  in  the  spiral  lamina  to  end  in  arborisations,  partly  in  the  inner  hair- 
cells  and  partly  among  the  outer  hair-cells. 

The  complexity  of  the  structure  above  described  suggests  that  a  large 
amount  of  discriminating  and  analysing  power  possessed  by  the  ear  for 
sounds  of  different  qualities  is  determined  by  the  differentiation  of  the  end- 
organ  itself.  Not  only  are  we  able  to  appreciate  differences  in  ampUtude  and 
pitch  of  the  sound  waves  which  arrive  at  the  ear,  but  we  are  also  capable  of 
analysing  the  compound  sounds  and  determining  the  simple  tones  out  of 
which  they  have  been  composed.  This  power  of  analysis  must  be  due  either 
to  the  presence  of  some  battery  of  resonators  in  the  end-organs  of  the 
auditory  nerve,  or  to  the  existence  of  a  large  number  of  different  nerve 
fibres,  each  of  which  is  excited  only  by  a  distinct  number  of  vibrations  per 
second,  or,  finally,  Ave  must  assume  that  the  end-organ  of  hearing  is  affected 
as  a  whole  and  that  the  nerve  fibres  transmit  to  the  brain  the  dift'erent  forms 
of  wave  caused  by  various  complex  sounds,  the  analysis  being  carried  out 
in  the  cerebral  cortex  itself.  This  last  hypothesis,  the  relegation  of  the 
powers  of  analysis  to  the  cerebral  cortex,  is,  at  the  present  time  at  any  rate, 
equivalent  to  giving  up  any  attempt  to  explain  the  power  of  analysis 
possessed  by  the  organ  of  hearing.  On  the  other  hand,  the  complex  structure 
of  the  organ  of  Corti  suggests  that  here  we  have  an  actual  battery  of  resona- 
tors, by  means  of  which  sense  waves  are  analysed  into  their  components. 
This  is  Helmholtz's  theory  of  the  function  of  the  cochlea.  It  assumes  that  in 
the  organ  of  Corti  there  are  vibrating  structures  tuned  to  frequencies  within 
the  limits  of  hearing,  viz.  from  30  vibrations  to  about  4000  vibrations  per 
second.  We  can  distinguish  notes  in  the  middle  of  the  musical  scale  which 
differ  from  one  another  only  by  0-3  to  0-5  vibration  per  second.  Within  the 
limits  of  this  scale  we  should  therefore  require  about  4200  resonators  in  the 
ear.  In  order  to  account  for  the  sensitiveness  of  the  ear  to  sounds  below  40 
vibrations  and  above  4000  per  second,  we  might  allow  another  300  vibrators, 
so  that  4500  different  resonators  would  be  necessary  altogether.  Helmholtz 
at  first  thought  that  these  resonators  were  represented  by  the  arches  of  Corti, 
but  on  Hensen  pointing  out  that  the  basilar  membrane  was  composed  of 
fibres  varying  from  0*041  to  0-495  nun.  in  length,  he  concluded  that  it  was 
probably  the  breadth  of  the  basilar  membrane  which  deternu'ned  the  tuning 
to  any  particular  note.     This  membrane  from  its  structure  behaves  like 


518  PHYSIOLOGY 

a  system  of  stretched  strings  bound  together  by  a  semi-fluid  substance.  The 
parts  of  the  membrane  near  the  fenestra  rotunda  would  be  adapted  for  the 
higher  notes,  while  those  near  the  helicotrema  would  vibrate  to  deep  tones. 
Each  fibre  would,  by  its  vibration,  set  the  overlying  part  of  the  organ  of 
Corti  into  vibration,  so  that  each  nerve  fibre  composing  the  auditory  nerve 
would  be  stimulated  by  a  different  note.  Miiller's  law  of  specific  irritabihty  is 
thus  observed,  each  nerve  fibre  transmitting  an  impulse  which  excites  one 
quahty,  and  only  one  quahty,  of  sensation.  When  a  compound  wave  falls  on 
the  organ  of  Corti,  it  is  actually  resolved  into  its  simple  component  waves 
by  the  fibres  of  the  basilar  membrane,  and  we  therefore  get  stimulation  of  a 
number  of  nerve  fibres  and  a  sensation  produced  which  is  a  true  mixed  sensa- 
tion compounded  of  a  number  of  simple  tone  sensations.  By  an  effort  of 
attention  therefore  it  is  possible  to  pick  out  from  a  mixed  sensation  its 
different  components,  and  in  this  way  we  may  explain  the  analytic  powers  of 
the  ear. 

Certain  observations  on  fatigue  of  the  auditory  fibres  support  the  notion 
that  each  fibre  reacts  to  notes  of  one  pitch,  and  only  to  these  notes.  If  the 
vibrations  of  a  tuning-fork  be  conducted  by  two '  telephones  to  both  ears 
the  sound  appears  to  come  from  somewhere  in  front  of  the  middle  fine  of  the 
body.  If  the  sound  be  transmitted  to  one  ear  for  some  time  so  as  to  produce 
a  condition  of  shght  fatigue,  and  then  the  other  telephone  be  held  up  to  the 
other  unfatigued  ear,  the  sound  is  at  once  referred  to  the  unfatigued  side.  In 
this  locahsed  projection  of  the  sound  waves  we  have  a  simple  means  of 
judging  of  the  presence  or  absence  of  the  apparatus  in  one  ear  or  the  other. 
It  was  pointed  out  by  Bonders  that,  when  one  ear  was  fatigued  by  a  note  of 
360  vibrations  per  second,  and  immediately  afterwards  a  note  of  365  vibra- 
tions per  second  was  conducted  equally  to  both  ears,  no  trace  was  per- 
ceptible of  fatigue,  the  sound  being  located  exactly  in  the  median  line.  We 
are  therefore  justified  in  concluding  that  the  end-organ  of  the  nerve  fibre 
which  carries  the  nerve  impulses  corresponding  to  a  vibration  frequency  of 
360  per  second  is  not  the  same  as  the  nerve  fibre  or  end  apparatus  which 
evokes  the  sensation  corresponding  to  a  note  of  365  vibrations  per  second.  If 
this  theory  is  correct,  destruction  of  the  lower  part  of  the  cochlea  should 
abohsh  the  power  of  appreciation  of  high  notes,  while  damage  to  the  region 
of  the  hehcotrema  should  impair  sensibility  to  low  notes.  Certain  results  of 
experiments  on  dogs  afford  confirmation  of  this  view,  although  all  such  results 
involving  judgment  of  the  powers  of  appreciation  of  high  or  low  sounds 
respectively  possessed  by  animals  must  be  received  with  caution.  A  few 
isolated  cases  have  been  recorded  in  man  in  which  atrophy  of  the  nerve  fibres 
supplying  the  lower  whorl  of  the  cochlea  was  attended  by  total  want  of 
perception  of  high  tones. 

According  to  Rutherford,  the  whole  of  the  basilar  membrane,  and  therefore  of  the 
auditory  hairs,  vibrates  equally  to  every  note,  just  as  the  plate  of  a  telephone  receiver 
reproduces  faithfully  the  shape  of  the  vibrations  impinging  on  the  transmitter  of  the 
telephone.  This  '  telephone  theory,'  as  it  has  been  called,  relegates  the  whole  work 
of  analysis  to  the  central  nervous  system,  and  gives  us  no  clue  as  to  how  such  an  act 
of  analysis  may  take  place.     One  would  imagine  that  a  much  simpler  apparatus  than 


AUDITORY  SENSATIONS  519 

that  represented  by  the  organ  of  Corti  would  be  sufficient,  if  no  analysis  of  the  stimulus 
took  place  in  the  peripheral  organ. 

When  a  bow  is  drawn  against  the  edge  of  a  plate  the  vibrations  afifect  different 
parts  of  the  plate  unequally,  so  that  lycopodium  powder  sprinkled  on  such  a  plate 
assumes  a  complicated  pattern.  Waller  suggests  that  the  basilar  membrane  vibrates 
as  a  whole  to  every  tone,  but  that  it  presents  nodal  and  internodal  points,  like  the 
vibrating  plate.  Since  the  hair-cells  move  with  the  basilar  membrane  they  produce 
what  may  be  called  '  pressure  patterns  '  against  the  membrana  tectoria,  so  that  different 
combinations  of  nerve  fibres  are  stimulated  according  to  the  pattern,  i.e.  according 
to  the  shape  of  the  compound  wave.  A  somewhat  similar  hjrpothesis  has  been  put 
forward  by  Ewald,  but  neither  of  these  theories  presents  any  advantages  over  the 
resonator  theory  of  Helmholtz,  nor  does  it  account  satisfactorily,  as  the  Helmholtz 
theory  does,  for  the  remarkable  powers  we  possess  of  analysing  all  kinds  of  complex 
sounds.  The  cochlea  becomes  more  elaborate  in  structm'e  as  we  ascend  the  animal 
scale,  and  there  is  no  doubt  that  this  elaboration  attains  its  greatest  height  in  man, 
who  possesses  greater  powers  of  analysing  sounds  than  are  possessed  by  any  other 
animal. 


SECTION  V 

VOICE  AND  SPEECH 

The  development  of  the  analytical  powers  of  the  auditory  apparatus 
is  so  closely  connected  with  that  of  the  faculty  of  speech  that  we  may 
conveniently  deal  with  the  latter  at  this  point  rather  than  relegate  it  to 
a  chapter  on  special  muscular  mechanisms.  We  may  first  consider  the 
mechanism  of  production  of  voice,  which  man  shares  with  many  other 
animals,  before  discussing  the  mechanism  of  the  wholly  human  faculty 
of  speech. 

Voice  is  produced  in  the  larynx,  a  modified  portion  of  the  wind-pipe, 
by  the  vibrations  of  two  elastic  bands,  the  vocal  cords,  which  are  set  into 
action  by  an  expiratory  current  of  air  from  the  lungs.  In  many  respects 
the  larynx  resembles  a  reed  instrument,  in  which  a  current  of  air  is  caused  to 
vibrate  by  the  vibrations  of  an  elastic  tongue.  Whereas,  however,  the  period 
of  the  vibrations  in  such  an  instrument,  and  therefore  the  note,  is  deter- 
mined by  the  length  of  the  tube  which  is  attached  to  the  reed,  in  the  larynx 
the  note  produced  by  the  blast  of  air  is  modified  partly  by  alterations  in 
the  tension  of  the  vocal  cord,  and  partly  by  varjang  the  strength  of  the 
blast  of  air. 

ANATOMICAL  MECHANISM  OF  THE  LARYNX.  The  essentia]  framework 
of  the  larynx  is  formed  by  four  cartilages,  viz.  the  cricoid,  the  thjrroid,  and  the  two 
arytenoid  cartilages.  The  cricoid  cartilage,  which  lies  immediately  over  the  upper- 
most ring  of  the  trachea,  is  shaped  like  a  signet  ring,  the  small  narrow  part  being 
directed  forwards  and  the  broad  plate  backwards.  The  thyroid  cartilage  consists  of 
two  parts  or  alse,  joined  together  in  front  and  forming  the  prominence  known  as  Adam's 
apple  ;  beliind,  it  presents  four  processes  or  cornua,  the  superior  of  which  are  attached 
by  ligaments  to  the  hyoid  bone,  while  the  inferior  cornua  articulate  with  the  postero- 
lateral portion  of  the  cricoid  cartilage.  By  means  of  this  articulation  very  free  move- 
ment is  permitted  between  the  two  cartilages,  the  general  direction  of  movement  being 
one  of  rotation  of  the  cricoid  cartilage  on  the  thyroid,  round  a  horizontal  axis  directly 
through  the  two  articular  siu'faces  between  the  two  cartilages,  while  movements  of  the 
thyroid  upon  the  cricoid  are  also  possible  in  the  upward,  downward,  forward,  and  back- 
ward directions.  The  two  arytenoid  cartilages  are  pyramidal  in  shape.  By  their  bases 
they  articulate  at  some  distance  from  the  middle  line  with  convex  articular  surfaces 
.situated  in  the  upper  margin  of  the  plate  of  the  cricoid  cartilage.  The  anterior  angle 
of  the  base  is  the  vocal  process,  wliile  the  external  angle  is  the  muscular  process  of 
the  arytenoid.  The  crico-arytenoid  joints  permit  of  two  kinds  of  movements  of  the 
arytenoid  cartilages,  viz.  : 

(1)  Rotation  on  their  base  around  their  vertical  long  axis,  so  that  the  anterior 
vocal  process  is  rotated  outwards  and  the  muscular  process  backwards  and  inwards 
or  conversely. 

620 


VOICE  AND  SPEECH 


521 


(2)  Sliding  movements  of  the  whole  arytenoid  cartilage  either  outwards  or  inwards, 
so  that  their  inner  margins  may  be  drawTi  apart  or  approximated. 

The  larynx  is  covered  internally  by  a  mucous  membrane  continuous  with  that  of 
the  trachea.  It  is  lined  with  ciliated  epithelium,  except  over  the  vocal  cords,  where 
the  epithelium  is  stratified.  The  two  vocal  cords,  or  thyro-arytenoid  ligaments,  con- 
sist of  elastic  fibres  which  rim  from  the  middle  of  the  inner  angle  of  the  thjToid  carti- 
lage to  be  inserted  into  the  anterior  angle  of  the  arytenoid  cartilages.  Their  length 
in  man  is  about  15  mm.,  in  woman  about  11  mm. 
The  cleft  between  them  is  known  as  the  glottis,  or 
rima  glottidis. 

Two  ridges  of  mucous  membrane  above  and 
parallel  to  the  vocal  cords  are  the  false  vocal 
cords  (Fig.  253).  Between  the  true  and  the  false 
vocal  cords  on  each  side  is  a  recess  known  as  the 
ventricle  of  Morgagni.  This  ventricle  permits  the 
free  vibration  of  the  vocal  cords.  The  false  cords 
take  no  part  in  phonation,  but  help  to  keep  the 
true  cords  moistened  by  the  secretion  of  the 
numerous  mucous  glands  with  which  they  are 
provided.  The  position  and  tension  of  the  vocal 
cords  are  determined  by  the  action  of  the  various 
intrinsic  muscles  of  the  larynx.  The  part  taken 
by  the  various  muscles  in  each  movement  cannot 
be  directly  ascertained.  We  can  in  most  cases 
only  study  the  direction  of  the  fibres,  and  judge, 
from  this  direction  and  consequent  isolated  action 
of  the  muscles,  the  part  taken  by  any  given  muscle 
in  the  production  of  voice.  The  chief  muscles 
(Fig.  254)  are  as  follows  : 

(1)  The  crico-thyroid  muscle  is  a  short  triangular 
muscle  attached  below  to  the  cricoid  cartilage  and 
above  to  the  inferior  border  of  the  thyroid  carti- 
lage ;  the  fibres  pass  from  below  upwards  and 
backwards.  When  this  muscle  contracts,  the 
cricoid  cartilage  is  drawn  up  under  the  anterior 
part  of  the  thyroid  cartilage  so  that  its  broad 
expansion  behind  with  the  arytenoid  cartilages, 
is  drawn  downwards  and  backwards,  thus  putting 
the  vocal  cords  on  the  stretch.  This  muscle  is 
probably  the  most  important  in  determining  the 
teasion  of  the  vocal  cord. 

(2)  The  posterior  crico-arytenoid  muscle  arises 
from  a  broad  depression  on  the  corresponding 
half  of  the  posterior  sm'face  of  the  cricoid  cartilage 
its  fibres  converging,  to  be  inserted  into  the  outer  angle  of  the  arytenoid  cartilage. 
These  muscles  rotate  the  outer  angle  of  the  arytenoid  cartilages  backwards  and 
inwards.  They  thus  cause  a  movement  outwards  of  the  anterior  angles,  so  that 
the  glottis  is  widened.  During  every  act  of  inspiration  there  is  a  widening  of  the 
glottis,  which  is  probably  effected  by  contraction  of  these  muscles.  If  they  are  paralysed 
the  vocal  cords  are  approximated  and  tend  to  come  together  during  inspiration,  so  that 
dyspncea  may  be  produced. 

(3)  The  lateral  crico-arytenoid  muscle  arises  from  the  upper  border  of  the  cricoid 
cartilage  and  passes  backwards  to  be  inserted  into  the  muscular  process  of  the  arytenoid 
cartilage.  These  muscles  when  they  contract  pull  the  muscular  process  of  the  arytenoid 
cartilage  forwards  and  dowaiwards,  thus  approximating  the  vocal  cords  at  their  posterior 
ends  and  antagonising  the  action  of  the  jxjsterior  crico-arytenoid  muscles. 

(4)  The  ari/tenoid  muscles  consist  of  transver.se  fibres,  .some  of  which  decussate, 

17* 


Fig.  253.  Anterior  half  of  the  larynx, 
.seen  from  behind.  The  section  on 
the  right  side  is  somewhat  in  front 
of  the  left  side. 

e,  epiglottis ;  e',  cushion  of  epi- 
glottis ;  t,  thyroid  cartilage  ;  s,  s', 
ventricle  of  larjnx  ;  h,  great  coruu 
of  hyoid  bone  ;  t  a,  thjTO-arytenoid 
muscle;  t'/,  vocal  cords.  Above  the 
ventricles  are  the  false  vocal  cords, 
r,  first  ring  of  trachea. 

(A.  Thomson.) 

It  passes  upwards  and  outwards. 


522 


PHYSIOLOGY 


miiting  the  posterior  sui'face  of  the  two  arytenoid  cartilages.     When  they  contract 
they  draw  the  arytenoid  cartilages  together. 

(5)  The  thyro-arytenoid  muscles  consist  of  two  portions.  The  outer  fibres  rise  in 
front  from  the  thyroid  cartilage  and  pass  backwards  to  be  inserted  into  the  lateral 
border  and  the  muscular  process  of  the  arytenoid  cartilage.  Some  of  the  fibres  pass 
obliquely  upwards  towards  the  aryteno-epiglottidean  folds.  These  are  often  spoken 
of  as  a  separate  muscle,  the  thyro-epiglottidean.     By  their  action  they  tend  to  draw 


Fig.  254.  Muscles  of  the  larynx.  (Sappey.) 
A,  as  shown  in  a  view  of  the  larynx  from  the  right  side. 
1,  hyoid  bone  ;  2,  3,  its  cornua  ;  4,  right  ala  of  thyroid  cartilage  ;  5,  posterior  part  of 
the  same  separated  by  oblique  line  from  anterior  part ;  6,  7,  superior  and  inferior  tubercles 
at  ends  of  oblique  line  ;  8,  upper  cornu  of  thyroid  ;  9,  thyro-hyoid  ligament ;  10,  cartilago 
triticea  ;  11,  lower  cornu  of  thyroid,  articulating  with  the  cricoid;  12,  anterior  jDart  of 
cricoid ;  13,  crico-thyroid  membrane ;  14,  crico-thyroid  muscle ;  15,  posterior  crico- 
arytenoid muscle,  partly  hidden  by  thyroid  cartilage. 

B,  as  seen  in  a  view  of  the  larynx  from  behind. 
1,  posterior  crico-arytenoid ;    2,  arytenoid  muscle  ;    3,  4,  oblique  fibres  passing  around 
the  edge  of  the  arytenoid  cartilage  to  join  the  thyro-arytenoid,  and  to  form  the  aryteno- 
epiglottic,  5. 

the  arytenoid  cartilages  forwards  and  to  relax  the  vocal  cords.  The  upper  fibres  may 
also  assist  in  depressing  the  epiglottis.  The  inner  fibres  are  called  the  musculus  vocalis. 
They  arise  from  the  lower  half  of  the  angle  of  the  thjrroid  cartilage,  and  passing  back- 
wards in  the  vocal  cords  are  attached  to  the  vocal  processes  and  to  the  adjacent  parts 
of  the  outer  surfaces  of  the  arytenoid  cartilages.  Many  fibres  do  not  run  the  whole 
distance,  but  end  in  an  attachment  to  some  part  of  the  vocal  cord.  Although  their 
action  must  be  to  draw  the  arytenoid  cartilages  forwards,  yet,  since  they  are  contained 
in  the  vibrating  portion  of  the  vocal  cords,  they  cannot  by  their  contraction  relax 
these  cords.  It  is  probable  that  they  play  a  great  part  in  determining  the  tension  of 
the  vocal  cords  after  these  have  been  put  on  the  stretch  by  the  action  of  the  crico- 
thyroid muscles.  They  may  possibly  act  as  a  sort  of  fine  adjustment  of  the  tension, 
the  coarse  adjustment  being  represented  by  the  crico-thyroids. 


VOICE  AND  SPEECH  :m 

THE  PRODUCTION  OF  VOICE 

In  order  to  study  the  changes  in  the  larynx  which  are  associated  with 
voice  production  we  must  make  use  of  the  laryngoscope.  The  principle 
of  this  instrument  is  very  simple.  A  large  concave  mirror  with  a  central 
aperture  is  fixed  before  one  eye  of  the  observer,  sitting  in  front  of  the  patient 
or  person  to  be  observed.  The  latter  is  directed  to  throw  his  head  slightly 
backwards  and  to  open  his  mouth.  In  order  to  keep  the  tongue  out  of  the 
way  the  patient  is  made  to  hold  the  end  of  it  by  means  of  a  towel.  The 
mirror  is  then  so  arranged  as  to  reflect  light  from  a  lamp  into  the  cavity 
of  the  mouth.  A  small  mirrer  fixed  in  a  handle  is  then  warmed,  so  as  to 
prevent  the  condensation  of  the  patient's  breath,  and  passed  to  the  back 
of  the  mouth  until  it  rests  upon  and  shghtly  raises  the  base  of  the  uvula. 
By  this  mirror  the  light  reflected  into  the  mouth  from  the  large  mirror  is 
again  reflected  down  on  to  the  larynx,  and  a  reflection  of  the  larynx  and 
trachea  is  seen  in  the  mirror.  By  laryngoscopic  examination  we  can  see 
the  base  of  the  tongue,  behind  which  is  the  outhne  of  the  epiglottis.  Behind 
this  again  in  the  middle  line  are  seen  the  two  vocal  cords,  white  and  shining 
(Fig.  255).  The  cords  appear  to  approximate  posteriorly  ;  between  them 
is  a  narrow  chink,  the  diameter  of  which  varies  with  each  respiration,  being 
wider  during  inspiration.  On  each  side  of  the  true  vocal  cords  are  seen 
the  pink  false  vocal  cords.  In  some  cases  the  rings  of  the  trachea,  and  even 
the  bifurcation  of  the  trachea  itself  (Fig.  255,  c),  may  be  seen  in  the  interval 
between  the  vocal  cords. 

In  order  that  the  vocal  cords  may  be  set  into  vibration,  they  must  be  put 
into  a  state  of  tension  and  the  aperture  of  the  glottis  narrowed,  so  as  to 
afford  resistance  to  the  current  of  air.  In  the  dead  larynx  it  is  possible 
to  produce  sounds  by  forcing  air  from  bellows  through  the  trachea,  after 
the  vocal  cords  have  been  put  on  the  stretch  by  pulling  the  arytenoid 
cartilages  backwards.  By  experimenting  on  patients  on  whom  tracheotomy 
has  been  performed,  it  has  been  found  that  the  pressure  of  air  in  the  trachea, 
necessary  to  cause  production  of  voice,  is,  for  a  tone  of  ordinary  loudness 
and  pitch,  between  140  and  240  mm.  of  water,  and  with  loud  shouting 
the  pressure  rises  to  as  much  as  945  mm.  of  water.  This  pressure  is  furnished 
by  the  contraction  of  the  expiratory  muscles,  i.e.  of  the  abdomen  and  of  the 
thorax.  Since  the  pitch  of  the  note  produced  rises  with  increasing  force 
of  the  blast,  while  the  tension  of  the  cords  remains  constant,  it  is  evident 
that,  in  the  act  of  '  swelhng  '  on  a  note,  the  increased  pressure  necessary 
for  the  crescendo  must  be  associated  with  diminishing  tension  of  the  cords. 
It  is  the  failure  to  secure  this  nuiscular  relaxation  that  so  often  causes  a 
singer  to  sing  sharp  when  swelling  on  any  given  note. 

The  voice,  like  the  sound  produced  on  any  musical  instrument,  may 
vary  either  in  pitch,  loudness,  or  in  quality  or  timbre.  The  range  of  any 
individual  voice  is  generally  about  two  octaves.  The  pitch  of  the  voice 
usually  employed  is  determined  chiefly  by  the  length  of  the  vocal  cords. 
Thus  in  children  the  voice  is  high-pitched.     Before  and  at  puberty  there 


524  PHYSIOLOGY 

is  a  considerable  development  in  the  size  of  the  larynx  in  both  sexes.  This 
is  especially  marked  in  the  male,  and  accounts  for  the  sudden  drop  in  pitch 
('  breaking ')  of  the  voice.  In  the  female  the  increased  size  of  the  larynx 
is  chiefly  perceptible  in  the  increase  in  fulness  and  richness  of  the  voice 
which  occurs  at  this  age.     Even  when  we  take  all  the  voices  together, 


Fig.  255.  Three  laryngoscopic  views  of  the  superior  aperture  of  the  larynx  and 
surrounding  parts  in  different  states  of  the  glottis  during  life.  (From  Czermak.  ) 
A,  the  glottis  during  the  emission  of  a  high  note  in  singing.  B,  in  easy  or 
quiet  inhalation  of  air.  C,  in  the  state  of  widest  possible  dilatation,  as  in  inhaling 
a  very  deep  breath.  The  diagrams  A',  B',  C  have  been  added  to  Czermak's 
figures  to  show  in  horizontal  sections  of  the  glottis  the  position  of  the  vocal  liga- 
ments and  arytenoid  cartilages  in  the  three  several  states  represented  in  the  other 
figures.  In  all  the  figures  so  far  as  marked,  the  letters  indicate  the  parts  as  follows, 
viz.  :  I,  the  base  of  the  tongue  ;  e,  the  upper  free  part  of  the  epiglottis  ;  e',  the 
tubercle  or  cushion  of  the  epiglottis  ;  p  h,  part  of  the  anterior  wall  of  the  pharynx 
behind  the  larynx  ;  in  the  margin  of  the  aryteno-epiglottidean  fold  w,  the  swelling  of 
the  membrane  caused  by  the  cuneiform  cartilage  ;  s,  that  of  the  corniculum  ;  a, 
the  tip  of  the  arj^enoid  cartilages ;  c  v,  the  true  vocal  cords  or  lips  of  the  rima 
glottidis ;  CVS,  the  superior  or  false  vocal  cords  ;  between  them  the  ventricle  of 
the  larynx  ;  in  C,  <  r  is  placed  on  the  anterior  wall  of  the  receding  trachea,  and  b 
indicates  the  commencement  of  the  two  bronchi  beyond  the  bifurcation,  which 
may  be  brought  into  view  in  this  state  of  extreme  dilatation. 

bass,  tenor,  alto,  and  soprano,  the  total  range  for  ordinary  individuals  does 
not  exceed  three  octaves.  In  singing  the  voice  may  be  produced  in  various 
ways,  i.e.  in  different  registers.  Thus  we  distinguish  the  chest  register,  the 
middle  register,  and  the  head  register.  The  deeper  notes  of  any  individual 
voice  are  always  produced  in  the  chest  register.  Observation  of  the  vocal 
cords  shows  that  when  producing  such  notes  the  glottis  forms  an  elongated 
slit,  all  the  muscles  which  close  the  glottis  and  increase  the  tension  of  the  cords 
being  in  action.  The  vocal  cords  are  relatively  thick  and  broad  and  can 
be  seen  to  vibrate  over  their  whole  extent.     When  singing  with  the  head  voice 


VOICE  AND  SPEECH  525 

the  vibrations  of  the  cord  are  apparently  confined  to  their  inner  margins  ; 
the  aperture  of  the  glottis  is  wider  in  front  than  behind,  so  that  more  air 
escapes  during  phonation  by  this  method  than  in  the  production  of  the 
chest  voice. 

In  order  to  change  the  pitch  of  the  note  the  following  means  are  probably 
employed  in  the  larynx  : 

(1)  Alteration  in  the  tension  of  the  vocal  cords. 

(2)  Alteration  in  the  length  of  the  part  of  the  vocal  cords  which  is 
free  to  vibrate,  which  can  be  accompUshed  by  the  approximation  of  the 
arytenoid  cartilages  to  one  another,  or  by  their  approximation  to  the  thyroid 
cartilage. 

(3)  The  alteration  in  the  shape  of  the  vocal  cords,  which  is  determined  by 
the  activity  of  the  different  portions  of  the  internal  thyro- arytenoid  muscles. 

(4)  The  varying  pressure  of  the  blast  of  air  passing  through  the 
glottis. 

The  loudness  of  the  tone  produced  is  practically  proportional  to  the 
force  of  the  blast  of  air  employed.  The  quality  or  timbre  of  the  voice 
depends  not  so  much  on  the  vocal  cords  as  on  the  accessory  resonating 
apparatus,  represented  by  the  trachea  and  chest  and  by  the  cavity  of  the 
mouth.  The  greater  part  of  the  education  involved  in  voice  training  is 
directed  to  the  modification  of  the  shape  of  the  mouth  cavity,  so  as  to 
secure  the  greatest  possible  fulness,  i.e.  richness  in  overtones,  of  the  tone 
produced  in  the  larynx. 

THE  MECHANISM  OF  SPEECH 

The  sounds  employed  in  speech,  viz.  vowels  and  consonants,  are  produced 
by  modifying  the  laryngeal  tones  by  changes  in  the  shape  of  the  mouth  and 
nasal  cavities.  In  whispering  speech  there  is  no  phonation  at  all,  but  the 
sound  is  produced  by  the  issue  of  a  blast  of  air  through  a  narrow  opening 
between  the  Ups,  between  the  tongue  and  soft  palate,  or  between  the  tongue 
and  the  teeth. 

The  vowel  sounds  are  continuous,  whereas  the  consonants  are  produced 
by  interruptions,  more  or  less  complete,  of  the  outflowing  air  in  dift'erent 
situations.  The  vowel  sounds,  u,  o,  a,  e,  i  (pronounced  oo,  oh,  ah,  eh,  ee), 
are  tones,  i.e.  are  produced  by  a  regular  series  of  vibrations.  These  tones 
take  their  origin  in  the  mouth  cavity,  as  can  be  shown  easily  by  the  fact 
that  we  can  whisper  these  soimds  distinctly  without  any  phonation  what- 
ever. To  each  of  them  corresponds  one  or  two  distinct  notes,  the  pitch,  i.e. 
the  resonance,  of  which  is  regulated  by  the  shape  of  the  cavity  in  which 
they  are  produced.  It  is  possible  to  determine  these  notes  by  means  of 
resonators.  The  pronunciation  even  of  the  simplest  vowel  sounds  differs 
in  dift'erent  individuals.  For  instance,  those  pronounced  by  a  Londoner 
dift'er  from  those  pronounced  by  a  man  from  Manchester  or  from  Yorkshire, 
and  the  French  vowels  differ  somewhat  in  pitch  from  those  employed 
by  the  German,  and  these  again  from  those  employed  by  the  average  English- 
man. 


526  PHYSIOLOGY 

The  characteristic  notes  were  given  by  Helmholtz  as  follows  : 

U  =  f 

0  =  b' 
A  =  b" 
E  =  f,  b"' 

1  =  f,  d'^' 


a] 


U 


i^^i: 


o 


E 


If  the  five  vowels  are  whispered  loudly,  the  gradual  rise  in  pitch  of  the 
tone  is  easily  perceptible.  We  do  not  in  this  way,  however,  note  the 
lower  component  of  the  sound  in  the  E  and  I ;  this  can  be  brought  out  by  a 
simple  device  (Fig.  256).  If  we  place  the  mouth  in  the  position  necessary 
to  produce  these  different  vowels,  and  then  percuss  over  the  cheek,  we 
obtain  the  typical  note  for  each  vowel,  the  air  in  the  mouth  cavity  being 
set  into  vibration  by  the  percussion.  Now  shift  the  finger,  which  is  to  be 
percussed,  so  that  it  lies  over  the  pharynx,  just  behind  the  angle  of  the 
jaw,  and  percuss  again.     The  note  will  be  observed  to  rise  with  U,  0,  A, 


A  (ah)  U{oo)  1  (ee) 

Fig.  256.     Shape  of  the  oral  cavity  in  the  production  of  the  vowel  sounds,  A,  U,  I. 

(Grutzner.) 

and  then  fall  with  E.  I.  With  the  three  vowels  U,  0,  A,  we  have  a  single 
cavity  formed  by  the  hps,  the  palate,  and  the  tongue  ;  this  cavity  is  longest 
and  narrowest  with  U  and  shortest  and  most  open  with  A.  With  E  and  I 
the  dorsum  of  the  tongue  comes  up  against  the  front  part  of  the  soft  palate, 
so  that  the  mouth  cavity  is  divided  into  two,  the  anterior  short  narrow 
cavity,  and  the  posterior  broader  cavity  between  the  soft  palate  and  the 
base  of  the  tongue.  We  therefore  have  two  notes  produced,  one  in  each 
cavity.  The  change  in  shape  of  the  mouth  cavity  is  shown  in  the  figures. 
With  U  and  A  the  cavity  seems  to  be  single  ;  with  I  the  development  of 
a  pharyngeal  resonating  cavity  is  well  shown.  Diphthongs  are  produced 
by  changing  the  form  of  the  mouth  cavity  from  that  of  one  vowel 
sound  to  another,  thus  AI  (the  Enghsh  i)  =  ah-ee  run  together  and 
abbreviated. 

Consonants  are  sounds  produced  by  a  sudden  check  being  placed  in  the 
course  of  the  expiratory  blast  of  air  by  closure  of  some  part  of  the  pharynx 


VOICE  AND  SPEECH  527 

or  mouth.  They  are  classified,  into  labials,  dentals,  or  gutturals,  according 
as  the  check  takes  place  at  the  lips,  between  teeth  and  tongue,  or  between 
back  of  tongue  and  soft  palate.  Each  of  these  again  can  be  divided  into 
soft  and  hard  consonants  as  they  are  accompanied  or  not  with  phonation. 
Thus  when  we  pronounce  D  the  production  of  the  laryngeal  sounds  goes  on 
during  the  check  of  the  sound  produced  at  the  teeth,  whereas  ^^^th  T  there 
is  an  absolute  interruption  of  phonation  during  the  pronunciation  of  the 
consonant.  It  is  thus  practically  impossible  to  make  any  marked  difEerence 
between  hard  and  soft  consonants  when  whispering. 

In  the  production  of  nasal  sounds  such  as  NG-  the  mechanism  is  the 
same  as  for  the  production  of  B,  D,  G,  except  that  the  posterior  opening 
of  the  nares  is  not  kept  shut  by  the  soft  palate,  so  that  part  of  the  sound 
comes  continually  through  the  nasal  passages,  when  it  acquires  a  peculiar 
resonance.  These  sounds  are  on  this  account  often  spoken  of  as  '  resonants.' 
The  aspirates  are  produced  by  the  passage  of  a  simple  blast  of  air  through 
a  narrow  opening  which  may  be  at  the  throat  as  in  H,  between  tongue  and 
teeth  as  in  TH,  or  between  lips  and  teeth  as  in  PH  or  F. 

The  vibratives,  such  as  R,  are  formed  by  placing  the  tip  of  the  tongue 
or  the  uvula,  or  the  lips,  in  the  path  of  the  blast  of  air  so  that  they  are  set 
into  vibration  by  the  blast.  In  Enghsh  the  vibrative  R  employed  is  entirely 
due  to  the  tongue. 

The  sibilants,  which  may  be  voiceless  as  in  '  S  '  or  accompanied  with 
phonation  as  in  '  Z,'  consist  of  continuous  noises  produced  by  a  narrowing 
of  the  path  of  the  air  between  the  tongue  and  the  hard  palate.  They  are 
therefore  similar  in  production  to  the  aspirates.  In  the  production  of  the 
sound  '  L  '  the  tongue  is  applied  by  its  edge  to  the  alveolar  process  of  the 
upper  jaw,  so  that  the  air  or  voice  escapes  by  two  small  apertures  in 
the  region  of  the  first  molar  and  between  the  inner  side  of  the  cheek  and 
the  teeth.  The  acoustic  characters  of  these  various  consonants  are  stiU  but 
imperfectly  studied. 


VISION 

SECTION    VI 

DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 

When  light  falls  on  any  object  a  certain  proportion  of  it  is  reflected  and 
scattered,  and  will  affect  any  organism  in  the  neighbourhood  possessing 
sensibiUty  to  light.  Mere  sensibility  of  the  surface  to  hght  would  not, 
however,  suffice  to  arouse  projected  sensations,  since  the  rays  of  hght  from 
a  number  of  different  objects  would  interfere  with  one  another.  An  animal 
with  such  sensibiUty  would  be  aware  of  or  be  able  to  react  to  differences 
of  hght  and  darkness,  but  could  not  direct  its  movements  in  accordance 
with  the  nature  of  the  objects  from  which  the  hght  proceeded.  For  this 
purpose  there  must  be  not  only  a  surface  sensitive  to  hght  impressions 
but  also  dioptric  mechanisms,  by  means  of  which  a  real  image  of 
external  objects,  in  their  proper  spatial  relationships,  is  thrown  on  to  an 
extended  sensory  surface.  Each  point  in  this  surface  will  correspond  to 
a  point  lying  outside  the  body  and  serving  as  a  source  of  hght,  and  the 
sensations  evoked,  since  they  correspond  to  the  rays  of  hght  coming  from 
external  objects,  can  be  projected,  and  referred  to  the  objects  themselves 
lying  outside  and  at  some  distance  from  the  body. 

The  organ  of  vision,  the  eye,  consists  of  two  parts,  viz.  : 

(a)  The  sensory  surface  or  retina,  composed  of  a  number  of  areas,  each 
of  which  can  be  separately  stimulated  by  hght. 

(6)  A  dioptric  mechanism  for  projecting  a  real  image  of  external  objects 
on  this  sensory  surface. 

We  have  in  fact  an  arrangement  very  analogous  to  a  photographic 
camera,  where  a  real  image  is  thrown  by  a  lens  on  to  a  sensitive  plate,  each 
point  of  which  undergoes  chemical  change  in  proportion  to  the  amount 
of  incident  hght,  so  that  a  photographic  record  is  the  result. 

THE  FORMATION  OF  AN  IMAGE  BY  A  LENS 
We  may  confine  our  attention  to  the  case  of  a  bi-convex  lens,  and  we  may 
assume  in  the  first  place  that  the  thickness  of  the  lens  is  neghgible.  In 
Fig.  257  c  and  c'  are  the  centres  of  the  sperical  surfaces  bounding  the  lens  ; 
the  hue  joining  them  is  the  optical  axis  of  the  lens.  The  surface  at  q  is 
parallel  to  the  surface  at  r,  so  that  a  ray  of  hght,  such  as  pq  falhng  on  the 

528 


DIOPTEIC  MECHANISMS  OF  THE  EYEBALL 


529 


lens  at  Q,  will  leave  the  lens  at  r  in  direction  rs  parallel  to  pq.  The  point 
o  where  the  ray  cuts  the  optical  axis  is  known  as  the  optical  centre  of  the 
lens.  This  optical  centre  in  a  bi-convex  lens  lies  within  the  lens,  its  distance 
from  the  two  surfaces  being  practically  as  their  radii. 


Fig.  257. 

Since  we  are  neglecting  the  thickness  of  the  lens  the  line  pqrs  may  be 
regarded  as  straight,  so  that  we  may  say  that  the  rays  which  pass  through 
the  centre  of  a  lens  do  not  deviate.  If  a  pencil  of  parallel  rays  falls  upon 
the  lens,  while  those  rays  which  pass  through  the  optic  centre  undergo  no 
deviation,  all  the  others  on  leaving  the  lens  wiU  be  convergent  towards 
a  point  which  is  known  as  the  principal  focus  of  the  lens  (Fig.  258).     Con- 


Fiu.  258.     Diagram  of  the  course  of  parallel  rays  through  a  bi-couvex  Icus   by 
which  they  are  converged  to  the  principal  focus,  f. 


Fig.  259. 


The  rays  of  light  from  a  converge  on  passing  through  the  lens  to  the 
secondar}'  focus,  f.     f  and  a  arc  conjugate  foci. 


versely,  if  a  point  of  hght  be  placed  at  the  principal  focus  the  rays  of  light 
passing  through  it  to  the  lens  will  take  the  reverse  course  and  leave  the 
lens  as  a  bundle  of  parallel  rays.  Any  point  of  light  situated  between 
infinite  distance  and  the  principal  focus  Avill  have  a  corresponding  point 
on  the  other  side  of  the  lens  to  which  its  rays  will  converge.  Such  corre- 
sponding points  are  known  as  a  conjugate  foci  (Fig.  259).     In  a  thin  lens, 


530  PHYSIOLOGY 

with  the  same  media  on  each  side,  the  anterior  and  posterior  focal  distances 
are  the  same,  so  that  from  which  ever  direction  a  parallel  beam  falls  on  the 
lens  the  point  to  which  its  rays  are  converged  on  the  other  side  of  the  lens 
is  constant. . 

If  instead  of  a  point  of  hght  we  have  a  series  of  points  such  as  that  coming 
from  a  bright  hne  in  the  plane  of  the  paper  (as  in  Fig.  260),  each  of  these 
points  will  have  a  corresponding  point  on  the  opposite  side  of  the  lens. 
Thus  from  the  point  p  three  rays  may  be  taken,  viz.  : 


Fig.  260. 

(1)  The  ray  po,  which  passes  through  the  centre  of  the  lens  and  does  not 
deviate. 

(2)  The  ray  pe,  which  is  parallel  to  the  axis  and  therefore  is  converged 
to  the  principal  focus  (j)^. 

(3)  The  ray  pg,  which  passes  through  the  focus  on  the  front  surface 
of  the  lens  0^  and  therefore  takes  a  course  on  the  other  side  of  the  lens 
parallel  to  the  axis.  The  intersection  of  any  two  of  these  three  hues  will 
be  the  situation  of  the  image  p  to  the  point  p.  In  the  same  way  all  the  other 
points  in  the  object  will  have  a  corresponding  image  on  the  opposite  side, 
so  that  an  inverted  real  image  of  the  luminous  object  is  formed  on  this 
side. 

The  size  of  the  image  as  compared  with  the  object  will  depend  on  the 
distance  of  the  object  from  the  lens.  It  is  greater  than  the  object  if  the 
latter  is  less  than  2/  (twice  the  focal  distance)  from  the  lens,  equal  if  the 
distance  is  2/,  and  diminished  if  the  distance  is  greater  than  2/. 

A  lens  with  a  focal  distance  of  1  metre  is  taken  as  unit  strength. 
Such  a  lens  is  said  to  have  a  strength  of  one  dioptre  ;  a  lens  of  two 
dioptres  would  have  a  focal  distance  of  \  metre ;  of  four  dioptres  one 
of  |-  metre,  and  so  on. 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 

The  eye  is  not  directly  comparable  to  a  camera  in  its  optical  arrange- 
ments, since  the  image  is  formed,  not  in  air,  but  in  the  fluids  of  the  eye 
itself.     Moreover  the  conditions  are  complicated  by  the  facts  that  it  is 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 


531 


impossible  to  neglect  the  thickness  of  the  refractive  media,  and  that  these 
are  many  in  number. 

If  we  take  the  simplest  case,  where  there  are  only  two  media  separated  from  one 
another  by  a  spherical  surface  of  contact,  we  can  easily  determine  the  course  taken 
by  any  ray  in  passing  from  the  first  to  the  second  medium. 

In  Fig.  261  (from  Landois)  let  L  be  the  hrst  {e.g.  air)  and  G  the  second  {e.g.  glass). 
These  are  separated  by  the  spherical  surface  ab,  with  its  centre  at  m.     Since  all  the 


a 

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h 

2 

n      p 

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Fig.  261. 


radii  drawn  from  m  to  ah  are  perpendicular  to  the  surface  all  rays  falling  in  the  direction 
of  the  radii  must  pass  unrefracted  through  m.  All  rays  of  this  sort  are  called  rays 
or  lines  of  direction  ;  m,  as  the  point  of  intersection  of  all  these,  is  called  the  ncdal 
point.  The  line  wliich  comiects  m  with  the  vertex  of  the  spherical  siirface,  .r,  and  which 
is  prolonged  in  both  directions,  is  the  optic  axis,  OQ.  A  plane  (ef)  in  x,  perpendicular 
to  OQ,  is  called  the  principal  plane,  and  in  it  x  is  the  principal  point.  The  following 
facts  have  been  ascertained  :  (1 )  All  rays  {a  to  a^),  which  in  the  first  mechum  are  parallel 
with  each  other  and  with  the  optic  axis,  and  fall  upon  ab,  are  so  refracted  in  the  second 
medium  that  they  are  all  again  united  in  one  point  {pi)  of  the  second  medium.  This 
is  called  the  second  principal  focus.  A  plane  in  this  point,  perpendicular  to  OQ,  is 
called  the  secoml  focal  plane  (cd).  (2)  All  rays  (c  to  Co).  which  in  the  first  medium 
are  parallel  to  each  other,  but  not  parallel  to  OQ,  reunite  in  a  point  of  the  second  focal 
plane  (r),  where  the  non-refracted  directive  ray  (c-i???.r)  meets  this.  (In  this  case  the 
angle  formed  by  the  rays  c  to  Co  with  OQ  must  be  very  small.)  Tlie  propositions  1  and 
2,  of  course,  may  be  reversed  ;  the  divergent  rays  proceeding  from  pk  towards  ah  pass 
into  the  first  medium  parallel  to  each  other,  and  also  with  the  axis  oq  (o  to  05)  ;  and 
the  rays  proceeding  from  r  pass  into  the  fii'st  medium  parallel  to  each  other,  but  not 
parallel  to  the  axis  oq  (as  c  to  (•2)-  (3)  AH  rays,  which  in  the  second  medium  are 
parallel  to  each  other  {h  to  65)  and  with  the  axis  oq,  reunite  in  a  ])oint  in  the  first  medium 
{p)  called  the  first  focal  point  ;  of  course,  the  converse  of  this  is  true.  A  plane  in  this 
point  pcrj)endicular  to  oq  is  called  the  first  focal  plane  (ab).  The  radius  of  the  refractive 
surface  (»i:r)  is  equal  to  tlie  difi'erenee  of  the  distance  of  both  focal  points  (;>  and /)i) 
from  the  princi})al  focus  (;r)  ;   tluis  mx  =  piX  —  px. 

In  compound  systems  composed  of  several  refractive  media  witli  splierieal  surfaces 
of  contact,  such  as  the  eye.  we  may  proceed  from  medium  to  medium  with  the  same 
methods  as  those  just  described.  Since,  however,  sucli  a  procedure  would  be  very 
tedious,  the  method  first  ^jroposed  by  Gauss  is  usually  adopted.  Gauss  showed  that 
if  the  several  media  are  '  centred  ' — i.e.  if  all  have  the  same  optic  axis — then  the  refractive 
indices  of  such  a  centred  system  may  be  represented  by  two  equally  strong  refractive 


532 


PHYSIOLOaY 


surfaces  at  a  certain  distance  apart.  The  rays  falling  upon  the  first  surface  are  not 
refracted  from  it,  but  are  regarded  as  projected  forwards  parallel  with  themselves  to 
the  second  surface.  Refraction  is  then  considered  to  take  place  at  the  second  surface 
just  as  if  that  were  the  only  surface  present  (represented  by  the  dotted  line  II  in 
Fig.  262). 


Fig. 


262.     The  position  of  the  cardinal  points  in  the  schematic  eye.     (Helmholtz.) 
h„  h,,,  principal  points  ;   Ic,,  k,„  nodal  points  ;   p^„  posterior  focus. 


All  such  systems  possess  three  pairs  of  cardinal  points,  viz.  two  principal 
foci,  two  principal  points,  and  two  nodal  points.  These  points  may  be 
defined  by  the  following  principles  : 

[a)  Rays  which  pass  through  the  principal  focus  are,  after  refraction, 
parallel  to  the  optic  axis. 

(6)  Rays  which  pass  through  the  first  principal  point,  after  refraction, 
pass  through  the  second. 

(c)  Rays  which  pass  through  the  first  nodal  point,  after  refraction  pass 
through  the  second,  and  the  direction  of  the  refracted  ray  is  parallel  to  the 
direction  of  the  incident  ray. 

In  Fig.  262  the  situation  of  these  cardinal  points  is  shown  in  the  human 
eye.  The  rays  of  Hght  pass  through  the  following  media,  cornea,  aqueous 
humour,  lens,  and  vitreous  humour,  and  may  be  refracted  at  the  following 
surfaces  ;  anterior  and  posterior  surfaces  of  the  cornea,  anterior  and  posterior 
surfaces  of  the  lens.  Since,  however,  the  refractive  indices  of  cornea, 
aqueous  humour,  and  vitreous  humour  are  practically  identical,  we  can 
reduce  the  refractive  media  to  two,  viz.  cornea,  aqueous,  and  vitreous 
in  the  one  case,  and  lens  in  the  other  ;  and  the  refractive  surfaces  to  three, 
viz.  anterior  surface  of  cornea,  anterior  surface  of  lens,  and  posterior  surface 
of  lens. 

In  order  to  determine  the  path  of  the  rays  in  the  eye  we  have  to  deter- 
mine the  following  data,  viz.  : 

(1)  The  radius  of  curvature  of  the  anterior  surface  of  the  cornea. 

(2)  The  distance  of  the  anterior  surface  of  the  cornea  from  the  anterior 
surface  of  the  lens. 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 


533 


(3)  The  radius  of  curvature  of  the  anterior  surface  of  the  lens. 

(4)  The  thickness  of  the  lens. 

(5)  The  radius  of  curvature  of  the  posterior  surface  of  the  lens. 

In  addition  we  must  know  the  refractive  index  of  the  cornea  and 
aqueous  or  vitreous  humour,  and  also  the  average  refractive  index  of  the 
lens.  There  is  a  considerable  difference  between  the  refractive  indices  of 
the  outer  and  the  inner  portions  of  the  lens,  the  inner  part  being  much 
denser  and  having  a  higher  refractive  index  than  the  periphery.  The 
following  Table  represents  the  constants  of  a  human  eye  as  determined  by 
Helmholtz  : 


Refractive  index  of  aqueous  and  vitreous  humours 

1-3365 

Total  refractive  index  of  lens         ...... 

1-4371 

mm. 

Radius  of  curvature  of  cornea       ...... 

8 

„                  ,,             anterior  surface  of  lens 

10 

„                  ,,             posterior  surface  of  lens 

6 

Distance  from  anterior  surface  of  cornea  to  anterior  surface  of 

lens     . 

3-6 

„                        „                     „                   posterior         surface 

of  lens 

7-2 

Anterior  focus  of  cornea       ....... 

23-692 

Posterior  focus  of  cornea 

31-692 

Focus  of  lens       .... 

43-707 

Posterior  focus  of  eye 

19-875 

Anterior  focus  of  eye  . 

14-858 

Distance  from  anterior  siurface  of  corne 

X  to  : 

First  principal  point 

1-9403 

Second  principal  point 

2-3565 

First  nodal  point 

6-957 

Second  nodal  point 

7-373 

Anterior  focus  of  eye 

12-918 

Posterior  focus  of  eye     . 

22-231 

It  will  be  seen  that  both  the  principal  points  lie  in  the  anterior  chamber, 
while  the  nodal  points  fall  in  the  back  part  of  the  lens.  The  posterior  focus 
of  the  eye  falls  upon  the  retina.  For  many  purposes  we  may  simplify  our 
calculations  by  running  the  two  principal  points  and  the  two  nodal  points  into 
one.  In  such  a  reduced  eye  the  single  principal  point  is  situated  2-3  mm.  behind 
the  anterior  surface  of  the  cornea,  and  the  single  nodal  point  0'47  mm.  in 
front  of  the  hinder  surface  of  the  lens.  If  a  circle  be  drawn  from  the  single 
nodal  point  as  a  centre  through  the  single  principal  point  as  a  circumference 
we  get  a  surface  II  in  the  figure,  which  represents  the  anterior  refracting 
surface  of  such  a  reduced  eye. 

A  reference  to  the  Table  of  Constants  of  the  human  eye  shows  that, 
whereas  the  anterior  focal  distance  of  the  cornea  is  23  mm.,  that  of  the  whole 
eye  is  15  mm.  and  that  of  the  lens  44  mm.  It  is  evident  from  this  that  the 
anterior  surface  of  the  cornea  is  the  most  important  refractive  surface  of  the 
eye,  and  that,  in  the  convergence  of  rays  necessary  for  the  formation  of  an 
image  on  the  retina,  it  is  the  refraction  at  this  surface  which  plays  the 


534  PHYSIOLOGY 

greatest  part.  Under  water  this  refraction  is  of  course  aboKshed,  since  the 
refractive  indices  of  the  aqueous  humour  and  cornea  are  practically  identical 
with  that  of  water.  The  eye  therefore  becomes  long-sighted  ;  it  is  impossible 
to  get  any  clear  image  of  near  objects,  and  distant  objects  can  only  be  seen 
with  a  strong  eSort  of  accommodation.  A  smaller  effect  is  produced  by 
removal  of  the  lens,  an  operation  often  undertaken  when  this  body  has 
become  opaque  as  a  result  of  cataract.  Such  an  operation  not  only  aboHshes 
the  power  of  accommodation  of  the  eye,  but  diminishes  the  refractive  power 
of  the  eye  at  rest  by  ten  dioptres,  so  that  a  lens  of  this  power  has  to  be  placed 
at  the  front  of  the  eye  in  order  to  render  possible  clear  vision  of  distant 
objects. 

PART  OF  THE   RAYS  IN  THE  FORMATION  OF  THE 
RETINAL  IMAGE 

In  the  reduced  eye  the  construction  of  the  path  of  the  rays  is  very  simple. 
When  the  eye  is  focused  for  the  object  which  is  being  looked  at,  the  rays  from 
any  point  of  the  object  come  to  a  point  on  the  retina.  All  that  is  necessary 
therefore  is  to  draw  lines  from  points  of  the  object  through  the  single  nodal 
point  to  the  retina,  as  is  shown  in  Fig.  263.     The  image  thus  produced,  like 


Fig.  263.     Path  of  the  rays  in  the  formation  of  an  image  on  the  retina. 

that  produced  by  a  bi-convex  lens,  is  real,  inverted,  and  diminished  in  size. 
The  further  the  distance  of  the  object  from  the  retina  the  smaller  will  be  its 
image  on  the  retina.  The  angle  formed  at  the  junction  of  two  hues  drawn 
from  the  extreme  points  of  an  external  object  to  the  nodal  point  is  the 
'  visual  angle.' 

In  the  schematic  eye  a  visual  angle  of  sixty  seconds  corresponds  to  a 
distance  on  the  retina  between  the  two  ends  of  the  image  of  -00438  mm. 
Few  people  can  distinguish  two  points  of  light  the  line  joining  which  sub- 
tends a  smaller  visual  angle  than  sixty  seconds.  If  we  measure  the  histo- 
logical elements  in  the  centre  of  the  retina  which  are  responsible  for  distinct 
vision,  viz.  the  cones,  we  find  that  in  the  yellow  spot  each  cone  is  about  -002 
to  -005  mm.  thick.  The  hmits  of  our  power  of  distinguishing  two  luminous 
points  is  approximately  in  agreement  with  the  diameter  of  each  end- organ 
of  vision.  In  order  that  the  images  of  the  two  points  may  give  rise  to  dis- 
tinct sensations  their  images  must  fall  upon  different  cones.  This  fineness 
of  vision  exists  only  at  the  yellow  spot,  the  accuracy  of  vision  in  the  peripheral 
parts  of  the  retina  being  very  much  lower.     Not  only  is  the  image  less 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 


535 


perfectly  focused,  but  the  number  of   sensory  elements  in  a  given  area  of 
the  retina  diminishes  steadily  as  we  pass  from  centre  to  periphery. 


OPTICAL  DEFECTS  OF  THE  EYE 

The  normal  eye  is  so  constructed  that  parallel  rays  come  to  a  point  on  the 
retina.  Rays  which  are  divergent  when  they  fall  on  the  anterior  surface  of 
the  cornea  are  brought  therefore  to  a  focus  behind  the  retina. 

In  such  an  eye  any  object  lying  at  a  distance  nearer  than  five  metres 
would  give  rise  to  an  image  behind  the  retina,  were  it  not  for  the  fact  that 
the  eye  possesses  means  of  altering  its  focus  and  so  of  bringing  divergent  rays 
to  a  focus  on  the  retina  ;  this  means 
is  known  as  accommodation.  In  a 
photographic  camera  the  process  of 
focusing  is  carried  out  by  altering  the 
distance  between  the  lens  and  the 
sensitive  plate.  The  same  method  is 
adopted  in  the  eyes  of  certain  animals. 
In  the  mammalian  eye,  however,  ac- 
commodation for  near  objects,  i.e.  the 
focusing  of  divergent  rays  on  to  the 
retina,  is  accomplished  by  a  change  in 
the  curvature  of  the  lens.  The  lens 
becomes  more  convex  on  its  anterior 
surface,  so  that  its  refractive  power  is 
increased  and  the  hinder  focus  of  the 
dioptric  mechanism  of  the  eye  is  there- 
fore diminished.  Every  eye  possesses 
a  certain  definite  range  of  vision,  which, 
in  a  normal  person,  has  its  far  point 
at  infinite  distance  and  its  near  point 
at  a  distance  from  the  eye  which  depends  on  the  elasticity  of  the  lens 
and  the  range  through  which  this  can  alter  its  curvature. 

The  normahty  of  an  eye  is  determined  by  the  fact  that  parallel  rays  come 
to  a  focus  on  the  retina  when  the  apparatus  of  accommodation  is  at  rest. 
Two  classes  of  de\aation  from  this  normal,  or  enmietropic,  eye  are  common. 
In  the  first  class  parallel  rays  come  to  a  focus  in  front  of  the  retina.  In  such 
eyes,  which  are  designated  myopic,  it  is  impossible  to  get  a  clear  image  on  the 
retina  of  distant  objects.  In  order  that  the  rays  may  be  focused  on  the 
retina  they  must  be  divergent,  so  that  even  when  accommodation  is  para- 
lysed the  far  point  of  distant  vision  Hes  at  some  finite  distance  from  the  eye, 
varying  with  the  extent  of  the  disorder.  If  in  such  eyes  the  range  of 
accommodation  is  normal,  the  near  point  will  be  much  nearer  to  the  eye  than 
in  the  emmetropic  eye  (Fig.  26J:). 

The  second  class  of  abnormal  eyes  are  known  as  hypermetropic.  These 
eyes  can  be  regarded  as  too  short  for  their  refractive  media.     Parallel  rays 


Fig.  264.  Diagrams  of  course  taken 
by  parallel  rays  in  entering  normal 
(emmetropic)  eye  (a),  hyper-metro- 
pic  eye  (b),  and  myopic  eye  (c). 


536  PHYSIOLOGY     , 

are  brought  to  a  focus  at  a  point  behind  the  retina.  Persons  so  afiected  can 
see  objects  at  a  distance,  but  always  with  some  effort  of  accommodation. 
If  accommodation  be  paralysed  by  means  of  atropine  everything  will  appear 
blurred.  Since  accommodation  is  required  even  for  infinite  distance,  the 
greatest  possible  effort  will  be  insufficient  to  bring  near  objects  into  accurate 
focus,  and  the  near  point  of  such  eyes  will  be  greater  than  normal.  Persons 
with  hypermetropia,  or  long-sightedness,  can  therefore  see  objects  at  a  dis- 
tance perfectly  well,  but  are  unable  to  read  small  print,  since  the  point  of 
near  vision  is  too  far  from  the  eye  to  allow  the  small  letters  to  subtend  a 
sufficiently  large  angle. 

Both  these  disorders  can  be  corrected  by  suitable  spectacles.  In  the 
case  of  the  myopic  eye  we  need  lenses  which  will  convert  the  parallel  rays  into 
divergent  rays  ;  such  cases  are  treated  therefore  with  concave  lenses.  Con- 
versely, hypermetropia  is  treated  with  convex  lenses,  which  will  aid  the  too 
feeble  refractive  power  of  the  eye,  and  so  bring  parallel  rays  to  a  focus  on 
the  retina  without  any  effort  of  accommodation.  The  degree  of  myopia 
or  hypermetropia  is  denoted  by  the  refractive  power  of  the  lens  which  is 
necessary  to  make  the  eye  emmetropic. 

In  order  to  determine  the  refractive  power  of  any  eye  it  is  usual  to  employ  Snellen's 
test  type.  This  consists  of  a  series  of  letters  which  are  placed  at  a  distance  of  five 
metres  from  the  eye.  At  this  distance  the  visual  angle  subtended  by  each  of  these 
letters  is  so  small  that  a  clear  retinal  image  is  necessary  for  their  recognition.  This 
is  easy  in  the  case  of  a  normal  eye.  After  allowing  the  patient  to  attempt  the  recogni- 
tion of  the  type  without  spectacles  he  is  then  made  to  regard  it  through  a  weak  convex 
lens.  If  the  patient  can  now  read  as  well  as  or  better  than  before  he  is  hypermetropic, 
since  it  is  only  the  hypermetropic  eye  which  is  able  to  unite  convergent  rays  of  light 
on  to  the  retina.  If,  on  the  other  hand,  the  reading  of  the  type  is  made  more  difficult 
the  patient  is  either  normal  (emmetropic)  or  myopic.  In  the  latter  case  a  concave 
lens  is  tried.     If  the  reading  is  rendered  more  easy  by  this  means  the  patient  is  myopic. 

In  prescribing  the  lenses  for  hypermetropia,  the  strongest  lens  with  which  the 
patient  is  able  to  see  represents  the  degree  of  hypermetropia.  Since  now  the  mechanism 
for  accommodation  mtLst  be  relaxed  as  far  as  is  possible,  the  strength  of  such  a  lens 
serves  as  a  measure  of  the  degree  of  hypermetropia.  On  the  other  hand,  in  myopia 
the  degree  of  the  disorder  is  determined  by  the  weakest  lens,  by  means  of  which  the 
patient  is  able  to  see  distant  objects. 

In  a  perfect  dioptric  mechanism  the  media  through  which  the  hght 
passes  must  be  perfectly  transparent,  and  the  centres  of  curvature  of  the 
various  refracting  surfaces  must  he  in  one  straight  hne,  i.e.  the  system  must 
be  properly  centred.  In  neither  of  these  respects  can  the  eye  be  regarded  as 
perfect.  If  a  strong  beam  of  Hght  be  thrown  into  the  eye,  the  refraction  of 
the  beam  caused  by  the  shght  difference  in  structure  between  adjacent 
portions  of  the  cornea  and  lens  makes  these  objects  immediately  visible,  and 
the  field  of  vision  is  filled  with  diffused  light  arising  from  the  illuminated 
points  in  these  structures.  Under  normal  circumstances,  however,  these 
shght  differences  in  the  regularity  of  the  refracting  media  do  not  make  any 
appreciable  difference  to  our  vision.  More  easily  detected  are  the  opacities 
due  to  structures  in  the  vitreous  humour.  These  opacities  can  be  seen,  when 
the  eyes  are  turned  towards  a  uniformly  illuminated  surface,  as  small  dark 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL  537 

points  or  strings  of  beads,  which,  since  they  alter  their  position  with  changes 
in  the  direction  of  the  eyes,  are  often  spoken  of  as  muscce  volitantes.  The 
centring  of  the  eye  is  also  never  perfect.  In  the  horizontal  meridian  the 
optic  axes  of  the  cornea  only  diverge  about  0  3°  from  the  axis  of  the  lens, 
but  in  the  vertical  meridian  there  is  as  much  as  1*3°  difference  between  the 
two  axes.  Moreover  the  visual  axis  does  not  correspond  exactly  with  the 
optic  axis  of  the  eye.  The  fovea  centralis,  the  point  of  distinct  vision  on 
which  the  image  of  any  object  must  be  brought  in  order  to  see  it  as  distinctly 
as  possible,  always  hes  outside  and  somewhat  below  the  point  at  which  the 
optic  axis  strikes  the  retina.  The  angle  between  the  two  axes  is  often  spoken 
of  as  the  angle  a.  This  angle  in  the  horizontal  meridian  varies  between  3*5° 
and  7°,  and  in  the  vertical  meridian  is  about  3-5°, 

Although  this  divergence  of  the  axes  causes  a  certain  amount  of  astigma- 
tism {v.  p.  538),  it  is  too  small  to  interfere  appreciably  with  the  sharpness 
of  vision. 

SPHERICAL  ABERRATION.  When  a  beam  of  parallel  rays  falls  on  to 
the  surface  of  a  spherical  lens  those  rays  which  pass  through  the  circum- 
ference are  converged  to  a  focus  which  lies  nearer  to  the  lens  than  the  focus 
of  those  rays  which  pass  through  its  centre.  In  an  optical  instrument  the 
blurring  of  the  image  thus  produced  is  counteracted  in  two  ways  : 

(1)  By  making  the  curvature  in  the  middle  of  the  lens  greater  than  at  its 
periphery. 

(2)  By  stopping  out  the  peripheral  rays  by  means  of  a  diaphragm,  or  by 
using  only  a  cyhnder  cut  from  the  centre  of  the  lens.  It  is  famihar  to  every 
photographer  that  where  sharpness  of  definition  is  required  it  is  necessary  to 
use  a  small  stop,  giving  a  corresponding  increased  exposure. 

In  the  eye  spherical  aberration  is  diminished  by  both  these  means.  The 
curvature  of  the  lens  is  greater  towards  its  centre  than  at  its  circumference, 
and  the  peripheral  rays  of  hght  are  shut  out  by  a  circular  diaphragm,  the  iris, 
the  diameter  of  the  aperture  in  which  varies  according  to  the  amount  of 
light  falhng  into  the  eye,  and  according  to  the  nearness  of  the  object  which  is 
the  point  of  regard. 

CHROMATIC  ABERRATION.  The  refraction  of  hght  in  passing  from 
a  lighter  to  a  denser  medium  is  due  to  the  fact  that  in  the  latter  the  velocity 
of  propagation  of  the  light  is  less  than  in  the  former.  This  diminution  of  the 
velocity  of  the  propagation  affects  rays  of  various  wave-lengths  differently, 
so  that  of  the  various  rays  which  make  up  white  hght  those  at  the  red  end 
with  a  long  wave-length  are  refracted  least,  and  those  at  the  violet  end  with 
a  short  wave-length  are  refracted  the  most.  On  this  account,  when  light 
passes  into  a  prism  it  is  split  up  into  its  component  rays  with  the  production 
of  a  spectrum.  The  same  splitting  up  of  rays  occurs  when  hght  passes 
through  a  simple  lens.  As  is  shown  in  Fig.  265,  the  violet  rays  come  to  a 
focus  at  a  point  nearer  the  lens  than  the  red  rays.  A  screen  held  at  v  will 
therefore  show  a  bluish- violet  centre  with  a  red  margin  ;  at  r  the  centre  will 
be  reddish  and  the  margin  \'iolet. 

In   optical    instruments    this    chromatic    aberration    is    corrected    by 


538 


PHYSIOLOGY 


combining  glasses  of  different  powers  of  dispersion,  with  the  production  of  so- 
called  achromatic  lenses.  In  the  eye  achromatism  is  practically  uncorrected. 
The  difference  in  the  focus  of  red  and  violet  rays  in  the  eye  amounts  to  about 
0-5  mm.  ;  hence,  if  we  are  looking  at  a  red  and  a  violet  spot  situated  close 
together,  it  requires  a  greater  act  of  accommodation  to  bring  the  image  of 
the  red  spot  on  the  retina  than  is  the  case  with  the  violet  spot.  The  red 
spot  therefore  looks  nearer,  i.e.  more  prominent.     It  may  be  this  special 


V    ^ 


effort  of  accommodation  necessary  for  the  appreciation  of  red  that  makes 
this  colour  stand  out,  so  to  speak,  and  be  conspicuous  as  compared  with  the 
other  colours  of  the  spectrum. 

The  fact  that  as  a  rule  we  do  not  see  coloured  fringes  around  every  object 
that  we  look  at  is  due,  not  to  the  optical,  but  to  the  physiological  quahties  of 
the  eye.  When  white  hght  falls  on  the  eye  and  is  focused  by  the  latter  on  to 
the  retina,  it  will  be  the  rays  of  medium  refrangibiHty  which  come  to  a  point 
at  the  retina ;  these  optically  will  be  surrounded  with  a  halo  composed  of 
the  red  and  violet  rays,  as  is  shown  in  the  figure  at/.  The  retina  is,  however, 
comparatively  insensitive  for  rays  at  the  two  extreme  ends  of  the  spectrum. 
Moreover  the  strong  illumination  produced  by  the  middle  rays  of  the 
spectrum,  i.e.  about  the  yellow,  at  the  centre  of  the  illuminated  spot,  by 
contrast  depresses  the  excitabihty  of  the  surrounding  parts  of  the  retina, 
so  that  the  halo  due  to  the  red  and  violet  rays  is  neglected  and  does  not  come 
into  consciousness. 

ASTIGMATISM.  We  have  assumed  so  far  that  the  refracting  surfaces 
of  the  eye  are  practically  spherical ;  this  does  not  apply  strictly  either  to  the 
cornea  or  the  lens.  The  small  differences  between  the  curvatures  of  the 
cornea  in  the  horizontal  and  vertical  meridian  towards  its  centre  do  not 
as  a  rule  give  rise  to  appreciable  disorders  of  vision.  In  many  cases,  however, 
the  asymmetry  in  the  anterior  surface  of  the  cornea  is  sufficient  to  cause  a 
considerable  difference  in  the  refraction  of  rays  in  the  different  meridians,  and 
this  disturbance  is  known  as  astigmatism. 

The  curvature  of  the  vertical  meridian  of  the  cornea  is  nearly  always 
somewhat  greater  than  that  of  the  horizontal  meridian.  When  this  difference 
is  sufficiently  pronounced  it  becomes  impossible  for  a  definite  image  of  a 
point  of  light  to  be  formed  on  the  retina,  since  the  rays  which  diverge  from 
the  luminous  point  in  the  vertical  plane  are  brought  to  a  focus  sooner  than 
those  in  a  horizontal  plane.  Such  an  eye  will  therefore  possess  two  posterior 
foci,  one  for  the  vertical  meridian,  the  other  for  the  horizontal  meridian.  The 
manner  in  which  such  rays  diverge  is  shown  in  Fig.  266. 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 


539 


The  ett'ects  of  astigmatism  are  especially  noticeable  when  the  patient  is 
trying  to  see  clearly  objects  composed  of  horizontal  and  vertical  lines,  such 
as  print.  A  vertical  hne  can  be  conceived  as  made  up  of  a  series  of  points 
each  of  which  sends  out  a  horizontal  sheaf  of  rays.  In  the  same  way  a 
horizontal  line  is  distinguished  as  a  series  of  points  sending  out  flat  sheafs 
of  vertical  rays.  If  the  curvature  of  the  cornea  in  the  vertical  meridian  is 
greater  than  in  the  horizontal  it  will  need  a  greater  effort  of  accommodation 
to  bring  the  vertical  Hnes  to  a  focus  on  the  retina  than  it  does  to  bring  the 
horizontal  lines.  In  reading  therefore  there  is  a  constant  shifting  of  the  focus 
of  the  eye,  and  the  mechanism  of  accommodation  becomes  rapidly  tired  and 


Fig.  266.  Diagram  showing  course  of  rays  in  an  astigmatic  eye.  (Waller.) 
The  curvature  of  the  cornea  is  greater  in  the  vertical  meridian  vvv  than  in  the 
horizontal  meridian  hhh.  Hence  the  rays  of  light  coming  from  the  point  p  and 
passing  through  the  vertical  meridian  come  to  a  focus  at  f^,  while  those  through 
the  horizontal  meridian  come  to  a  focus  at/^.  There  is  thus  no  point  behind  the 
cornea  at  which  all  the  rays  from  p  will  come  to  a  focus,  and  the  image  of  the  point 
must  be  blurred,  being  elongated  in  a  horizontal  direction  at/i,  and  in  a  vertical 
direction  at /^. 

strained,  with  the  production  of  pain  in  the  eyes  or  of  headache.  In  order  to 
correct  astigmatism  it  is  necessary  to  find  out  first  the  curvature  of  the  corner 
in  the  different  meridians,  and  then  to  reinforce  the  curvature  of  the  weakei 
meridian  by  means  of  a  cylindrical  lens.  If  the  eye  is  myopic  the  cyhndrical 
lens  may  be  concave  and  placed  so  that  its  curvature  counteracts  that  of  the 
cornea  in  the  meridian  in  which  the  curvature  is  greatest. 


ACCOMMODATION 

The  rays  falling  on  the  eye  from  a  point  of  light  at  a  distance  greater  than 
five  metres  from  the  eye  may  be  regarded  as  practically  parallel,  and  are 
converged  in  the  normal  eye  to  a  focus  on  the  retina.  As  the  point  of  light 
is  moved  nearer  to  the  eye  the  latter  is  still  able  to  focus  the  rays  on  the 
retina  through  a  considerable  range.  On  approximating  the  points  of  light 
to  a  distance  which  is  less  than  the  near  point  of  distinct  vision,  the  rays  are 
no  longer  converged  to  a  point  on  the  retina,  and  a  blurred  image  is  the 
result.  This  near  point  of  vision  may  be  determined  in  any  eye  by  finding  out 
the  smallest  distance  from  the  eye  at  wliich  small  print  can  be  easily  dis- 
tinguished. The  distance  is  measured  by  means  of  a  graduated  rod  between 
the  eye  and  the  printed  object.  This  '  accommodation,'  by  which  the 
eye  is  able  to  focus  divergent  rays  on  to  the  retina,  imphes  either  a  change 
in  the  distance  of  the  refracting  surfaces  from  the  retina,  or  an  increase 
in  the  total  refractive  powers  of  the  eye. 

In  man  and  the  higher  animals  it  is  by  the  latter  means  alone  that 


540 


PHYSIOLOGY 


Fig.  267.     Diagram  of  phakoscope. 


accommodation  is  effected.  The  fact  that  accommodation,  as  was  shown 
by  Young,  may  be  carried  out  under  water,  i.e.  under  conditions  in  which  the 
curvature  of  the  cornea  does  not  cause  any  appreciable  deviation  of  the  rays 
passing  through  it,  shows  that  the  change  in  the  combination  cannot  be 
located  in  the  cornea.     It  was  shown  by  Helmholtz  that  the  essential  process 

in  accommodation  is  an  altera- 
tion in  the  curvature  of  the 
lens,  the  anterior  surface  be- 
coming more  convex  when  the 
eye  is  accommodated  for  near 
objects. 

This  may  be  shown  by  means 
of  the  phakoscope  (Fig.  267). 
This  is  simply  a  box,  blackened 
inside,  with  holes  at  a,  6,  c, 
and  d.  At  a  is  the  observer's 
eye  ;    at  6  the  observed  eye.  Across  the  middle  of  (Z  a  wire  is  stretched. 

A  candle  is  placed  at  c.  The  observer  at  a  then  sees  three  reflections 
of  the  candle  from  the  eye  at  6  :  a  bright  erect  image  from  the  anterior 
surface  of  the  cornea  ;  a  larger  but  dimmer  erect  image  from  the  anterior 
surface  of  the  lens ;  and  a  small  very  dim  inverted  image  from  the 
posterior  surface  of  the  lens.  These  images  must  be  observed  first  when 
the  eye  at  h  is  accommodated  for  a 
distant  object,  and  then  when  it  is 
accommodated  for  the  wire  stretched 
across  the  opening  d.  It  will  be 
noticed  that  the  change  of  accom- 
modation from  far  to  near  objects  is 
accompanied  by  a  change  in  the 
second  image  (that  from  the  anterior 
surface  of  the  lens),  which  becomes 
smaller.  The  change  in  this  image 
is  more  easily  seen  if  the  candle  be 
made  to  throw  two  images  on  the 
eye  by  interposing  a  double  prism 
at  c.  Then,  as  the  lens  becomes  more 
convex  to  accommodate  for  near  objects,  the  two  images  of  the  candle 
reflected  from  its  anterior  surface  approach  one  another  (Fig.  268). 

By  measuring  the  size  of  the  image  of  the  candle-flame  produced  by  the 
anterior  surface  of  the  lens,  and  knowing  the  size  of  the  flame  itself  and  the 
distance  from  the  observed  eye,  it  is  possible  to  calculate  the  curvature  of  the 
lens  in  the  living  body. 

The  radius  of  curvature  of  a  reflecting  surface  is  given  approximately  by  the  follow- 
ing formula  : 

R  =2-— 


a         b         to  a         b         c 

Fig.  268.  Diagram  of  reflected  images 
from  cornea  and  lens  surfaces  seen  in 
phakoscope. 

a,  from  anterior  surface  of  cornea  ; 
h,  from  anterior  surface  of  lens  ;  c,  from 
posterior  surface  of  lens.  1,  during  accom- 
modation for  distance  ;  2,  during  accom- 
modation for  near  objects. 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 


541 


where  R  is  the  radius  of  curvature,  a  tha  distance  of  the  object,  b  the  size  of  the  image, 
C  the  size  of  the  object.  The  object  generally  used  is  the  distance  between  two  lights 
or  two  white  objects  called  mires  ;  the  '  image  '  being  the  distance  between  their  images. 
Owing  to  the  movements  of  the  eye  the  latter  cannot  be  accurately  measiired  by  the 
usual  method,  employed  by  physicists,  of  looking  at  the  images  thi'ough  a  telescope 
which  has  a  micrometer  at  the  focus  of  the  object.  This  difficulty  is  overcome  by 
doubling  the  image.  For  this  purpose  Helmholtz  devised  the  ophthalmometer,  in  which 
the  doubling  is  brought  about  by  two  plane  glass  plates  set  at  a  variable  angle  to  one 
another.  The  principle  of  the  instrument  can  be  gathered  from  the  diagram  (Fig.  269). 
We  may  suppose  it  is  necessary  to  measm-e  the  line  ah,  which  may  be  taken  to  repre- 
sent an  image  reflected  from  the  anterior  surface  of  the  cornea  or  lens.  If  we  look 
at  this  line  through  a  plate  of  glass  the  plane  of  which  is  at  right  angles  to  our  line 
of  sight,  no  distortion  of  the  line  ab  takes  place.     If,  however,  the  plate  be  placed 


Fig.  269.     Diagram  to  illustrate  principle  of 
ophthalmometer.     (After  Schenck.) 

obliquely,  as  at  g^  g^,  there  will  be  an  apparent  shifting  of  the  line  sideway  to  cd.  In 
the  ophthalmometer  there  are  two  glass  discs,  g^  g^,  and  g.^  i72»  one  immediately  over 
the  other,  so  placed  that  the  image  ah  is  looked  at  thi'ough  the  junction  between  the 
two  plates.  The  plates  are  then  turned,  as  in  the  diagram,  until  ab  appears  as  two 
distinct  lines  ec  and  cd  just  touching  one  another  at  c.  At  this  point  each  image  of 
the  line  ah  has  been  shifted  through  one  half  the  length  of  ab.  Knowing  the  thickiiess 
of  the  plates  and  their  refractive  index,  it  is  easy  to  calculate,  from  the  angle  through 
which  the  plates  have  been  turned,  the  apparent  shifting,  of  the  line  ah.     This  lateral 

movement  amounts  to  ac,  i.e.  to  — ,  and  we  have  merely  to  double  this  result  in  order 

Ji 

to  obtain  the  actual  size  of  the  image  on  the  cornea  or  lens. 

A  table  is  generally  supplied  with  the  instrument  giving  the  actual  size  of  the  image 
corresponding  to  the  angle  through  which  the  plates  have  been  turned  ;  the  eye  always 
being  placed  at  a  constant  distance  from  the  instrument  and  the  luminous  object 
always  being  the  same  size. 

The  size  of  the  image  is  calculated  in  the  following  way  *  : 

"Let  aa  (Fig.  270)  be  one  of  the  plates,  AB  the  incident,  CD  the  refracted  lay. 
Then,  since  the  refracted  ray  is  parallel  to  the  incident  ray,  the  angle  ABN  is  equal 


*  Parson's  "  Elementary  Ophthalmic  Optics. 


542  PHYSIOLOGY 

to  the  angle  DON'  ( =  a).  Similarly  the  angle  of  refraction  CBn  is  equal  to  the  angle 
BCn'  ( =  /3).  Let  h  be  the  thickness  of  the  glass  plate.  Produce  DC  backwards  to 
A'.     It  is  required  to  find  the  perpendicular  distance  between  A  and  A'  ( =  x). 

X 

Now  -g^  =  sin  BGA' 

=  sin  {n'CA'  -  n'CB) 
=  sin  (a  —  /3). 

And  -gp  =  cos  j3. 

sin  (a  —  /3) 

Therefore  x  =  ft.. g — . 

cos  /j 

If  there  are  two  such  plates,  arranged  as  in  Fig.  269,  then 

ab  =  2x 

cos  fi 

The  angle  a  is  measured  by  the  instrument  ;  the  angle  /3  is  calculated  from  the 
formula  for  refraction,  sin  a  =  n.  sin  /3  ;  and  the  thickness  of  the  plates,  h,  is  known. 
Therefore  the  distance  between  the  images  can  be  calculated." 

In  the  normal  eye  in  a  position  of  repose,  i.e.  focused  for  parallel  rays, 
the  curvatures  of  the  three  principal  refracting  surfaces  are  as  follows  : 

mm. 
Anterior  surface  of  cornea        ....  8 

Anterior  surface  of  lens  ....         10 

Posterior  surface  of  lens  ....  6 

During  maximum  accommodation  the  radius  of  curvature  of  the  anterior 
surface  of  the  lens  changes  to  6  mm.  At  the  same  time  there  is  a  slightly 
increased  curvature  at  the  periphery  of  the  posterior  surface,  but  the  effects 
of  this  change  are  neghgible  as  compared  with  those  produced  by  the  altera- 
tion of  the  anterior  surface. 

In  order  to  determine  the  method  in  which  this  change  in  curvature  of 
the  anterior  surface  of  the  lens  is  brought  about  we  must  refer  in  some  detail 
to  the  structure  of  the  anterior  half  of  the  eye  and  the  manner  in  which  the 
lens  is  hung  up  between  the  aqueous  and  vitreous  humours.  The  outermost 
layer  of  the  eye  is  formed  by  the  sclerotic  coat,  a  strong  tough  membrane  of 
white  fibrous  tissue.  In  front  this  is  continuous  with  the  cornea,  which, 
having  a  smaller  radius  of  curvature  than  the  globe  of  the  eye,  protrudes  like 
a  watch-glass  from  its  anterior  surface.  The  main  substance  of  the  cornea  is 
formed,  hke  the  sclerotic,  by  white  fibrous  tissue,  modified  however  in  its 
consistence  so  as  to  be  perfectly  transparent  instead  of  white  and  opaque  hke 
the  rest  of  the  sclerotic.  Internal  to  the  sclerotic  is  the  choroid  coat,  a  mem- 
brane with  a  double  pigmented  internal  layer,  and  supphed  with  blood- 
vessels which  furnish  the  vascular  supply  to  the  whole  eye.  In  front  the 
choroid  coat  presents  a  series  of  folds,  arranged  in  a  circle  around  the  anterior 
part  of  the  cavity  of  the  vitreous  and  known  as  the  cihary  processes.  In 
front  of  the  ciliary  processes  the  choroid  leaves  the  sclerotic  and  hangs  as  a 
curtain  into  the  cavity  of  the  aqueous  humour,  between  the  cornea  and  the 
lens.     The  curtain,  which  is  known  as  the  iris,  presents  a  circular  orifice  at 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL  543 

its  centre,  the  fwpil,  and  is  provided  with  muscular  fibres  by  means  of  which 
the  pupil  may  be  constricted  or  dilated.  The  posterior  surface  of  the  iris, 
like  the  inner  surface  of  the  choroid  generally,  is  Hned  by  a  pigmented 
epithelium.  The  posterior  layer  of  the  cornea  is  formed  by  a  tough  elastic 
membrane  {Descemet's  membrane)  which  is  covered  posteriorly  by  a  layer  of 
cubical  epithelial  cells.  At  the  circumference  of  the  cornea  Descemet's 
membrane,  or  the  posterior  elastic  lamina,  breaks  up  into  a  number  of 
fibres,  which  pass  outwards  and  backwards  to  be  inserted  into  the  anterior 
part  of  the  choroid  and  root  of  the  iris.  These  fibres  are  the  ligamentum 
pectinatum  iridis.  Between  the  fibres  of  the  ligamentum  pectinatum  are  a 
number  of  spaces  lined  with  endothelium  continuous  with  the  anterior 
chamber  and  known  as  the  spaces  of  Fontana,  and  outside  these  spaces,  in  the 
corneo-sclerotic  junction,  is  a  circular  sinus  continuous  with  the  venous 
system,  the  ca7ial  of  Schlemm  or  sinus  venosus.  The  iris  rests  at  its  inner 
margin  on  the  lens,  so  dividing  the  cavity  of  the  aqueous  humour  into  two 
parts.  In  front  is  the  anterior  chamber  and  behind  the  posterior  chamber. 
The  latter  is  a  small  annular  space,  triangular  in  cross-section,  and  bounded 
by  the  iris  in  front,  the  lens  behind,  and  the  cihary  processes  externally. 

The  crystalline  lens,  made  up  of  radiating  lens  fibres,  each  of  which 
is  produced  by  the  modification  of  an  epithehal  cell,  is  biconvex,  the  posterior 
surface  being  more  convex  than  the  anterior.  It  is  surrounded  by  a  tough 
structureless  membrane,  the  capsule  of  the  lens,  and  rests  in  a  cavity  hollowed 
out  of  the  anterior  surface  of  the  vitreous  humour.  At  its  circumference  it  is 
hung  up  and  fastened  to  the  cihary  processes  by  the  suspensory  ligament,  or 
zonule  of  Zinn  [zonula  ciliaris).  (Fig.  271.)  This  hgament  is  formed  in  the 
follo'v^ang  way  : 

The  vitreous  humour  is  bounded  externally  by  the  hyaloid  membrane, 
which  separates  it  from  the  retina.  In  front  the  hyaloid  membrane  passes 
behind  the  lens,  but  as  it  lies  on  the  ciliary  processes  is  closely  adherent  to 
these  structures  and  sends  of?  fibres  which  pass  radially  from  the  cihary  pro- 
cesses to  the  capsule  of  the  lens  and  form  the  zonule,  or  suspensory  ligament. 
The  greater  part  of  the  suspensory  ligament,  i.e.  from  the  ora  serrata  of  the 
retina  to  the  edge  of  the  cihary  processes,  is  closely  attached  to  these  pro- 
cesses. From  their  edge  a  number  of  fibres  pass  and  fuse  at  their  inner 
extremities  with  the  lens  capsule.     These  fibres  are  arranged  in  three  groups  : 

(1)  The  anterior  group  passing  to  the  anterior  capsule  of  the  lens. 

(2)  A  middle  group  passing  to  the  equator  of  the  lens. 

(3)  A  posterior  group  lying  close  to  the  hyoid  membrane  and  passing  to 
the  posterior  lens  capsule. 

The  suspensory  ligament  is  always  in  a  condition  of  tension.  If  the  finger 
be  pressed  on  the  outside  of  the  eyeball,  it  will  be  felt  that  this  organ  presents 
a  resistance  to  deformation  which  cannot  be  ascribed  simply  to  the  firmness 
of  the  sclerotic  coat,  but  must  be  determined  by  the  existence  of  a  positive 
pressure  in  the  fluid  filling  the  eyeball.  This  pressure,  which  is  known 
as  the  infra-ocuhr  pressure^  may  be  measured  by  means  which  we  shall 
have  to  discuss  later,  and  amounts  to  about  25  mm.  Hg.     As  a  result  of 


544 


PHYSIOLOGY 


this  pressure  the  membranes  which  confine  the  fluids  of  the  eyeball  are  dis- 
tended, i.e.  pressed  outwards,  and  this  pressure  keeps  the  bases  of  the  cihary 
processes  pressed  against  the  choroid  coat  and  thus  enables  them  to  withstand 
the  pull  exerted  by  the  tense  suspensory  ligament. 

The  pull  exerted  by  the  suspensory  ligament  affects  mainly  the  tough  an- 
terior surface  of  the  lens  capsule  and  so  has  a  constant  flattening  effect  on  the 
anterior  surface  of  the  lens.  This  may  be  proved  by  measuring  the  curvature 
of  the  lens  in  a  recently  excised  eye,  and  then  removing  the  lens  altogether 
from  the  eyebaU  and  measuring  the  curvatures  of  its  surfaces  again.     It 


Sinus  venosus 


Conjunctiva 


Retina 


Fig.  271.     Section  through  anterior  part  of  eyeball  to  show  mode  of 
suspension  of  lens.     (After  Mekkel  and  Kallitjs.) 

will  be  found  that,  as  soon  as  the  lens  is  free  from  its  attachments  in  the 
eyeball,  the  curvature  of  its  anterior  surface  is  increased.  The  change 
therefore  in  the  lens,  which  is  responsible  for  the  alterations  in  its  refractive 
power  determining  accommodation,  may  be  effected  by  any  means  which 
will  relax  the  suspensory  ligament,  such,  for  instance,  as  approximation  of 
the  ciliary  processes  to  the  margin  of  the  lens.  This  movement  of  the  ciliary 
processes  is  effected  by  the  ciliary  muscle.  The  attachments  of  this  muscle 
are  shown  in  Fig.  271 .  It  forms  a  circle  of  unstriated  muscle  fibres,  triangular 
in  cross- section,  and  extending  round  the  whole  circumference  of  the  eyeball. 
The  fibres  of  the  muscle  are  divided  into  three  groups  : 

(a)  The  meridional  fibres,  which  run  from  the  corneo- sclerotic  junction 
backwards  and  outwards  to  be  attached  to  the  anterior  part  of  the  choroid 
coat  behind  the  ciliary  processes. 

(6)  The  radial  fibres,  which  pass  from  the  margins  of  the  canal  of  Schlemm, 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 


545 


and  from  the  fibres  of  the  hgamentum  pectinatum  to  be  attached  behind  to 
the  whole  extent  of  the  cihary  processes. 

(c)  The  circular  bundle,  which  forms  a  ring-muscle,  composed  of  fibres 
running  around  the  circumference  of  the  eye  in  the  inner  part  of  the  ciliary 
processes.     This  bundle  is  best 
marked  in  hypermetropic  eyes      ,„ 
and  is  almost  absent  in  myopic 
eyes. 

When  this  muscle  contracts 
it  draws  the  anterior  part  of 
the  choroid  and  the  cihary  pro- 
cesses forwards  and  inwards, 
while  the  ring-fibres  approxi- 
mate the  ciliary  processes  to 
the  margin  of  the  lens.  By 
this  approximation  of  the  cili- 
ary processes  to  the  lens  the 
suspensory  ligament  is  relaxed, 
and  the  anterior  surface  of  the 
lens  bulges,  i.e.  becomes  more 
convex  as  a  result  of  its  inherent 
elasticity  (Fig.  272). 

This  explanation  of  accommoda- 
tion, which  was  first  put  forward 
by  Helmholtz,  is  almost  universally 
accepted.  According  to  some  the 
change  of  shape  of  the  lens  dm'ing 
accommodation  is  brought  about  by 
the  actual  pressm'e  of  the  ciliary 
processes  on  its  margin  by  which 
the  middle  of  its  anterior  surface 
is    pressed    forwards.    According  to 

Tscherning  this  effect  is  produced,  not  by  relaxation,  but  by  a  tightening  of  the 
suspsnsory  ligament  through  the  contraction  of  the  ciliary  muscle.  There  is  no 
doubt,  however,  that  during  forced  accommodation,  such  as  can  be  brought  about 
by  instillation  of  eserine  into  the  eye,  which  produces  spasm  of  the  ciliarj^  muscle,  the 
suspensory  ligament  is  so  relaxed  that  the  lens  lies  loosely  in  the  eyeball.  Bending 
the  head  downwards  causes  therefore  an  actual  change  in  the  position  of  the  lens, 
which  may  drop  as  much  as  1mm.  forwards  towards  the  cornea.  Under  the  same 
conditions  a  quick  movement  of  the  head  causes  the  lens  to  shake,  and  the  quiver  of  the 
lens  can  be  seen  by  an  external  observer  and  proved  by  the  subjective  oscillation  of 
external  objects  which  is  noticed  after  such  a  movement.  Moreover,  if  a  needle  be 
passed  through  the  sclerotic  so  that  its  point  lies  in  the  ciliary  processes,  stimulation 
of  the  ciliary  muscle  causes  a  movement  of  the  outer  part  of  the  needle  backwards, 
showing  that  the  point  ot  the  needle  which  is  in  the  ciliary  processes  has  been  moved 
forwards  (Fig.  273).  The  loosening  of  the  lens  dm-ing  spasm  of  accommodation  is  well 
sho\vninrare  cases  where  there  is  congenital  absence  of  the  whole  iris.  In  such  cases  the 
shaking  of  the  patient's  head  is  seen  to  cause  an  oscillation  of  the  lens  within  the  eyeball. 

During  acconamodation  the  increased  curvature  of  the  anterior  surface 
of  the  lens  causes  an  approximation  of  this  surface  to  the  cornea,  which  may 

18 


Fig.  272.    Diagram  of  mechanism  of  accommoda. 

tion.      (TiGEKSTEDT  after  Schon.) 
The  dotted  line  shows  the  form  of  the  lens  during 

accommodation  for  near  objects. 


546  PHYSIOLOGY 

be  directly  observed  {cp.  Fig.  273),  especially  in  people  with  somewhat 
prominent  eyes.  No  change  takes  place  in  the  intraocular  pressure,  in  either 
aqueous  or  vitreous  cavities,  as  the  result  of  acconmaodation.  The  passage 
of  fluid  takes  place  with  such  ease  between  the  fibres  of  the  suspensory 


Fig.  273.     Accommodation  in  the  cat's  eye.     b,  distance  ;   a,  for  near  vision. 

(After  BebPv.) 
Two  needles  have  been  passed  through  edge  of  cornea  into  ciliary  bodies,  to  show 
forward  movement  of  latter  during  accommodation. 

ligament  that  a  slight  movement  of  the  lens  forwards  or  backwards  does 
not  upset  the  equaUty  of  pressures  in  the  two  chambers. 

THE  RANGE  OF  ACCOMMODATION.  Assuming  that,  as  is  the  case  with 
the  normal  eye,  the  tension  of  the  suspensory  Ugament  is  sufficient  to  keep 
the  eye  focused  for  parallel  rays,  the  near  point  of  vision  will  be  determined 
by  the  unconstrained  shape  of  the  lens,  i.e.  the  amount  by  which  its  curvature 
can  increase  when  the  suspensory  hgament  is  completely  relaxed. 

The  shape  of  the  lens  varies  with  age,  its  convexity,  being  greatest 
directly  after  birth  and  diminishing  steadily  from  that  time  to  the  age  of 
sixty  or  seventy  (Fig.  274).     In  consequence  of  the 
Of  h  c         small  size  of  the  eyeball,  the  eye  at  birth  is  generally 

somewhat  hypermetropic,  but  from  the  age  of  ten 
onwards  we  find  that  the  point  of  near  vision  re- 
cedes continuously  with  advancing  age.  The  range 
of  accommodation  is  measured  by  the  strength  of 
the  lens  which  will  give  to  rays  coming  from  the 
near  point  of  distinct  vision  the  same  direction  as  if 
they  came  from  the  far  point.  In  a  normal  eye  the  far 
point  is  at  infinite  distance  and  the  rays  are  parallel.  The  change  in  the  range 
of  accommodation  with  advancing  years  is  shown  in  the  following  Table  : 


Fig.  274.  Lens  from  human 
eye  at  different  periods  of 
life.   (Allen Thomson.) 

a,  at  birth ;  b,  adult ; 
c,  old  age. 


Age 

10 

20 

30 

40 

60 

60 

70 


Range  of  accommodation  in  dioptres 

14 

10 

7 

4-5 
2-5 
1 
0-25 


This  gradual  diminution  in  the  range  of  accommodation  gives  rise  finally 
to  disturbances  of  vision  which  are  known  as  presbyopia.  The  ordinary  reading 


I 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL  547 

distance  is  about  ten  inches.  A  smaller  distance  than  this  is  rarely  made 
use  of  even  in  youth,  when  the  point  of  near  vision  is  only  three  or  four 
inches  from  the  eye,  on  account  of  the  effort  required  to  converge  the  axes  of 
the  two  eyes  to  this  extent.  The  effect  of  the  gradual  dimination  in  the  elas- 
ticity of  the  lens  is  noticed  as  soon  as  the  point  of  near  vision  recedes  beyond 
ten  or  twelve  inches,  i.e.  25  to  30  cm.  This  occurs  as  a  rule  between  forty- 
five  and  fifty,  when  we  begin  to  experience  difficulty  in  reading  small  print, 
since  the  visual  angle  subtended  by  such  print  at  a  distance  over  ten  or 
twelve  inches  is  too  small  to  allow  of  distinct  vision.  The  condition  of 
presbyopia,  is  remedied  by  employing  reading  glasses,  i.e.  by  wearing 
spectacles  which  converge  the  rays  of  Hght  and  so  enable  small  objects 
to  be  brought  nearer  to  the  eye  than  its  near  point.  It  is  evident  that  these 
glasses  must  be  strengthened  continually  with  advancing  age.  No  trouble 
is  experienced  in  seeing  distant  objects,  the  refraction  of  the  eye  at  rest 
remains  as  before.  The  dimness  of  vision  in  extreme  old  age  for  distant 
as  well  as  near  objects  is  due  to  changes,  not  in  the  refractive  power  of  the 
eye,  but  in  the  transparency  of  the  refractive  media,  such  as  cataract,  i.e. 
opacity  of  the  lens,  opacity  of  the  cornea,  and  so  on.  The  former  condition 
can  often  be  remedied  by  extracting  the  lens.  Strong  convex  glasses  (ten 
dioptres)  must  then  be  used  to  take  the  place  of  the  lens. 


THE   COMPARATIVE   PHYSIOLOGY   OF   ACCOMMODATION 

The  mechan'.sm  of  accommodiition  which  we  have  studied  in  man  is  found  with  very 
little  modification  throughout  the  whole  group  of  mammalia,  though,  in  the  domestic 
animals  at  any  rate,  the  range  of  accommodation  is  very  much  less  than  in  man.  On 
examining  other  types  of  animals  we  meet,  as  was  shown  by  Beer,  an  amazing  variety 
of  methods  by  which  the  range  of  the  eye  may  be  altered.  In  order  to  bring  distinct 
images  of  objects  at  various  distances  on  to  the  retina,  practically  every  possible  focusing 
method  is  made  use  of  in  one  type  or  another  of  the  animal  kingdom.  The  following 
details  are  taken  from  Beer's  papers. 

In  birds  the  eye,  like  that  of  man,  is  normally  focused  for  distant  objects,  and  accom- 
modation for  near  objects  is  accomplished  by  a  change  in  cmvatm'e  of  the  anterior 
surface  of  the  lens.  Whereas,  however,  in  man  the  suspensory  ligament  is  relaxed 
by  a  drawing  forwards  of  the  choroid  membrane,  in  the  bird's  eye  this  relaxation  is 
effected  by  a  drawing  backwards  of  the  posterior  lamina  of  the  cornea,  where  it  breaks 
up  into  the  ligamentum  pectinatum  iridis.  In  these  eyes  the  main  attachment  of  the 
suspensory  ligament  is  to  the  ligamentum  pectinatum  ;  the  retraction  of  this  ligament 
is  effected  by  a  special  muscle  known  as  Cravipton' s  muscle,  which  corresponds  to  the 
ciliary  muscle  in  man,  but  unlike  this  consists  of  striated  voluntary  muscle.  This 
movement  of  the  posterior  elastic  lamina  of  the  cornea  can  be  easily  sIioaati  by  passing 
two  needles  through  the  corneo-sclerotic  junction  until  their  points  lie  in  the  anterior 
chamber.  On  exciting  Crampton's  muscle  electrically,  the  outer  end  of  the  needle 
moves  forwards,  showing  that  the  deeper  part  of  the  corneo-sclerotic  junction  is  being 
pulled  backwards  towards  the  ciliary  portion  of  the  eye  (Fig.  275).  The  histological 
character  of  the  muscle  of  accommodation  in  birds  seems  to  be  connected  with  the 
rapid  accommodation  that  is  necessary  when  a  bird  swoops  down  towards  the  ground 
to  pick  up  some  food  insect.  Moreover,  since  binocular  vision  is  not  present  in  many 
birds,  and  convergence  of  the  optic  axes  must  be  minimal,  it  is  probable  that  the  con- 
tractions of  Crampton's  muscle  play  a  great  part  in  guiding  the  movements  of  the 
bird,  and  especially  in  aiding  it  to  judge  distances.  In  oiu-  selves  such  judgment  is 
very  faulty  without  the  co-operation  of  the  two  eyes. 


548 


PHYSIOLOGY 


In  amphibia  and  snakes,  wliich  at  rest  are  also  focused  for  distance,  active  accom- 
modation for  near  objects  is  effected,  not  by  change  in  curvatmre  of  the  lens,  but  by 
an  increase  in  the  distance  between  the  lens  and  the  retina.  In  amphibia  the  ciliary 
muscle,  which  lies  between  the  root  of  the  iris,  the  sclerotic  and  choroid,  causes  a  rise 
of  pressure  in  the  vitreous  cavity,  and  the  lens,  being  the  most  movable  part  of  the 
boundary  wall  of  this  cavity,  is  pushed  forwards  towards  the  cornea.  The  aqueous 
humour,  which  is  displaced  by  this  forward  movement  of  the  lens,  finds  a  place  in  the 
lateral  angle  of  the  eye,  which  is  increased  in  depth  by  the  pull  of  the  muscle  fibres. 

In  snakes  the  same  action  is  effected  by  a  muscle,  often  cross-striated,  which  is 
situated  in  the  root  of  the  iris.  In  both  these  cases  the  movement  of  accommodation 
is  unaffected  by  opening  the  aqueous  cavity,  whereas  in  mammals  it  is  at  once  rendered 
impossible  if  the  aqueous  cavity  be  laid  open. 


Fig.  275.     Accommodation  in  a  bird's  eye.     (Beer.) 
K,  rest ;  A,  accommodation  for  near  objects. 

Most  of  the  teleostean  fishes  are  short-sighted,  i.e.  at  rest  they  are  focused  for  near 
objects.  Active  accommodation  in  these  animals  diminishes  the  refractive  power 
of  the  eye,  so  that  accommodation  occurs  for  distant  objects.  In  the  fish's  eye  there 
are  no  ciliary  processes,  ciliary  muscle,  zonule  of  Zinn,  or  spaces  of  Fontana,  such  as 
are  foimd  in  the  higher  vertebrata.  The  iris  only  approaches  the  margin  of  the  lens, 
and  does  not  shut  out  its  peripheral  rays.  The  lens,  which  is  spherical  (Fig.  276),  is 
hung  up  by  means  of  a  flat  band  attached  to  its  uppei  pole.  This  is  known  as  the 
'  suspensory  ligament,'  but  is  quite  different  in  structure  and  mechanism  from  the  sus- 
pensory ligament  or  zonule  of  Zinn  of  the  vertebrate  eye.  From  the  lower  and  inner 
pole  of  the  lens  a  dark  pigmented  structure  passes  backwards  ;  this  was  described 
by  its  first  discoverer  as  the  campanula,  but  since  it  is  muscular  in  character  is  better 
named  the  '  retractor  lentis.'  On  stimulation  this  muscle  pulls  the  lens  backwards, 
and  so  lessens  the  distance  between  it  and  the  retina,  in  this  way  accommodating  the 
eye  for  distance. 

The  eye  of  the  cephalopod  mollusc,  such  as  sepia,  is  also  short-sighted,  and  active 
accommodation,  as  in  the  fish's  eye,  is  accommodation  for  distance.  The  mechanism 
is,  however,  quite  different.  The  globe  of  the  cephalopod's  eye  has  the  shape  shown 
in  the  diagram  (Fig.  277).  The  most  resistant  part  of  the  globe  is  formed  by  a  strong 
ring  of  cartilage  wliich  passes  round  the  equator  of  the  eye.  The  rest  of  the  sclerotic 
is  formed  of  delicate  membrane,  which  is  thinnest  in  the  ring  just  behind  the  cartilagin- 
ous ring.  In  the  anterior  wall  of  the  eye  is  a  strong  muscular  ring,  composed  of 
meridional  fibres,  which  run  from  the  cartilaginous  ring  to  be  inserted  into  the  ciliary 
processes  or  corpus  ciliare,  which  is  closely  attached  to  the  equator  of  the  lens. 

When  this  muscle  contracts  it  pulls  back  the  whole  anterior  wall  of  the  eye  together 
with  the  lens,  approximating  it  to  the  retina.  This  movement  is  of  necessity  accom- 
panied by  a  rise  of  ocular  pressure,  but  room  for  the  displaced  fluid  is  found  by  a  bulging 
of  the  walls  of  the  eyeball  at  their  thinnest  part,  i.e.  just  behind  the  cartilaginous 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 


549 


ring,  so  that  there  is  an  actual  diminution  of  the  distance  between  the  lens  and  the 
retina. 

In  every  class  of  animals,  except  in  the  cephalopod  and  in  birds,  species  are  found 
which  possess  no  power  of  accommodation  at  all,  or  only  to  a  very  slight  extent.     This 

A 


Fig.  276.     Diagrams  from  Beer  to  show  mode  of  accommodation  (for  distance) 

in  a  fish. 
A,  vertical  section  of  the  eyeball ;    B,  view  of  eye  from  front ;    L,  lens  ;   Ls, 
suspensory  ligament ;    J,  iris  ;    Rl,  retractor  lentis  or  '  campanula  '  ;    C,  changes 
in  position  of  lens  when  eye  is  accommodated  for  an  object  at  varying  distances. 


Fi(i.  277.     Aceoiiimodatiou  in  cyo  of  sepia.     (Beek.) 
R,  at  rest  ;   a,  during  accommodation  (for  distance). 


is  the  case  in  frogs,  alligators,  vipers,  and  in  many  rodents.  Man}-  of  these  animals 
arc  distinguished  by  nocturnal  habits,  and  in  daylight  their  pupils  may  be  constricted 
to  such  an  extent  aS  to  render  accommodation  unnecessary.  In  many  of  them,  too, 
the  exact  form  of  an  object  is  not  so  important  as  the  power  to  follow  its  movements. 
In  such  cases  the  movement  of  the  extrinsic  ocular  muscles  or  of  the  head  are  more 
important  than  the  exact  focusing  of  the  object  on  the  retina. 


550  PHYSIOLOGY 

THE  FUNCTIONS  OF  THE  IRIS 

The  iris  is  the  forward  prolongation  of  the  pigmented  choroid  coat. 
It  is  covered  anteriorly  by  a  layer  of  epithehum  continuous  with  Descemet's 
epithelium,  and  behind  by  a  thick  layer  of  pigmented  epithehum  which  is 
prolonged  forwards  from  the  retina.  It  is  composed  of  delicate  connective 
tissue,  attached  at  its  circumference  to  the  fibres  of  the  Hgamentum  pec- 
tinatum,  and  contains  two  sets  of  unstriated  muscular  fibres.  The  one  set, 
the  sphincter  fwpillce,  is  composed  of  fibres  which  run  a  circular  course 
around  the  margin  of  the  pupil.  The  other  set,  the  dilatator  pupillcB,  forms 
a  flattened  layer  of  radiating  fibres,  which  he  close  to  the  posterior  surface  and 
extend  from  the  attachment  of  the  iris  nearly  to  the  rim  of  the  pupil. 

The  pigment  in  the  iris  and  choroid  serves  the  same  purpose  as  the 
blackened  fining,  which^is  supphed  to  every  optical  instrument,  in  preventing 
reflection  and  dispersion  of  the  incident  light,  and  therefore  preventing  any 
hght  falhng  on  the  retina  except  those  rays  which  pass  through  the  pupil 
and  refractive  surfaces  of  the  eye.  The  pigment  in  the  iris  has  an  additional 
importance  in  that  it  ena,bles  this  organ  to  act  as  a  diaphragm.  It  not  only 
shields  the  retina,  the  sensory  apparatus  of  the  eye,  from  the  effects  of  any 
excess  of  illumination,  but,  by  stopping  out  the  rays  of  light  passing  through 
the  periphery  of  the  lens,  it  diminishes  spherical  aberration  and  enables  a 
clear  image  of  external  objects  to  be  formed  on  the  back  of  the  eyeball.  The 
diameter  of  the  pupil  is  continually  varying,  according  to  the  amount  of  hght 
falhng  into  the  eye  and  the  condition  of  the  mechanism  of  accommodation. 

Contraction  of  the  pwpil  occurs  under  the  following  circumstances  : 

(1)  When  hght  falls  on  the  retina.  This  movement,  which  is  known 
as  '  the  hght  reflex,'  is  determined  by  a  contraction  of  the  sphincter  pupillee, 
together  with  a  relaxation  of  the  dilatator  muscle.  The  contraction  ensues 
within  a  period  of  0*04  to  0-05  sec.  after  the  moment  at  which  the  hght  has 
access  to  the  retina,  and  attains  its  maximum  within  0-1  sec.  In  man  as  well 
as  in  other  animals  which  have  binocular  vision,  and  in  which  there  is  a 
partial  decussation  of  the  fibres  of  the  optic  nerves  in  the  optic  chiasma, 
the  reflex  is  bilateral,  i.e.  light  falhng  into  one  eye  causes  simultaneous  con- 
traction of  both  pupils.  In  the  higher  animals  this  reaction  of  the  pupil  to 
hght  demands  the  integrity  of  the  nervous  paths  between  the  eye  and  the 
brain  ;  but  in  many  of  the  lower  animals,  e.g.  in  the  frog  and  eel,  the  reflex 
nervous  mechanism  is  aided  by  a  local  sensibihty  of  the  iris  to  hght.  In  these 
animals  the  contraction  of  the  pupil  in  response  to  illumination  takes  place 
even  in  the  excised  eye,  and  seems  to  be  determined  by  a  direct  stimulation 
of  the  pigmented  contractile  fibres  of  the  sphincter  pupillse  by  means  of  the 
hght. 

The  effect  of  light  on  the  pupil  varies  considerably  according  to  the 
condition  of  adaptation  of  the  eye.  The  dilatation  of  the  pupil  is  maximal 
when  the  eye  has  been  in  the  dark  for  some  time  and  may  amount  then  to  7*3 
to  8  mm.  In  one  experiment,  on  exposing  the  eye  to  a  feeble  hght,  e.g.  1-6 
candles  at  a  moderate  distance,  the  pupil  diminished  in  size  to  6  3  mm.  ; 


DIOPTEIC  MECHANISMS  OF  THE  EYEBALL  551 

with  an  illumination  of  50  to  100  candles  the  size  of  the  pupil  was  3-7  mm., 
and  with  500  to  1000  candles,  3-3  mm.  This  efiect  was  obtained  by  a  rajiid 
change  of  the  illumination  of  the  eye.  When  the  change  in  illumination  is 
sufficiently  slow  no  alteration  of  the  pupil  takes  place,  and  when  the  illumina- 
tion, which  has  at  first  caused  a  maximal  constriction  of  the  pupil,  is  con- 
tinued the  pupil  gradually  relaxes  with  the  adaptation  of  the  retina  to  light. 
This  relaxation  occurs  within  three  or  four  minutes  after  exposure  to  light 
has  taken  place.  The  same  influence  of  adaptation  will  be  observed  if  two 
individuals  are  brought  into  a  moderately  Ughted  room,  one  from  bright 
dayhght  and  the  other  from  a  dark  room.  The  pupils  of  the  first  will  dilate 
widely,  while  those  of  the  second  will  constrict  to  their  maximimi  extent. 
In  each  case  the  change  will  pass  off  gradually,  so  that  at  the  end  of  five  or 
ten  minutes  there  will  be  no  difference  observable  between  the  eyes  of  the 
two  persons. 

(2)  When  vision  is  directed  to  a  near  object  the  contraction  of  the 
ciliary  muscle  which  results  in  accommodation  is  accompanied  by  con- 
vergence of  the  visual  axes,  brought  about  by  contraction  of  the  two  internal 
rectus  muscles.  With  these  two  movements  is  always  associated  a  third,  viz. 
contraction  of  the  sphincter  pupillae,  the  increased  sharpness  of  the  image 
obtained  by  this  means  being  an  indispensable  condition  for  the  fineness  of 
vision  which  we  desire  when  we  examine  any  object  closely.  The  fact  that 
the  amount  of  light  which  will  fall  into  the  eye  from  any  given  object  in- 
creases inversely  as  the  square  of  the  distance  of  the  object  from  the  eye 
ensures  that  sufficient  light  wiU  pass  through  the  constricted  pupil  for  the 
appreciation  of  the  finer  details  of  the  object. 

(3)  In  sleep  the  pupils  are  always  contracted.  This  fact  seems  at  first 
in  opposition  to  the  other  conditions  regulating  the  size  of  the  pupil,  since 
during  sleep  no  light  is  falling  into  the  eye.  If  the  eyelid  of  a  sleeping  person 
be  raised  the  pupil  will  be  found  to  be  constricted  ;  as  the  person  wakes  up, 
in  consequence  of  the  interference,  the  pupil  dilates  and  may  then  constrict 
again  if  the  light  is  held  so  as  to  fall  into  the  eye.  This  behaviour  of  the 
pupil  may  enable  us  to  distinguish  feigned  from  real  sleep.  The  constriction 
of  the  pupil  is  really,  like  that  which  accompanies  accommodation,  an 
associated  condition,  and  depends  on  the  fact  that  during  sleep  the  axes  of 
the  eyeballs  are  directed  upwards  and  inwards. 

(4)  Contraction  of  the  pupil  is  a  marked  eft'ect  of  the  action  of  certain 
drugs,  especially  opium  and  its  alkaloid,  morphia,  as  well  as  of  the  alkaloids 
eserine,  or  physostigmine,  and  pilocarpine.  Contraction  of  the  pupil  also 
occurs  in  general  excitatory  conditions  of  the  central  nervous  system  and  is 
therefore  found  during  the  stage  of  induction  of  chloroform  and  ether 
anaesthesia. 

Dilatation  of  the  pupil  occurs  : 

(1)  On  the  removal  of  light  stimulus  from  the  eye.  If  the  removal 
is  complete  the  pupil  remains  dilated,  but  if  there  is  any  light  at  all  the 
pupil  gradually  constricts  again  as  the  eye  becomes  dark-adapted. 

(2)  Dilatation  of  the  pupil  can  be  reflexly  excited  by  the  stimulation  of 


552 


PHYSIOLOGY 


many  sensory  nerves,  and  is  constantly  observed  as  a  result  of  severe  pain. 

The  presence  or  absence  of  dilated  pupils  may  serve  therefore  as  a  means  of 

testing  how  far  an  emotional  expression  of  pain  is  to  be  credited  to  a  physical 

cause. 

(3)  The  pupils  are  often  dilated  in  emotional  conditions  such  as  fear. 

(4)  Dilatation  of  the  pupils  occurs 
in  every  condition  of  extreme  exhaus- 
tion, when  the  activities  of  the  nervous 
centres  are  lowered.  It  is  therefore  seen 
during  the  third  stage  of  chloroform 
anaesthesia,  or  in  the  comatose  condi- 
tion produced  by  excess  of  alcohol. 
Among  the  drugs  which  cause  dilatation 
of  the  pupil  the  beUadonna  alkaloids, 
atropine  and  homatropine,  are  the  best 
known.  These  alkaloids  will  produce 
dilatation  of  the  pupil  when  simply 
dropped  into  the  conjunctival  sac,  and 
are  therefore  largely  used  to  dilate  the 
pupil  as  a  prehminary  to  ophthalmo- 
scopic investigation  of  the  eye. 


INNERVATION  OF  THE  INTRINSIC 
MUSCLES  OF  THE  EYE 
The  eyeball  is  supphed  by  the  short 
ciliary  nerves,  which  come  from  the 
lenticular  or  cihary  ganghon  and  pass- 
ing forwards  pierce  the  sclerotic  coat 
about  half-way  between  the  equator 
and  the  posterior  pole  of  the  eyebaU. 
The  lenticular  ganglion  has  three  so- 
called  roots,  by  which  it  is  connected 
with  or  receives  fibres  from  : 

(1)  The  third  or  oculo-motor  nerve, 
by  the  '  short  root.' 

(2)  With    the    sympathetic    plexus 


oc.m 


sym ''  ' 

Fig.  278.  Nerve-supply  to  the  eyeball. 
(After  Foster.) 
l,g,  lenticular  ganglion  with  its  three 
roots,  viz.  :  r.h,  radix  brevis  or  short 
root  ;  r.l,  radix  longus  or  long  root ; 
sym,  sympathetic  root ;  F.  opth.  oph- 
thalmic division  of  F  nerve  ;  ///  oc.m, 
oculo-motor  nerve  ;  II,  optic  nerve  ;  l.c, 
long  ciliary  nerves  ;  s.c,  short  ciliary 
nerves. 


lying  in  the  cavernous  sinus,  and, 
through  the  fibres  lying  on  the  internal  carotid  artery,  with  the  cervical 
sympathetic  nerve. 

(3)  With  the  nasal  branch  of  the  ophthalmic  division  of  the  fifth  nerve  by 
means  of  the  '  long  root.' 

The  eyeball  is  also  supplied  by  the  two  long  ciliary  nerves  (Fig.  278) 
which  come  direct  from  a  branch  of  the  ophthalmic  division  of  the  fifth 
nerve  and  pass  forwards  on  to  the  eyeball,  piercing  the  sclerotic  coat  in 
front  of  the  point  at  which  this  coat  is  penetrated  by  the  short  cihary 
nerves.     There  are  thus  three  nerves  by  means  of  which  the  activity  of  the 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL  553 

muscular  fibres  forming  the  ciliary  muscle,  the  sphincter,  and  the  dilatator 
iridis  can  be  influenced,  viz.  the  third  nerve,  the  fifth  nerve,  and  the  sym- 
pathetic nerve.     On  exciting  the  root  of  the  third  nerve  we  obtain  : 

{a)  Constriction  of  the  pupil. 

(b)  Contraction  of  the  ciliary  muscle,  i.e.  spasm  of  accommodation. 

The  same  effects  are  produced  by  stimulating  the  lenticular  gangUon 
or  the  short  cihary  nerves. 

Excitation  of  the  long  cihary  nerves  of  the  ophthalmic  division  of  the 
fifth  nerve,  or  of  the  Gasserian  ganghon,  causes  dilatation  of  the  pupil,  but 
is  without  influence  on  the  cihary  muscle. 

Stimulation  of  the  sympathetic  in  the  neck  causes  maximal  dilatation 
of  the  pupil  accompanied  by  constriction  of  the  vessels  of  the  iris  and  the 
eyeball  generally.  If  the  superior  cervical  ganghon  be  extirpated  so  as  to 
cause  degeneration  of  aU  the  sympathetic  fibres  passing  up  to  the  eye,  it  will 
be  found  a  fortnight  later  that  stimulation  of  the  Gasserian  ganghon  has  no 
longer  any  influence  on  the  size  of  the  pupil.  We  may  therefore  come  to 
the  following  conclusions  as  to  the  functions  of  the  nerves  suppl}aug  the 
interior  of  the  eyeball : 

The  third  nerve  supphes  fibres  which  run  through  the  lenticular  gan- 
ghon and  the  short  cihary  nerves  and  cause  constriction  of  the  pupil  and  con- 
traction of  the  cihary  muscle.  These  fibres  arise  in  the  oculo-motor  nucleus, 
which  is  situated  at  the  back  part  of  the  floor  of  the  third  ventricle,  immedi- 
ately below  the  anterior  corpora  quadrigemina. 

The  sympathetic  nerve  sends  fibres  which  pass  to  the  eye  along  two 
routes.  A  certain  number  which  run  on  the  external  carotid  artery  in  the 
cavernous  sinus  pass  by  the  sympathetic  root  to  the  ganghon  and  by  the 
short  cihary  nerves  to  the  eyeball  and  cause  contraction  of  the  blood-vessels. 
Other  fibres  pass  from  the  superior  cervical  ganghon  to  the  Gasserian  ganghon 
of  the  fifth  nerve,  along  the  nasal  branch  of  its  first  division  and  then  along 
the  long  cihary  nerves  to  the  eyeball.  These  fibres  carry  impulses  which 
dilate  the  pupil.  The  sympathetic  fibres  to  the  eyeball  arise  in  the  cord, 
probably  from  ceUs  of  the  lateral  column  in  the  lower  cervical  or  uppermost 
dorsal  region.  They  leave  the  cord  by  the  first  two  dorsal  anterior  roots, 
pass  through  the  stellate  ganghon,  the  ansa  Vieussenii,  and  up  the  cervical 
sympathetic  to  the  superior  cervical  ganglion  where  they  terminate.  New 
relays  of  fibres  start  in  this  ganghon  and  travel  direct  to  their  destination 
in  the  eyeball.  Excitation  of  the  cervical  spinal  cord  easily  evokes  dilatation 
of  the  pupil,  and  it  was  on  this  account  that  Budge  located  in  this  part  of  the 
cord  a  ciho- spinal  centre. 

The  fibres  derived  from  the  fifth  nerve  itself  must  be  looked  upon  as 
chiefly  afferent  or  sensory  in  fimction.  Some  observers  have  ascribed  to 
them  a  dilatator  effect  on  the  blood-vessels  of  the  eye,  but  confirmation  for 
this  view  is  wanting.  The  cihary  muscle  is  normaUy  at  rest  and  is  only  set 
into  activity  as  a  result  of  vohtional  or  reflex  efforts  to  direct  the  gaze  to 
near  objects.  The  iris  is  imder  the  influence  of  tonic  impulses  which  arrive 
at  it  along  both  sets  of  nerve  fibres,  oculo-motor  and  s}Tnpathetic,     Section 

18» 


554 


PHYSIOLOGY 


therefore  of  the  sympathetic  nerve  causes  constriction,  and  section  of  the 
third  nerve  dilatation  of  the  pupil.  These  tonic  influences  are  probably- 
reflex  in  origin,  since  it  is  foimd  that,  after  cutting  off  afferent  impressions 
from  the  retina  by  division  of  the  optic  nerve,  section  of  the  third  nerve 
produces  no  further  dilatation  of  the  pupil. 

Since  the  dilatator  muscle  is  often  difficult  to  demonstrate  under  the  microscope, 
the  view  has  been  put  forward  that  dilatation  of  the  pupil  on  stimulation  of  the  sym- 
pathetic nerve  is  due  merely  to  the  relaxation  of  the  tonic  contraction  of  the  sphincter 


Fig.  279.     Effect  on  iris  of  cat  of  local  stimulation. 
The  first  effect,  as  in  a,  is  to  cause  contraction  of  the  constrictor  pupil!  se  below 
the  electrodes,  and  this  is  succeeded  in  b  by  a  strong  localised  contraction  of  the 
radiating  fibres.     (Langley  and  Andekson.) 

pupillse.     The  following  experiments   by  Langley  and  Anderson  showed  definitely 
the  erroneousness  of  this  view : 

On  stimulating  the  corneo-sclerotic  junction  so  as  to  excite  a  limited  portion  of 
the  iris,  a  well-defined  local  dilatation  of  the  pupil  is  produced.  If  the  dilatation  were 
due  to  the  relaxation  of  the  sphincter,  the  dilatation  could  not  be  local,  but  would 
have  extended  to  the  whole  circumference  of  the  pupil  (Fig.  279).  In  another  experi- 
ment they  isolated  a  sector  of  the  iris  by  two  radial  cuts  ;  on  exciting  this  sector  it 
shortened,  and  the  same  effect  was  produced  by  excitation  of  the  sympathetic  in  the 
neck,  although  any  action  of  the  sphincter  must  have  been  abolished  by  the  mode 
of  preparation.  Section  of  the  sympathetic  in  the  neck  causes  lasting  constriction 
of  the  pupil,  and  the  same  effect  is  produced  by  extirpation  of  the  superior  cervical 
ganglion.  After  the  lapse  of  some  time,  however,  the  muscles,  freed  from  their  nervous 
connections  with  the  ganglion,  enter  easily  into  a  condition  of  hypertonus,  so  that  the 
pupil  on  the  side  of  the  lesion  may  be  more  dilated  than  on  the  normal  side.  This 
hypertonus  is  especially  marked  when  a  slight  amount  of  asphyxia  or  rise  of  blood 
pressure  is  present.* 

THE  OPHTHALMOSCOPE 

By  means  of  this  instrument  we  are  enabled  to  obtain  a  magnified  picture  of  the 
back  of  the  eyeball,  as  well  as  to  judge  of  the  presence  and  degree  of  abnormalities 
in  the  refracting  apparatus  of  the  observed  eye. 

*  Probably  on  account  of  the  escape  of  adrenaline  into  the  circulation,  and  its 
sympatho-mimetric  action  on  the  iris. 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 


555 


When  light  falls  on  the  eye  through  the  pupil  the  greater  part  of  it  is  absorbed 
by  the  pigment  of  the  retina  and  the  choroid  coat.  A  small  amount,  however,  is 
diffusely  reflected,  and  is  sent  out  by  the  "way  it  came,  viz.  through  the  pupil.  If  the 
vision  is  directed  on  the  luminous  point  at  the  source  of  the  rays,  the  reflected  rays 
leaving  the  eye  will  be  converged  to  a  point  and  form  an  image  which  will  coincide 
with  the  source  of  illumination.  It  is  on  this  account  that  the  pupil  always  appears 
black.  When  we  look  at  a  person's  eye,  we  necessarily  interpose  oiu-  head  and  eye 
between  the  observed  eye  and  the  source  of  light,  so  that  no  reflected  light  can  come 
back  to  our  eyes.     Only  in  albinos,  where  the  pigment  of  the  choroid  coat  and  retina 


Fig.  280.     Indirect  ophthalmoscopy. 

A,  course  of  raj's  from  source  of  light  E  to  observed  eye ;    o,  observer's  eye  ; 
M,  miri'or  ;   l,  lens. 

B,  course  of  rays  from  an  illuminated  spot  on  the  retina  of  the  observed  eye  to 
the  observer's  eye. 

is  lacking,  do  we  get  a  red  appearance,  due  to  the  reflected  light  passing  through  the 
vascular  tissues  of  the  choroid  and  iris. 

In  a  hypermetropic  eye  at  rest  only  those  rays  are  brought  to  a  focus  on  the  retina 
which  are  convergent  as  thej'-  enter  the  pupil.  Light  reflected  from  the  retina  of  such 
an  eye  will  therefore  be  divergent  as  it  leaves  the  pupil,  and  we  may  obtain  a  '  red 
reflex  '  by  direct  observation  of  the  eye. 

In  order  that  we  may  obtain  an  image  of  the  interior  of  a  normal  eye  we  must 
arrange  that  our  eye  coincides  with  the  soirrce  of  illumination.  For  tliis  purpose 
we  use  the  device  invented  by  Helmholtz,  viz.  a  slightly  concave  mirror  M-ith  a  hole  in 
the  centre.  By  means  of  this  mirror  light  is  converged  on  to  the  pupil,  and  the  light 
reflected  by  the  retina  is  brought  to  a  focus  at  the  centre  of  the  mirror,  where  is  placed 
the  observer's  eye.     This  ophthalmoscope  may  be  used  in  one  of  two  ways  : 

(a)  INDIRECT  OPHTHALMOSCOPY.  In  carrying  out  ophthalmic  observations 
the  examination  is  much  facilitated  by  instilling  atropine  into  the  ob.^erved  eye,  so  as  to 
dilate  the  pupil  to  the  widest  extent  and  paralyse  the  mechanism  of  accommodation. 
If  a  beam  of  light  be  tlu'OAvn  into  the  pupil,  the  emergent  rays  from  the  eye  -will  be  parallel 
and  will  give  rise  to  a  red  reflection  seen  by  the  observer's  eye  at  the  centre  of  the  opht  hal- 
moscopic  mirror.  If  the  ej^e  be  myopic,  the  issuing  rays  viill  he  convergent  and  will 
therefore  be  brought  to  a  focus  at  some  point  in  front  of  the  eye,  giving  rise  to  a  real 
image  of  the  retina.  If  the  eye  be  hypermetropic,  the  issuing  rays  vriW  be  divergent, 
and  the  observer  will  see  the  red  reflection  of  light  from  the  back  of  the  retina. 

If  now  a  lens  of  low  power,  say  about  ten  dioptres  (4  in.  focus),  be  held  a  few  centi- 


556 


PHYSIOLOGY 


metres  in  front  of  the  observed  eye  (Fig.  28Cb),  the  reflected  rays  issuing  from  the 
pupil  will  be  brought  to  a  focus  at  a  point  between  the  observer  and  the  lens,  so  that 
at  this  point  will  be  formed  a  real  inverted  image  of  the  back  of  the  eyeball.  This 
image,  in  the  case  of  the  normal  eye,  will  lie  at  the  focus  of  the  lens.  If  the  eye  be 
myopic,  the  convergent  rays  will  be  brought  to  a  focus  nearer  to  the  lens  than  its 
principal  focus,  while  the  divergent  rays  from  the  hypermetropic  eye  will  give  rise  to 

an  image  in  a  plane  between  the  principal 
focus   and  the  observer.      From   the  figxire 

(Fig.  281)  it  is  evident  that  -— -  =  — ,  i.e.  the 
"■     ^         '  AB      AO 

magnification  of  the  image  will  be  propor- 
tional to  the  focal  length  of  the  lens  used 
divided  by  the  posterior  focal  length  of  the 
eyeball.  If  we  are  using  a  bi-convex  lens  of 
10  cm.  local  length  and  the  eye  be  assumed 
to  have  a  posterior  focal  length  of  1-5  cm., 
the  real  inverted  image  that  we  see  in  the 


Fig.  iSl.  To  illustrate  how  the  rays 
from  an  illuminated  point  of  the  retina 
form  a  parallel  beam  on  leaving  the 
eye,  and  are  brought  to  a  focus  at  b 
by  interposing  the  lens  L. 


bi-convex  lens  will 


be  — , 
1-5 


i.e.  6-7  times  as 


large  as  the  retinal  structures  represented. 
(&)  THE  DIRECT  METHOD.     In  this  method  the   observer   places   himself  close 
to  the  observed  eye,  throwing  light  into  the  latter  from  the  mirror,  and  relaxes  by 
an  effort  of  will  his  accommodation  absolutely.* 


Fig.  282.     Path  of  rays  in  examination  by  the  direct  method. 

A,  path  of  illuminating  rays  ;    b,  path  of  rays  from  iUuminated  retina 

to  observer's  eye. 

If  both  the  observer's  eye  and  the  observed  eye  are  normal  and  unaccommodated, 
i.e.  focused  for  distance,  the  rays  of  light,  is-uing  from  any  point  on  ihe  retina  of  the 
observed  eye,  will  leave  the  corneal  surface  as  a  beam  of  parallel  rays,  which  on  entering 
the  observing  eye  will  in  turn  be  focused  to  a  point  on  its  retina.  The  observer  there- 
fore sees  an  erect  magnified  image  of  the  retina  of  the  observed  eye.     If  we  take  the 

*  In  the  use  of  the  opththalmoscope  it  is  very  difficult  to  relax  accommodation 
when  trying  to  see  something  which  is  quite  close.  The  student  will  find  it  an  advan- 
tage to  try  to  imagine  that  he  is  looking  tlu-ough  a  telescope  at  an  object  at  a  con- 
siderable distance  off.  He  will  then  find  the  picture  at  the  back  of  the  eyeball  Fuddc  nly 
come  into  view. 


DIOPTRIC  MECHANISMS  OF  THE  EYEBALL 


557 


focus  of  the  eye  as  1-5  cm.  the  magnification  of  the  image  is  equivalent  to  that  which 

20 
would  be  produced  by  a  lens  of  the  same  focus  and  is  equal  to — ,  i.e.  about  thirteen  times. 

Since  this  method  gives  us  a  highly  magnified  image  of  the  back  of  the  eyeball,  it  is 
of  extreme  value  in  judging  of  the  existence  of  pathological  conditions  of  the  retina 
or  choroid.  It  is  also  of  value  in  enabling  the  oculist  to  determine  by  objective  methods 
the  existence  of  any  errors  of  refraction  in  a  patient's  eye.  On  examining  the  eye 
by  the  direct  method,  if  the  eye  be 
myopic  and  the  rays  leaving  it  con- 
vergent, it  will  be  impo-ssible  for  the 
observing  eye  to  bring  them  to  a 
focus,  and  it  will  be  necessary  to 
place  a  concave  lens  in  front  of  the 
hole  in  the  ophthalmoscopic  mirror 
in  order  to  bring  the  back  of  the 
observed  eyeball  into  view.  The 
weakest  di vergent  lens  through  whi ch 
an  image  of  the  observed  eye  can  be 
obtained  will  give  the  degree  of 
myopia  of  the  eye.  On  the  other 
hand,  the  rays  from  a  hypermetro- 
pic eye,  being  divergent,  will  need 
a  certain  effort  of  accommodation 
to  bring  them  to  a  focus  in  the 
observer's  eye,  and  here  the  degree 
of  hypermetropia  will  be  given  by 
the  focus  of  the  strongest  convex 
lens  through  which  it  is  just  possible 
to  obtain  a  clear  image  of  the  retina 
and  retinal  vessels.  By  the  same 
means  we  may  judge  of  the  existence 

of  astigmatism  and  form  an  idea  of  the  meridians  in  which  the  refractive  power  of  the 
eye  is  faulty.  For  this  purpose  observations  are  taken  of  the  focus  of  the  eye — firstly, 
for  horizontal  retinal  vessels  ;  secondly,  for  vessels  which  are  rumiing  vertically. 

On  examining  the  back  of  the  eyeball  by  either  of  these  methods,  the  most  prominent 
object  is  the  optic  disc  or  optic  nerve-papilla,  which  marks  the  point  of  entrance  of  the 
optic  nerve.  It  is  seen  as  a  pale  oval  disc  surrounded  by  a  deep  red  background  (Fig. 
283).  From  the  middle  of  the  papilla  the  retinal  vessels  pass  into  the  eyeball,  and 
they  are  seen  diverging  from  the  papilla  to  ramify  over  the  rest  of  the  retina.  The 
arteries  can  be  distinguished  from  the  veins  by  their  brighter  red  colour  as  well  as  hy  the 
stronger  reflection  of  light  from  their  sm'faces.  The  yellow  spot  is  very  difficult  to  see, 
except  in  atropinised  eyes,  since  it  only  comes  into  view  when  the  observed  eye  is  looking 
straight  into  the  ophthalmoscope.  Under  these  conditions  there  is  a  strong  '  light 
reflex,'  and  the  pupil  contracts  up  to  a  pin-point,  unless  paralj'sed  by  means  of  atropine. 
In  order  to  see  the  blind-spot,  or  optic  disc,  the  observed  eye  must  be  directed  inwards  ; 
thus  if  A  is  looking  at  the  right  eye  of  B,  B  must  be  told  to  look  over  A's  right 
sioulder. 


Fig.  283.  Ophthalmoscopic  view  of  fundus  of 
eye,  showing  the  optic  disc,  or  point  of  entry 
of  the  optic  nerve,  with  the  retinal  vessels 
branchinc;  from  its  centre. 


SECTION   VII 

THE  RETINAL  CHANGES  INVOLVED  IN  VISION 

In  nearly  all  sense-organs  the  essential  constituent  is  a  bipolar  nerve-ceU 
lia^ang  one  process  extending  towards  the  surface  and  ending  between 
epithelium-cells  covering  that  sui'face,  and  a  central  process,  which  runs 
towards  the  central  nervous  system,  where  it  forms  synapses  with  the  pro- 
cesses of  other  nerve-cells  (Fig.  284).  In  some  cases,  such  as  the  oKactory 
cells  and  the  sense-cells  embedded  in  the  epidermis  of  worms  and  other 


7^il  "-mm 


^'^^^^'J'r^^^'. 


B 


C 


Fig.  284. 

A,  olfactory  sense-cell ;     b,  auditory  sense-cell ;     c,  connections   of   gustatory  fibres 

(taste-bud);  d,  nerve-ending  in  skin  or  corneal  epithelium  (probably  pain  fibres). 

invertebrata,  the  peripheral  process  is  quite  short.  In  other  cases,  as  in  the 
ordinary  posterior  root  ganghon-cell,  the  peripheral  process  may  be  several 
feet  in  length.  The  retina,  however,  cannot  be  regarded  as  a  simple  sense- 
organ,  but  is  homologous  with  a  complete  lobe  of  the  brain.  It  is  formed, 
like  the  cerebral  hemispheres,  as  a  hoUowed  outgrowth  from  the  fore-brain 
or  anterior  cerebral  vesicle.  The  stalk  of  this  outgrowth  narrows  so  as  to 
produce  an  optic  vesicle  connected  with  the  rest  of  the  fore-brain  by  the 
optic  stalk.  As  the  vesicle  grows  towards  the  surface  its  anterior  wall  is 
invaginated  so  that  an  '  optic  cup '  is  formed,  at  the  mouth  of  which  the 
lens  and  other  parts  of  the  eye  are  developed  at  the  expense  of  the  over-lying 
epiblast  and  the  surrounding  mesoblast.  The  posterior  wall  of  the  cup 
develops  into  the  retinal  pigment,  while  the  nervous  elements  which  make 
up  the  retina  are  formed  by  division  and  differentiation  from  the  anterior 

558 


RETINAL  CHANGES  INVOLVED  IN  VISION 


559 


wall.  That  part  of  the  cup  originally  derived  from  the  external  surface 
of  the  body  is  turned  towards  the  posterior  layer  or  retinal  pigment.  From 
it  is  developed  the  special  end-organ  of  vision,  viz.  the  rod  and  cone  layer 
of  the  retina.  Besides  this  special  sensory  epithehum,  the  retina  presents 
two  other  sets  of  neurons  through  which 
impulses  generated  in  the  sensory  epi- 
thehum must  pass  before  they  arrive  at 
the  optic  nerve.  The  three  relays  of 
nervous  elements  in  the  retina  have  the 
following  arrangement  : 

(1)  The  first  relay — the  sense  epithe- 
himi — consists  of  rods   and  cones  with 
their  nuclei  (Fig.  285),  the  latter  being 
situated  in  the  outer  nuclear  layer.    Each 
rod  presents  an  external  (a)  and  an  in- 
ternal limb  {b).     The  former,  in  the  eye 
which  has  been  kept  in  the  dark,  has  a 
purphsh   colour    from    the   presence    of 
rJwdopsin  or  visual  'purple.     From  the 
inner  end  of  the  inner  hmb  a  fine  fibre  c 
passes  to  its  nucleus  in  the  outer  nuclear 
layer,  and  from   the  nucleus  a  central 
process  g  passes  into  the  outer  molecular 
layer  where  it   ends  freely  in   a    little 
knob  e.     The  cones,  which  are  thicker 
than  the  rods,  also  possess  outer  and 
inner  hmbs.     From  the  inner   hmb   a 
thick     process    containing    a    nucleus, 
passes    through    the    external    nuclear 
layer  and  ends  with  a  broad  base  e  in 
the  outer  molecular  layer,    from   which 
short   fibres   are   given  ofi  to  come   in 
contact   with  the   bipolar   cells    of   the 
imier  nuclear  layer. 

(2)  The  second  relay  is  formed  by 
the  bipolar  cells  of  the  inner  nuclear 
layer.  Each  of  these  sends  ofi  one 
fibre  peripherally  to  make  contact  with 
endings  of  the  rod  and  cone  fibres  in 
the  outer  molecular  layer,  and  another  process  which  passes  centrally  into 
the  inner  molecular  layer.  Here  the  process  of  the  rod  bipolar  forms  an 
arborisation  aromid  the  body  of  a  cell  in  the  ganghon-cell  layer,  while  the 
processes  of  the  cone  bipolars  end  at  various  levels  in  the  inner  molecular 
layer,  forming  synapses  with  the  dendrites  of  the  ganghon-cells. 

(3)  The   ganghon-cells,   which   represent   the   third   relay,    receive  the 
impulses  from  the  more  peripheral  parts  of  the  retina  and  send  them  towards 


Fig.  2S5. 
I.  a  rod  ;   II,  a  cone  of  mammalian 
retina;   /(.  externa]  limiting  membrane. 
(R.  Greeff.) 


560 


PHYSIOLOGY 


tlie  brain  along  the  fibres  of  the  optic  nerve,  each  of  which  is  the  axon  of  one 
of  the  ganghon-cells.  These  axons,  which  form  the  inner  layer  of  the  retina, 
the  so-called  '  nerve-fibre  layer,'  are  non-mednllated  as  they  pass  over  the 
surface  of  the  retina,  but  acquire  a  medullary  sheath  as  they  pass  out  of  the 
eyeball  through  the  cribriform  plate  of  the  sclerotic  and  join  to  form  the 
optic  nerve. 

Most  of  the  bipolar  cells  are  connected  with  several  rods  or  cones  ;   only 
in  the  fovea  centraHs  do  we  find  a  special  bipolar  cell  provided  for  every  cone. 


a  TO  b 

Fig.  286.  Schema  of  retina.  (From  Bohm  and  Davidoff  after  Cajal.) 
1,  nerve-fibre  layer  ;  2,  ganglion-cell  layer  ;  3,  inner  molecular  layer  ;  4,  inner 
nuclear  layer  ;  5,  outer  molecular  layer  ;  6,  outer  nuclear  layer  ;  c,  cone  ;  r,  rod  ; 
b,  bipolar  cells  ;  S,  spongioblast ;  am,  amacrine  cell ;  c.n,  centrifugal  nerve  fibre  ; 
M,  fibre  of  Miiller  ;  n.M,  nucleus  of  fibre  of  Miiller  ;  n,  neuroglia  ;  o,  outer  limiting 
membrane. 

Every  ganghon-cell  comes  into  connection  with  and  receives  the  impulses 
from  a  considerable  number  of  bipolar  cells,  so  that  the  number  of  fibres  in 
the  optic  nerve  running  centrally  is  not  so  great  as  the  number  of  sense 
elements  in  the  rod  and  cone  layer  of  the  retina.  Besides  these  cells  situated 
on  the  direct  path  of  the  visual  impulse,  other  cells  of  a  nervous  nature  are 
found  in  the  inner  nuclear  layer  (the  outer  and  inner  horizontal  cells),  and  also 
in  the  inner  molecular  layer,  the  so-called  '  amacrine  '  cells.  These  cells  have 
been  imagined  to  serve  as  a  means  of  connection  or  association  between 
different  parts  of  the  retina,  and  may  be  taken  as  analogous  to  the  association- 
cells  found  in  the  cerebral  cortex.  The  analogy  of  the  retina  with  a  lobe  of 
the  brain  is  illustrated  by  the  fact  that,  in  addition  to  the  fibres  originating  in 
the  retina  and  passing  towards  the  brain,  a  considerable  number  of  fibres  pass 
from  the  central  nervous  system  into  the  retina,  where  they  end  chiefly  in  the 
two  molecular  layers.  These  may  have  as  one  of  their  functions  the  correla- 
tion of  processes  occurring  in  the  retinae  of  the  two  eyes  and  may  be  asso- 
ciated with  phenomena  such  as  those  of  binocular  contrast,  which  we  shall 
have  to  study  later  on. 


RETINAL  CHANGES  INVOLVED  IN  VISION 


561 


Important  differences  are  found  in  the  structure  of  the  retina  in  its 
different  parts.  At  the  point  of  entrance  of  the  optic  nerve — ^the  optic  disc — 
the  only  elements  present  are  the  nerve  fibres,  which  diverge  from  this 
point  over  the  whole  inner  surface  of  the  retina.  A  short  distance  externally 
to  the  optic  disc  is  found  the  macula  lutea  with  a  small  depression  in  the 
middle,  the  central  spot  oi  fovea  centralis  (Fig.  287).  When  we  fix  our  gaze 
on  any  object  the  visual  axes  are  so  directed  that  the  image  of  the  object  falls 
on  the  fovea  centrahs.  At  this  spot  the  retina  is  thinned  by  the  gradual 
disappearance  of  all  its  layers  except  the  outermost.  The  outermost  layer 
is  moreover  distinguished  by  the  fact  that  the  rods  have  disappeared  and  that 


\\\\\\ 


mm. 


\\\\\\\\\\\\\m\mmmmmmM 


iiMUiinUiUIUUW 


Fig.  287 


Section  through  half  the  fovea  centralis, 
and  GoLDiNG  Bird.) 


only  the  cones  are  present,  and  are  very  much  larger  than  the  cones  in  any 
other  part  of  the  retina.  The  fibres  fi'om  those  cones,  passing  to  the  inner 
nuclear  layer,  diverge  as  they  leave  the  fovea  centralis,  all  the  layers  of  the 
retina  being  displaced  towards  the  circumference  in  order  to  allow  the  light 
to  fall  on  the  cones  without  having  to  pass  through  any  of  the  other  layers  of 
the  retina.  As  we  pass  from  the  centre  to  the  periphery  of  the  retina  the 
cones  become  fewer  and  the  rods  more  nmnerous.  At  the  extreme  margin 
the  rods  also  are  scattered  more  diffusely,  and  at  the  ora  serrata,  which  hes 
a  short  distance  behind  the  cihary  processes,  the  special  nervous  elements 
come  to  an  end,  and  the  retina  is  continued  forwards  over  the  ciliary  pro- 
cesses and  the  posterior  surface  of  the  iris  as  a  layer,  two  cells  thick,  closely 
packed  with  pigment  granules  (the  uvea). 

The  following  facts  show  that  the  layer  of  the  rods  and  cones  represents 
the  end-organ  of  vision,  and  that  for  distinct  vision  to  take  place  the  image  of 
an  external  object  must  be  formed  in  this  layer  : 


562 


PHYSIOLOGY 


(a)  The  point  of  entry  of  the  optic  nerve,  where  the  whole  thickness 
of  the  retina  is  composed  of  nerve  fibres,  is  absolutely  insensitive  to  hght 
and  constitutes  the  blind-spot  (Fig.  288).     If  the  hght  of  a  small  flame  be 


Fig.  288. 

directed,  by  means  of  a  mirror,  into  the  eye  so  that  it  falls  only  on  to  the  optic 
disc,  the  individual  receives  no  sensation  of  hght.  The  existence  of  the 
bhnd-spot  is  more  easily  shown  by  the  following  experiment :  On  closing  the 

left  eye  and  gazing  fixedly  with  the  right  eye 
at  the  white  cross  in  the  figure,  on  approxi- 
mating the  book  to  the  eye  a  point  will  be 
found,  when  the  book  is  at  a  distance  of  eight 
inches  from  the  eye,  at  which  the  white  circle 
becomes  invisible  and  the  whole  figure  appears 
to  be  covered  by  the  black  ground.  By 
measuring  the  apparent  size  of  the  bhnd-spot 
and  its  distance  from  the  point  of  fixation, 
we  find  that  its  situation  on  the  retina  corre- 
sponds exactly  to  the  point  of  entry  of  the 
optic  nerve.     The  bhnd-spot  is  so  large  that 


ii  V) 


Fio.  289.     Diagram  of  the  path 
of  the  rays  of  light  in  the  for- 
mation of  Purkinje's  figures. 
V  represents  a  retinal  vessel. 
When  this  is  lluminated  from  a, 
a  shadow  is  formed  on  the  hinder 
layers  of  the  retina  at  a'.     This 
is  projected  along  a  line  passing 
through  the  optic  axis,  and  ap- 
pears to  come  from  a  point  {a") 
on   the  wall.      On  moving  the 
light  from  a  to  b,  the  image  of 
the  vessel  appears  to  move  from 
a"  to  b". 


at  a  distance  of  about  six  feet  the  image  of 


the  head  of  a  man  will  fall  on  it  and  therefore 

be  invisible. 

(6)   At  the  point  of  most  distinct  vision, 

i.e.  the  fovea  centralis,  all  the  layers  of  the 

retina   are   absent  except  the  outermost,  i.e. 

that  of  the  cones. 

(c)  '  Purkinje's  figures.'      If  a  strong  light 

be  focused  by  means  of  a  lens  on  to  the  sclerotic 

just  outside  the  cornea,  and  the  eye  be  made  to 
stare  fixedly  at  a  dull  background,  an  arborescent  image  of  the  retinal  vessels 
will  appear  on  the  background.  On  moving  the  illumination  the  image  of  the 
vessels  will  move  in  the  same  direction.  Knowing  the  dimensions  of  the 
eyebaU  and  the  distance  of  the  background  from  the  eye  as  well  as  the  angle 
through  which  the  light  is  moved  and  the  apparent  displacement  of  the  image 
of  the  vessels,  the  distance  of  the  sensory  part  of  the  retina  behind  the  vessels 
may  be  calculated  (Fig.  289).     Direct  measurements  in  this  way  have  shown 


RETINAL  CHANGES  INVOLVED  IN  VISION 


563 


that  the  distance  between  the  vessels  and  the  sensitive  elements  of  the  retina 
must  amount  to  between  0-17  and  0-36  mm.  Anatomical  measurements  of 
the  thickness  of  the  retina  show  also  that  the  average  distance  between  the 
vessels  and  the  layer  of  rods  and  cones  varies  between  0-2  and  0-3  mm., 
showing  that  it  is  in  this  layer  that  the  actual  transformation  of  a  hght 
stimulus  into  a  nerve  impulse  must  take  place. 

On  spreading  out  the  retina  under  the  microscope  and  looking  at  its 
external  surface  we  see  that  the  rods  and  cones  form  a  sort  of  mosaic,  the 
thicker  cones  being  surrounded  by  the  smaller  circles  representing  the 
cross-sections  of  the  rods.  Since  each  of  these  is  a  terminal  sense-element 
the  image  thrown  by  the  dioptric  mechanism  of  the  eye  on  to  the  retina  must 
be  converted  into  a  mosaic-hke  expanse  of  small  isolated  pictm-es,  and  our 
impression  of  external  objects  must  be  formed  by  a  synthesis  of  the 
elementary  sensations  produced  by  the  stimulation  of  every  single  rod  or 
cone  cell. 

DIRECT   AND  INDIRECT  VISION 
If  we  fix  our  attention  on  to  an  object,  we  direct  our  eyes  so  that  the 
image  of  the  centre  of  the  object  falls  exactly  on  the  fovea  centraHs  of  each 
retina.    The  diameter  of  the  central 
spot  is  about  1  to  1-5  mm.,  which 

corresponds  to  a  visual  angle  of  4:° 

to  6°.     This  angle  therefore  repre- 
sents the  extent  of  the  visual  field 

in  which  we  have  distinct  vision. 

The  hght  which  falls  into  the  eye 

forms  an  image  of  external  objects 

which  extends  over  the  whole  of 

the  retina.    The  sensations  excited 

by  the  stimulation  of  the  periphery 

of  the  retina  are  much  more  in- 
distinct than  those  excited  by  the 

image  on  the   central  spot.     The 

appreciation  of  external    objects, 

by  means  of  the  image  they  throw 

on  the  external  parts  of  the  retina, 

is  spoken  of  as  indirect  vision  in 

contradistinction  to  direct  vision, 

which  implies  fixation  of  the  object 

and  the  formation  of  an  image  of 

it  on  the  fovea  centralis.     The  whole  extent  of  the  objects  which  we  can 

see  by  direct  and  indirect  vision  is  spoken  of  as  the  visual  field.     In  order 

to  determine  the  visual  field  we  make  use  of  a  perime'^er  (Fig.  290). 

ThLs  instrument  consists  of  a  band  of  metal  forming  the  arc  of  a  circle  of  about 
35  cm.  radius.  At  one  end  this  arc  is  fastened  to  a  pillar,  and  can  be  turned  through 
the  axis  imssing  through  the  i^illar  so  as  to  lie  in  various  meridians.  At  the  centre 
of  the  circle  is  another  pillar,  which  provides  a  chin-re^t,  so  arranged  that  the  eye 


Fig.  293.      Priestlov  Suuth's  perimeter. 


564 


PHYSIOLOGY 


of  the  observed  person  lies  exactly  at  the  centre  of  the  circle  at  the  top  of  the  pillar. 
At  the  point  round  which  the  arc  rotates  is  a  small  white  disc.  In  using  the  instru- 
ment the  person,  whose  field  of  vision  is  to  be  determined,  places  his  eye  at  the  top  of 
the  pillar  and  gazes  fixedly  at  the  white  disc  ;  another  small  white  disc  is  then  moved 
along  the  curved  arc  and  the  point  noted  atwhich  it  is  no  longer  visible,  while  theobserved 
person  is  gazing  fixedly  at  the  white  disc  on  the  axis  of  rotation.  The  arc  is  then 
moved  20°  and  the  same  experiment  carried  out,  and  this  is  continued  until  the  limit 
has  been  determined  in  every  meridian  of  the  visual  field.  The  rotating  arc  is  graduate  d, 
the  graduations  showing  the  visual  angles  subtended  by  any  portion  of  the  arc.     As 


xn 


Fig.  291.     Perimeter  chart  showing  the  field  of  vision  in  a  normal  (right)  eye. 

the  readings  are  made  they  are  marked  down  on  a  chart,  such  as  that  shown  in  Fig. 
291,  so  that  finally  a  graphic  representation  of  the  visual  field  is  obtained.  The  visual 
field  is  more  extensive  on  the  outer  than  on  the  nasal  side  of  the  eye,  the  latter  being 
contracted  by  the  cutting  off  of  some  of  the  rays  falling  on  the  outer  side  of  the  retina 
by  means  of  the  nose. 

Although  stimulation  of  the  peripheral  parts  of  the  retina  does  not 
give  us  much  idea  of  the  nature  of  the  things  vfe  are  looking  at,  yet  it  is 
of  great  importance  in  informing  us  of  the  relation  of  the  object,  which  is 
the  immediate  point  of  attention,  to  its  surroundings.  It  therefore  plays 
a  great  part  in  regulating  the  movements  of  the  body.  Its  importance  will 
be  at  once  appreciated  if  one  eye  be  closed  and  the  stimulation  of  the  peri- 
pheral parts  of  the  retina  in  the  other  eye  be  excluded  by  allowing  this  eye 
only  to  look  through  a  tube.  Although  we  can  then  see  the  objects  to  which 
we  direct  our  gaze  perfectly  distinctly,  we  find  that  on  trying  to  move  towards 
any  given  object  our  movements  are  uncertain  and  misdirected. 


CHEMICAL   AND  PHYSICAL  CHANGES  IN  THE   RETINA 
When  light  falls  on  the  retina  chemical  and  physical  changes  take  place  ; 
these  either  originate  or  accompany  the  transmutation  of  the  ether  vibrations 
into  the  nerve  impulses,  which  ascend  the  optic  nerve.     If  a  frog  that  has  been 


RETINAL  CHANGES  INVOLVED  IN  VISION 


565 


in  the  dark  for  some  time  be  killed,  an  eye  taken  out,  bisected,  and  the 
retina  removed  and  examined  by  a  weak  light,  it  will  be  found  to  have 
a  purplish-red  colour.  On  microscopical  examination  this  colour  is  seen  to 
be  confined  to  the  outer  limbs  of  the  rods.  After  a  very  short  exposure  to 
diffuse  daylight  the  colour  disappears.  The  colouring- matter  {rhodopsin) 
may  be  dissolved  out  by  means  of  a  solution  of  bile  salts.  The  purple-red 
solution  thus  formed  also  bleaches  rapidly  on  exposme  to  hght.  By  means 
of  this  rhodopsin  photographs  or  '  optograms '  of  external  objects  may  be 
taken  on  the  retina.  The  rabbit's  eye  is  cut  out  and  placed  in  front  of  a 
window.  After  some  time  the  eye  is  bisected  and  plunged  into  a  4  per  cent, 
solution  of  alum,  which  partially  fixes  the  optogram,  and  an  inverted  picture 
of  the  window  with  its  cross-bars  is  obtained  on  the  retina. 

If  a  retina,  which  has  been  bleached  by  exposure  to  light,  be  replaced  on 
the  pigment  layer  Kning  the  choroid,  in  a  short  time  the  colour  will  be 


Fig.  2'J2.     Sections  of  the  frog's  retina. 
A,  kept  in  the  dark  ;    b,  after  exposure  to  the  light,  showing  retraction  of  the 
cones,  and  protrusion  of  the  pigmented  epithelium  between  the  outer  limbs  of  the 
rods.     (Engelmann.) 

restored.  On  examining  sections  through  the  retina  it  is  found  that,  in  one 
which  has  been  exposed  to  light,  the  cells  of  the  layer  of  pigmented  epithehimi 
send  up  fine  processes  full  of  pigmented  granules  between  the  outer  hmbs  of 
the  rods.  In  an  eye  which  has  been  kept  in  the  dark,  on  the  other  hand,  the 
cells  of  the  pigment  layer  are  quite  fiat,  so  that  the  front  part  of  the  retina, 
including  the  rods  and  cones,  can  be  removed  without  any  difficulty  (Fig. 
292).  Thus  the  function  of  the  pigmented  epithelium  is  to  supply  visual 
purple  to  the  outer  hmbs  of  the  rods  as  fast  as  the  pigment  already  there  is 
bleached  by  light.  It  might  be  thought  that  this  chemical  change  was  the 
active  agent  in  producing  excitation  of  the  optic  nerve  fibres  ;  but  the  fact 
that  in  the  fovea  centrahs,*  the  region  of  most  distinct  vision,  we  find  only 
cones  which  contain  no  visual  pmple  indicates  that  this  chemical  process 
is  not  essential  for  the  conversion  of  hght-waves  into  a  nervous  impulse. 

*  According  to  Edridge  Green  visual  purple  diffuses  into  the  fovea  centralis,  and 
p'.iys  an  es^eatial  part  in  vision  as  a  sensitiser  of  the  cones. 


566 


PHYSIOLOGY 


When  light  falls  upon  the  retina  the  cones  are  retracted,  and  lie  close  upon 
the  external  hniiting  membrane  ;  whereas  in  an  eye  that  has  been  kept  in  the 
dark  they  extend  down  between  the  rods  as  far  as  the  pigmented  layer. 


II. 


^tapltttl^ 

itt 

lid 

Ir 

▼^. :  ■ ; '  r^^WB^*|to|l»^irj^^ 

i 

.;  t  !  i  . 

■■:^u]-\]rii\i-,.,.,..\,Awm 

m 

^^^i^ 

i 

,-L-^  ;,,::.;;  ::-Mii:±rtliiiii!.U!:i. 

Fig.  293.     Electrical  variation  in  frog's  eye  as  recorclcd  by  the  string  galvanometer. 
(EiXTHOVEN  and  Jolly.) 
I,  on  exposure  to  a  single  flash ;    II,  on  exposure  to  light  of  moderate 
duration  ;  III,  effect  on  a  light  eye  of  momentary  darkening. 

The  falling  of  light  on  the  retina  is  also  accompanied  by  an  electrical  change,  which 
may  be  regarded  as  analogous  to  the  current  of  action  in  nerve.  It  is,  however,  much 
more  complicated  than  the  latter.  The  eyeball  of  the  frog  led  off  from  its  anterior  and 
posterior  surfaces  shows  a  current  directed  in  the  eyeball  from  behind  forwards  (the 
resting  or  demarcation  current).  It  was  first  shown  by  Holmgren  that  this  resting 
current  undergoes  modification  when  light  is  allowed  to  fall  on  the  eyeball.  Of  late 
years  the  nature  of  this  modification  has  been  studied  especially  by  Waller  with  the 
galvanometer,  by  Gotch  with  the  capillary  electrometer,  and  by  Einthoven  and  Jolly 
with  the  string  galvanometer.     The  nature  of  the  response   varies  according  to  the 


EETINAL  CHANGES  INVOLVED  IN  VISION  567 

strength  and  duration  of  the  stimulus,  and  to  the  conditirn  of  the  eye,  whether  fatigued 
or  fresh,  light-  or  dark-adapted.  A  typical  response  to  a  momentary  flash  is  shown 
in  Fig.  293,  I.  Within  a  very  short  latent  period  after  the  incidence  of  the  flash,  i.e. 
after  a  latent  period  of  not  more  than  -01  sec,  there  is  a  small  short  negative  variation 
of  the  resting  cm-rent,  which  is  immediately  followed  by  a  large  positive  variation,  i.e. 
the  resting  current  is  increased.     This  is  followed  immediately  by  a  diminution  and 


II. 


Fig.  294.      Diagrammatic  representation  of    the  reactions  to  light  of   the  three 
hypothetical  substances  a,  b,  and  c.     (Eintho\ten  and  Jolly.) 
I,  the  three  effects  shown  separately  ;   II,  the  three  effects  combined  to  form  a 
single  curve,     a  is  the  lighting  and  a'  the  darkening  effect  of  the  iirst  substance. 
I,  light ;    d,  darkness. 

then,  after  a  considerable  latent  period,  by  a  second  slow  prolonged  increase  of  the 
ciurent.  When  the  duration  of  the  stimulus  is  longer  the  moment  of  shutting  oflE 
the  light  is  seen  to  be  followed  immediately  by  a  second  positive  vaxiation.  This 
.  is  shown  in  Fig.  293,  II.  It  is  possible  to  obtain  this  response  to  darkness  bj'^  shutting 
ofE  for  a  sliort  period  of  time  the  light  falling  into  the  eye.  The  result  of  such  an  ex- 
periment is  shown  in  Fig.  293,  III.  Einthoven  and  Jolly  explain  these  results  by  the 
assumption  that  three  separate  processes  are  concerned  when  the  retina  is  stimulated. 
For  convenience  they  speak  of  the  changes  in  tliree  distinct  substances,  A,  b,  and  c. 
Of  these  a  reacts  more  rapidly  than  the  other  two,  and  its  action  is  specially  marked 
in  a  'light'  eye,  appearing  almost  isolated  on  sudden  darkening  of  short  duration 
(a  flash  of  darlaiess).  On  lighting,  it  develops  a  negative,  on  darkening  a  positive 
potential  difference.  The  substance  B  reacts  less  rapidly  than  A.  On  lighting,  it 
develops  a  positive,  on  darkening  a  negative  potential  difference.  Its  action  is  especially 
marked  in  a  dark  eye  wliich  is  illuminated  for  a  short  time  with  a  weak  light.  Sub- 
stance o  reacts  in  the  same  sense  as  B,  but  much  more  slowly.  Its  action  is  wanting 
in  a  completely  light  eye.  The  actions  of  these  three  substances  are  represented 
diagrammatically  in  Fig.  294,  I.  and  II. 

It  is  interesting  to  note  that  the  latent  period  of  the  photo-electric  reaction  agrees 
with  the  latent  period  of  the  light  perception  of  the  human  eye,  and  may  vary  from 
•01  sec.  with  strong  stimuli  to  as  much  as  2  sec.  with  very  weak  stimuli. 


SECTION   VIII 
VISUAL   SENSATIONS 

The  retinal  changes  which  we  have  just  described  as  occurring  in  the  retina 
on  .exposure  to  Hght  give  us  very  little  information  as  to  the  nature  and 
conditions  of  the  physiological  activity  excited  in  this  organ  by  the  physical 
stimulus  of  Hght.  We  are  therefore  driven  to  use  as  our  criterion  of  these 
physiological  processes  the  changes  excited  in  consciousness,  and  the  greater 
part  of  our  knowledge  of  the  physiology  of  vision  is  derived  from  examination 
of  such  of  our  own  sensations  as  have  their  primary  origin  in  the  retina. 
How  far  these  sensations  can  be  regarded  as  having  their  seat  in  the  retina, 
how  far  they  are  determined  by  physiological  changes  in  the  visual  and  ad- 
jacent portions  of  the  brain,  it  is  not  possible  to  say.  We  are  only  able  to 
deal  with  the  sensations  as  they  spring  ready  formed  into  our  consciousness. 

NATURE  OF  THE  STIMULUS 

The  word  '  hght,'  as  employed  by  physicists,  imphes  a  particular  kind 
of  energy,  which,  arriving  at  the  retina  in  a  certain  way,, excites  in  us  a 
sensation  of  hght.  The  conception  is  therefore  primarily  physiological. 
Every  material  substance  is  endowed  with  a  certain  amount  of  internal 
energy,  the  index  to  which  is  its  temperature.  In  virtue  of  this  energy 
it  is  constantly  radiating  energy  at  a  greater  or  less  rate  through  the  sur- 
rounding ether,  its  internal  energy  at  any  given  moment  being  determined 
by  the  balance  between  the  amount  of  energy  it  gives  off  and  the  amount 
of  energy  which  it  receives  from  surrounding  bodies.  This  radiant  energy 
is  transmitted  through  space  as  transverse  oscillations  of  the  ether  at  the 
rate  of  about  two  hundred  thousand  miles  per  second  and  with  very  variable 
wave-length  and  rate  of  oscillation.  The  whole  energy  available  to  us  on  the 
surface  of  the  earth  is  derived  from  that  portion  of  the  radiant  energy  of  the 
sun  which  is  intercepted  by  the  earth. 

Since  the  velocities  of  transmission  of  rays  of  various  wave-lengths  differ 
as  these  rays  pass  through  a  dense  medium,  such  as  glass,  it  is  possible  to 
break  up  the  compound  waves  of  radiant  energy  arriving  at  us  from  the  sun, 
or  emitted  by  any  hot  body,  by  allowing  them  to  pass  through  a  prism. 
When  the  luminous  solar  rays  are  passed  in  this  way  through  a  prism  we  get, 
as  is  known,  a  spectrum,  the  rays  which  are  refracted  the  least  being  red, 
while  those  which  are  most  refracted  are  violet.  Between  these  two 
extremes  we  have  rays  of  the  following  colours — orange,  yellow,  green,  blue, 
indigo,  which  merge  one  into  the  other  without  any  perceptible  break.     The 

568 


VISUAL  SENSATIONS  569 

different  parts  of  the  visible  spectrum,  when  obtained  from  the  sun,  show 
vertical  dark  hues,  which  are  known  as  Fraunhofer's  lines.  These  are  due  to 
the  fact  that  certain  rays  emitted  by  the  glowing  centre  of  the  sun  are 
absorbed  in  passing  through  the  gaseous  envelope  which  surrounds  the  sun. 
The  hues  are  distinguished  by  certain  letters  and  have  all  been  assigned  to  the 
existence  of  known  elements  in  a  gaseous  form  in  the  solar  envelope.  Any 
part  of  the  spectrum  is  distinguished  according  to  its  relation  to  these  hues, 
since  each  of  them  has  a  constant  wave-length.  The  visible  spectrum  ex- 
tends from  the  hne  A  at  the  hmit  of  the  red,  which  has  a  wave-length  of 
760  milHonths  of  a  milhmetre,  to  the  hne  H  at  the  end  of  the  violet  with  a 
wave-length  of  397.  The  visible  part  of  the  spectrum  does  not,  however, 
include  even  the  majority  of  the  rays  which  arrive  at  the  earth  from  the  sun. 
Beyond  the  red  we  get  the  ultra-red  rays,  which  have  a  large  amount  of 
energy,  so  that  their  presence  can  be  easily  detected  by  their  warming  effect 
on  blackened  bodies,  such  as  the  blackened  bulb  of  a  thermometer  or  a 
thermo-junction,  held  in  this  part  of  the  spectrum.  In  the  same  way, 
beyond  the  violet  end  there  is  a  long  extent  of  rays  with  high  refrangibihty 
and  small  wave-length.  Though  not  perceptible  to  the  eye,  they  reveal  their 
existence  by  the  marked  influence  they  exert  on  salts  of  silver ;  they  are 
therefore  often  spoken  of  as  the  actinic  or  photographic  rays. 

If  the  investigation  of  the  constituent  rays  of  the  solar  spectrum  were 
carried  out  at  a  considerable  altitude  above  the  sea  and  by  means  of  c^uartz 
prisms  and  lenses,  the  extent  of  the  imasible  spectrum  would  be  found  to  be 
largely  increased,  since  the  ultra-red  and  ultra-violet  rays  are  absorbed  by 
the  constituents,  especially  the  aqueous  vapour,  of  the  atmosphere.  Why 
can  we  not  see  these  rays  as  well  as  those  in  the  middle  of  the  spectrimi  ? 
Is  it  that  they  are  absorbed  by  the  media  of  the  eye,  through  which  the  ray 
of  light  has  to  travel  before  it  reaches  the  retina,  or  is  their  invisibility  due 
to  an  actual  insensibility  of  the  retina  to  rays  of  high  and  low  wave-lengths  ? 
On  testing  the  absorption  of  these  rays  by  the  transparent  media  of  the 
eye,  we  find  that  the  absorption  of  the  ultra-red  rays  is  but  slight  and  that  a 
considerable  proportion  of  these  rays  must  be  always  arriving  at  the  retina, 
so  that  their  invisibiUty  must  be  determined  by  the  fact  that  they  are 
unable  to  excite  the  special  sensory  elements  of  the  retina.  On  the 
other  hand,  the  absorption  of  the  ultra--saolet  rays  by  the  eye  media  is 
practically  complete,  although  these  rays  on  arriving  at  the  retina  have  the 
power  of  evoking  sensation.  Thus  it  has  been  observed  that  after  extraction 
of  the  lens  for  cataract  the  visibility  of  the  spectrmn,  which  in  the  normal 
eye  only  extends  to  the  line  H  with  a  wave  length  of  397,  is  increased  on  the 
violet  side  so  that  the  spectrum  may  be  seen  as  far  as  a  point  corresponding 
to  a  wave  length  of  313.  It  is  evident  from  this  that  in  the  absorption  of  the 
ultra-violet  rays  by  the  eye  the  lens  takes  a  preponderating  part. 

LUMINOSITY  OF   DIFFERENT  PARTS  OF  THE  SPECTRUM 
The  physiological  nature  of  om*  conception  of  light  is  shown  by  the  fact 
that  the  spectrum  dift'ers  in  its  luminosity,  i.e.  in  its  total  stimidating''eftect 


570 


PHYSIOLOGY 


on  the  retina  in  its  different  parts,  and  that  the  relative  luminosities  of 
different  parts  of  the  spectrum  bear  no  relation  to  the  amount  of  radiant 
energy  represented  by  each  kind  of  wave  length.  The  greatest  energy  is 
attained  by  the  ultra-red  rays  and  there  is  a  gradual  diminution  from  here  to 
the  violet  end  of  the  spectrum.  The  yellow  part  of  the  spectrum,  however, 
appears  much  brighter  than  any  other  part.  The  relative  luminosity  of 
different  parts  is  shown  in  the  following  Table  by  Vierordt : 

Part  of  spectrum 
Red'B'    . 
Orange  '  C ' 


Reddish  yellow  '  D  ' 
Yellow  '  D  '  to  '  E  ' 
Green  '  E  ' 
Bluish  green  '  F  ' 
Blue  '  G  '  . 
Violet  '  H ' 


Luminosity 

22 

128 

780 

1000 

370 

128 

8 

1 


The  limited  excitabihty  of  the  retina  and  its  special  sensitivity  to  rays 
in  the  middle  of  the  spectrum  present  considerable  advantages  for  the 
normal  functioning  of  the  optical  apparatus.  No  pro^asion  is  made  for 
securing  achromatism.  The  dispersion  of  the  ultra-red  and  ultra-violet 
rays  is  so  great  in  passing  through  the  refracting  surfaces  of  the  eyeball  that, 
if  they  all  arrived  at  the  retina,  and  this  organ  were  sensitive  to  both  kinds 
of  rays,  it  would  be  impossible  to  obtain  any  clear  image  of  external  objects. 
The  image  formed  by  the  ultra-red  rays  would  be  far  behind  the  retina  when 
the  ultra-violet  rays  were  focused  on  the  retina  and  vice  versa.  As  it  is,  the 
retina  is  unstimulated  by  the  two  ends  of  the  spectrum,  and  its  stimulation 
by  the  red  as  well  as  by  the  blue  rays  is  only  minimal,  so  that,  for  the  excita- 
tion of  a  mosaic  of  spots  on  the  retina  in  spatial  extension  and  arrangement 
corresponding  to  that  of  the  objects  from  which  the  light  reaches  the  retina, 
practically  only  the  middle  part  of  the  spectrum  is  of  importance,  and  the 
distance  of  the  image  formed  by  the  reddish-yellow  rays  from  that  formed  by 
the  green  rays  will  not  be  great  enough  to  cause  any  appreciable  distortion 
of  the  exciting  image. 


THE  RELATION  OF  THE  INTENSITY  OF  SENSATION  TO 
THE  STRENGTH  OF  STIMULUS 
Weber's  law,  viz.  that  the  increase  of  stimulus  necessary  to  give  an  in- 
crease of  sensation  always  bears  the  same  ratio  to  the  whole  stimulus,  holds 
good  for  visual  sensations.  This  ratio  in  the  case  of  white  hght  is  about  j- 1^ . 
We  can  thus  distinguish  between  two  lights  of  20  and  20 1  candle-power,  both 
of  them  at  the  same  distance  from  the  eye,  or  between  two  of  99  and  100 
candle-power.  If  the  illumination  be  excessive  the  law  no  longer  holds  good, 
and  we  should  be  unable  to  tell  the  difference  between  two  lights  of  the 
latter  power  if  held  close  to  the  eye,  or  between  two  arc  lamps  at  a  con- 
siderable distance,  even  though  one  might  be  much  stronger  than  the  other. 
According  to  some  authors  our  power  of  distinguishing  differences  in  lumin- 
osity varies  with  different  colours. 


VISUAL  SENSATIONS  571 

TIME  RELATIONS  OF  THE  EXCITATORY  PROCESS 
When  a  stimulus  of  short  duration,  such  as  an  induction  shock,  is  applied 
to  a  muscle,  the  response  of  the  latter  bears  no  hkeness  in  its  intensity  and 
its  time-relations  to  the  exciting  stimulus.  The  muscle  after  a  short  latent 
period  begins  to  contract  when  the  stimulus  has  abeady  ceased  to  act.  It 
contracts  rapidly  at  first,  then  more  slowly,  and  then  relaxes.  In  the  same 
way  the  sensation  evoked  by  a  momentary  light  stimulus  takes  a  certain 
time  to  attain  its  maximum  and  then  dies  away  slowly,  persisting,  that  is  to 
say,  during  a  certain  interval  after  the  stimulus  has  been  entirely  withdrawn. 
This  persistence  of  the  visual  sensation  is  experienced  whenever  we  look  at  a 
brilliant  source  of  hght,  such  as  a  candle  or  lamp,  and  then  either  shut  the 
eyes  or  direct  the  gaze  on  to  a  blackened  surface.  We  then  see  on  the  dark 
background  a  bright  image  of  the  candle  or  lamp,  which  gradually  fades 
This  phenomenon  is  often  spoken  of  as  a  '  positive  after-image.'  If  the 
object  has  been  very  bright  the  image  in  fading  becomes  coloured.  It  first 
appears  greenish  blue,  which  changes  later  to  violet,  rose  colour,  and  finally 
orange  or  green. 

The  slow  rise  and  fall  of  the  sensation  evoked  by  a  momentary  stimulus, 
or  by  a  change  in  the  intensity  of  hght  falling  on  the  retina,  are  responsible 
for  the  blurred  outhne  of  any  object 
that  is  regarded  while  in  rapid  motion. 
If  a  disc  with  alternate  sectors  of  black 
and  white,  such  as  is  shown  in  Fig.  295, 
be  caused  to  rotate  slowly,  it  is  easy  to 
distinguish  both  black  and  white  sectors. 
As  the  speed  of  rotation  increases  the 
margins  of  the  sectors  become  blurred, 
and  the  fact  that  both  margins  of  each 
white  sector  are  blurred  shows  that  the 
sensations  produced  both  by  the  appli- 
cation and  by  the  shutting  off  of  the 

stimulus,  and   due  to  the  white  light  

reflected  from  the  surface,  are  gradual  yio.  295. 

and  not  instantaneous.     With  further 

increase  in  rate  the  whole  disc  takes  a  grey  colour,  which,  however,  oscillates 
or  '  flickers,'  and  with  a  still  further  increase  the  '  flicker '  disappears  and 
the  disc  has  a  uniform  gi-ey  appearance.  The  phenomenon  is  analogous  to 
the  phenomenon  observed  in  muscle  as  the  result  of  intermittent  excitation. 
Each  single  shock  gives  rise  to  a  contraction  which  is  more  prolonged  than 
the  shock  itself.  When  the  shocks  are  repeated  we  obtain,  according  to 
their  frequency,  a  series  of  single  contractions,  a  partial  fusion  of  contrac- 
tions, so  that  an  imperfect  tetanus  is  produced  ('  flicker  '),  or  finally — with 
a  certain  rate  of  interruption  of  the  stimulus— complete  fusion  of  contrac- 
tion, i.e.  complete  tetanus. 

We  see  therefore  that  when  a  portion  of  the  retina  is  excited  for  a  certain 


572  PHYSIOLOGY 

period  by  rays  of  a  given  intensity  during  a  period  A,  and  is  then  unillumin- 

ated  during  a  period  B,  if  A  +  B  is  sufficiently  small,  e.g.  in  the  case  of  the 

disc  if  the  rotation  is  sufficiently  rapid,  the  sensation  evoked  is  a  continuous 

one  and  is  equal  to  that  which  would  be  produced  by  a  continuous  stimulation 

A 

which  is  equal  to — .     This  fact  is  spoken  of  as  Talbot's  law.     It  enables 

A  +  B  ^ 

us  to  produce  a  grey  of  any  desired  intensity  by  varying  the  relative  sizes  of 
black  and  white  sectors  on  a  rotating  disc.  For  complete  fusion  to  take  place 
the  period  A  +  B  need  not  be  less  than  -04  sec.  if  we  are  using  light  of 
moderate  strength.  With  low  intensity  of  iUumination  this  value  rises,  i.e: 
complete  fusion  is  obtained  with  a  lower  rate  of  rotation  of  disc  than  when 
we  are  using  bright  illumination.  The  value  also  varies  according  to  the 
colour  of  the  light.  Different  colours  require  different  times  for  their  action 
on  the  retina  in  order  to  produce  the  maximum  sensation.  If  a  spectrum  be 
exposed  to  the  eye  for  a  very  short  period  of  time  it  appears  colourless  and 
shortened  at  the  red  end.  If  the  period  of  exposure  be  increased  the  red  and 
blue  ends  are  seen,  but  no  other  colour  is  perceptible.  The  sensations  due  to 
the  incidence  of  red  rays  attain  their  maximum  in  the  shortest  time,  then 
come  blue  rays,  while  the  green  take  the  longest  time  to  attain  their  maxi- 
mum. This  difference  between  the  time-relations  and  the  sensations  evoked 
by  the  various  rays  accounts  for  the  fact  that  on  rotating  a  disc  of  alternate 
white  and  black  sectors  at  a  certain  rate  the  sectors  appear  blurred  and  bounded 
by  coloured  fringes. 

FATIGUE 
If  a  constant  stimulus  be  prolonged,  the  intensity  of  the  resulting  sensa- 
tion rapidly  diminishes,  i.e.  the  apparatus  concerned  in  the  production  of 
the  sensation  shows  signs  of  fatigue.  This  diminution  in  the  intensity  of 
sensation  may  be  observed  so  early  as  one-fifth  of  a  second  after  the  beginning 
of  the  stimulus.  Connected  with  this  fatigue  of  the  retina  is  the  phenomena 
known  as  the  '  negative  after-image.'  If  we  look  at  a  bright  spot  or  source 
of  hght  for  some  seconds  and  then  turn  our  gaze  to  a  uniformly  illuminated 
white  surface,  we  see  in  the  middle  of  the  white  surface,  i.e.  at  the  point  of 
fixation,  a  dark  image  of  the  bright  object  which  we  had  previously  looked  at. 
The  stimulus  applied  to  all  parts  of  the  retina  in  this  case  is  uniform. 
Certain  elements,  however,  i.e.  those  which  had  been  previously  stimulated 
by  the  bright  object,  are  fatigued.  Their  response  is  therefore  less  than  that 
of  the  surrounding  untired  retinal  elements,  and  the  resulting  sensation  is  a 
dark  image,  which  is  referred  to  that  part  of  the  white  surface  from  which 
proceeds  the  light  falhng  on  the  fatigued  elements  of  the  retina. 

ADAPTATION 

It  is  common  experience  that  our  eyes  have  the  power  of  adapting  their 
sensitiveness  according  to  the  degree  of  illumination.  When  we  pass  from 
dayUght  into  a  dark  room,  such  as  the  developing  chamber  of  the  photo- 
grapher, it  is  at  first  impossible  to  distinguish  any  objects  even  by  the  dim 
red  light  coming  from  the  photographer's  lamp  or  the  window.     After  a  short 


VISUAL  SENSATIONS  573 

time,  however,  we  begin  to  distinguish  objects  more  clearly.  Any  slight 
defects  in  the  dark  chamber  begin  to  make  themselves  apparent,  such  as 
entry  of  light  under  the  door  and  through  cracks  or  nail-holes  in  the  ceihng 
or  walls.  By  direct  measurement  it  can  be  shown  that  within  ten  minutes 
after  passing  from  dayhght  into  complete  darkness  the  sensitiveness  of  the 
retina  increases  twenty-iive-fold,  and  after  two  hours'  exposure  to  complete 
darkness  thirty-five-fold.  On  the  other  hand,  on  coming  out  of  the  dark 
room  we  are  at  first  dazzled  by  the  flood  of  hght  with  which  we  appear  to  be 
surrounded ;  the  pupils  constrict  to  their  utmost,  and  accurate  vision  is 
impossible  on  account  of  the  excess  of  hght  which  seems  to  pour  into  our 
eyes.  Very  shortly  this  condition  passes  off,  and  within  five  minutes 
vision  is  once  more  normal,  and  the  ordinary  size  of  the  pupils  re- 
estabUshed. 

The  process  of  adaptation  affects  not  only  the  quantitative  relation 
between  the  intensity  of  the  stimulus  and  the  resulting  sensation,  but  deter- 
mines also  a  qualitative  alteration  in  the  reaction  of  the  retina  to  hght.  This 
is  especially  marked  in  the  case  of  colours.  On  going  into  a  flower-garden 
on  a  summer  morning,  when  dawn  is  just  beginning,  although  all  objects 
in  the  garden  can  be  clearly  distinguished,  there  is  a  striking  difference 
in  its  colom-tone  as  compared  with  that  which  it  presents  in  dayhght.  The 
scarlet  geraniums  have  disappeared.  On  close  examination  this  disappear- 
ance is  found  to  be  due  to  the  fact  that  the  flowers  are  dark,  i.e.  the  hght  from 
them  does  not  stimulate  the  retina  at  all.  The  other  coloured  flowers  can  be 
distinguished,  but  only  in  shades  of  grey.  With  a  very  Uttle  increase  in 
illumination  the  blue  flowers  come  into  evidence  and  the  prevailing  tone  of 
the  garden  is  cold,  made  up  as  it  is  of  greens,  blues,  and  greys.  With  in- 
creasing illumination  the  reds  finally  make  their  appearance.  After  long 
exposm-e  to  the  darkness  of  night  the  eyes  have  become  dark-adapted.  The 
same  behaviour  of  the  dark-adapted  eye  may  be  demonstrated  in  the 
laboratory.  If  a  person  who  has  been  in  a  dark  room  for  half  an  hour  ob- 
serves a  spectrum  of  low  intensity  the  whole  spectrum  appears  colom'less,  its 
red  end  being  cut  off.  The  distribution  of  luminosity  over  the  spectrum  is 
also  altered.  Whereas  the  spectrum  to  the  normal  Hght-adapted  eye 
appears  brightest  in  the  yellow  between  the  hnes  D  and  E,  the  spectrum  of 
low  intensity  to  the  dark-adapted  eye  has  its  point  of  greatest  luminosity  in 
the  green. 

This  striking  difference  between  the  light-adapted  and  the  dark-adapted 
eye  does  not  apply  to  small  objects  the  image  of  which,  when  the  vision 
is  directed  towards  them,  will  fall  entirely  on  the  fovea  centrahs  of  the  retina. 
In  the  dark-adapted  eye,  the  sensitiveness  of  the  central  spot  of  the  retina 
is  not  nearly  so  great  as  that  of  the  more  peripheral  portion.  On  a  dark 
night  we  are  often  able  to  distinguish  a  star  which,  however,  disappears  as 
soon  as  we  turn  our  eyes  so  as  to  bring  its  image  on  the  central  spot  of  the 
two  retinae.  Moreover  the  qualitative  change  in  relation  to  the  colours 
observed  in  the  dark-adapted  eye  does  not  apply  to  the  fovea  centralis. 
In  a  dark  room  a  small  spot  of  light,  whatever  its  colour,  when  the  visual 


574  PHYSIOLOGY 

axes  are  directed  on  it,  is  seen  in  its  true  colour  as  soon  as  its  intensity  is  suffi- 
cient for  it  to  be  seen  at  all.  Before  this  takes  place  it  may  be  seen  by  the 
peripheral  parts  of  the  retina,  but  as  a  colourless  spot  of  light  which  dis- 
appears as  soon  as  the  gaze  is  directed  on  it.  This  marked  difference  between 
the  beha^dour  of  the  fovea  centrahs  and  the  more  peripheral  parts  of  the 
retina  in  the  dark-adapted  eye  has  been  attributed  to  the  difference  we  have 
already  studied  in  the  anatomical  structure  of  these  parts.  The  only  per- 
cipient elements  foimd  in  the  fovea  centrahs  are  the  cones.  In  the  adjacent 
portion  of  the  retina  we  find  also  the  rods  which  increase  in  relative  number 
as  we  pass  from  the  central  spot  towards  the  periphery.  Schultz  long  ago 
pointed  out  that  in  the  retinae  of  many  night  animals,  such  as  the  owl,  the 
mouse,  the  cat,  the  rods  are  the  predominating  element,  the  cones  being 
absent  or  very  few  in  number.  Von  Kries  has  suggested  that  in  aU  proba- 
bihty  the  retina  is  endowed  with  two  kinds  of  vision. 

{a)  Vision  by  means  of  rods,  which  are  colour-bhnd,  so  that  on  stimula- 
tion by  any  rays  of  the  retina  a  sensation  of  white  or  grey  is  produced. 
The  rods  are  chiefly  excited  by  the  more  refrangible  rays  of  the  spectrum, 
being  totally  unaff'ected  by  the  red  rays.  They  show  great  power  of  adapta- 
tion. This  form  of  rod  vision  may  be  connected  with  the  visual  purple.  In 
the  dark-adapted  eye  this  pigment  is  found  pervading  the  whole  of  the  outer 
limbs  of  the  rods  ;  it  rapidly  fades  on  exposure  of  the  eye  to  light,  so  that  it 
must  be  absent  in  the  hght-adapted  eye.  On  examining  its  absorption 
spectrum  we  find  that  its  absorptive  power  is  greatest  for  the  rays  in  the  green 
part  of  the  spectrum,  and  that  it  allows  the  red  rays  to  pass  almost  without 
absorption,  i.e.  it  absorbs  just  those  rays  which  experiment  shows  us  have 
the  greatest  effect  in  producing  a  sensation  of  hght  in  the  dark-adapted  eye. 

(6)  The  cones,  on  this  view,  would  represent  a  more  highly  differentiated 
apparatus  of  vision.  They  alone  are  present  in  that  part  of  the  retina 
which  we  use  exclusively  for  distinguishing  the  finer  details  of  surrounding 
objects ;  they  are  sensitive  to  all  colours,  and  when  stimulated  by  all  the 
rays  of  the  spectrum  simultaneously  give  rise  to  a  sensation  of  white  light. 
Their  sensitiveness  to  illumination  is,  however,  inferior  to  that  of  the  rod 
apparatus.  According  to  this  theory,  therefore,  whereas  in  a  dim  hght  we 
determine  the  position  of  surrounding  objects  and  differences  in  their 
luminosity  by  means  of  the  rods,  the  greater  part  of  our  visual  impressions, 
including  all  that  we  obtain  by  dayhght  and  our  knowledge  of  the  finer 
visual  qualities  of  things,  are  brought  to  us  by  the  intermediation  of  the 
cones. 

COLOUR  VISION 

If  a  ray  of  white  hght  be  passed  through  a  prism  it  is  widened  out  into  a 
bright  coloured  band  or  spectrum,  the  red  rays,  which  are  least  refrangible, 
being  at  one  end,  and  the  blue  rays  at  the  other.  It  is  usual  to  divide  the 
colours  of  the  spectrum  into  seven — red,  orange,  yellow,  green,  blue,  indigo, 
violet ;  but  the  division  is  an  arbitrary  one,  and  the  colours  shade  into  one 
another  so  gradually  that  no  two  observers  would  agree  exactly  on  the 
limits  between  them.     The  difference  of  wave-length  necessary  to  give  a  dis- 


VISUAL  SENSATIONS  575 

tinct  difference  in  colour  varies  according  to  the  part  of  the  spectrum  which 
is  under  observation.  In  the  middle  of  the  spectrum  it  is  between  0-7  /x/a  and 
2-0 /w/i.  At  the  red  end  a  difference  of  4-7 /x/x  is  required  to  evoke  a  new 
quahty  of  sensation,  and  at  the  extreme  end,  both  red  and  violet,  there  is  a 
section  of  the  spectrum  over  which  no  variation  in  colour  can  be  perceived. 
By  passing  the  rays  forming  a  spectrum  through  a  similar  prism  placed  in  the 
reverse  direction,  all  these  rays  can  be  recomposed  to  form  white  hght.  The 
sensation  of  white  hght  is  therefore  due  to  the  simultaneous  incidence  on  the 
retina  of  all  the  rays  of  the  spectrum.  That  we  have  no  suspicion  of  the 
existence  of  these  rays  when  we  experience  a  sensation  of  white  shows 
that  our  eye  does  not  possess  any  resolving  or  analysing  apparatus  such  as 
exists  in  the  internal  ear  for  the  compound  wave  of  sound. 

Any  part  of  the  spectrimi,  or  any  coloured  object,  may  be  characterised 
in  three  different  ways  : 

(1)  LUMINOSITY.  The  luminosity  of  different  parts  of  the  spectrum 
varies,  being  greatest  in  the  yellow  for  the  hght-adapted  eye.  We  could, 
however,  match  the  luminosity  of  the  red  of  one  spectrimi  with  that  of  the 
yellow  of  a  second  spectrum  by  increasing  the  intensity  of  the  beam  of  hght 
used  to  produce  the  first  spectrum. 

(2)  SHADE  OR  COLOUR.  It  has  been  reckoned  by  Konig  that  in  the 
spectrum  we  can  distinguish  165  different  shades  of  colom*.  Edridge-Green 
has  shown  that  when  a  normal  observer  screens  off  the  rest  of  the  spectrum 
until  the  part  left  appears  monochromatic,  and  repeats  this  operation  through 
the  whole  length  of  the  spectrum,  he  wiU  mark  off'  not  more  than  eighteen 
to  twenty-seven  '  monochromatic  patches.'  There  are  certain  colours 
which  can  be  appreciated  by  the  eye  which  are  not  present  in  the  spectrum, 
such  as  the  varpng  shades  of  purple. 

(3)  SATURATION.  When  we  look  at  a  colom-ed  surface,  e.g.  red,  our 
eye  is  stimulated  partly  by  the  white  light  which  is  reflected  in  toto  from 
the  surface,  partly  by  the  red  rays  which  are  specifically  reflected  and  give 
the  colour  of  the  object.  According  as  these  red  rays  are  free  from  niixtme 
with  white  rays,  so  their  satm'ation  is  said  to  increase.  The  degree  of 
saturation  of  any  colour  can  be  determined  by  regarding  it  through  a  spectro- 
scope. A  completely  saturated  red  would  give  only  rays  at  the  red  end  of  the 
spectrum.  We  can,  however,  speak  not  only  of  a  physical  but  of  a  physio- 
logical saturation.  xVccording  to  the  condition  of  the  retina  and  nature 
of  the  stimuh  to  which  it  has  been  previously  exposed,  so  does  the  saturation 
of  any  given  colour  vary. 

It  might  at  first  be  thought  that  the  retina  could  respond  with  a  simple 
sensation  to  a  stimulus  by  any  part  of  the  spectrum,  a  low  number  of  ether 
vibrations  per  second  producing  a  sensation  of  red,  a  number  rather  higher 
a  sensation  of  orange  ;  so  that  there  might  be  as  many  simple  coloiu-sensa- 
tions  as  we  can  appreciate  different  shades  in  the  spectrum.  But  a  simple 
analysis  of  our  own  sensations  seems  to  show  that  some  of  the  spectral  colours, 
although  simple  in  so  far  as  the  stimuli  are  concerned,  are  compomid  so  far  as 
the  sensation  is  concerned.     Thus  most  people  would  say  at  once  that  orange 


576  PHYSIOLOGY 

is  a  mixture  of  red  and  yellow,  and,  as  a  matter  of  fact,  we  find  that  on 
mixing  rays  from  the  red  with  others  from  the  yellow  part  of  the  spectrum 
we  do  obtain  a  sensation  of  orange.  The  stimulus  obtained  by  mixing  the 
red  and  yellow  rays  is  not  the  same  as  a  stimulus  caused  by  rays  from  the 
orange  part  of  the  spectrum.  In  the  former  case  compound  waves  made  up 
of  the  two  wave-lengths,  656  ijljjl  and  564  ixfx,  are  falling  on  the  retina,  in  the 
latter  case  a  simple  wave  with  a  length  of  608  /x^t,  and  yet  the  sensations 
produced  are  identical.  Experience  shows  that  there  are  relations  between 
the  physiological  effects  produced  by  different  parts  of  the  spectrum  which 
have  no  physical  analogue  in  the  stimuli  themselves.  Such,  for  instance,  are 
the  phenomena  known  as  the  coloured  after-image.  We  have  seen  that,  as 
the  result  of  fatigue,  stimulation  of  any  part  of  the  retina  by  a  bright  object 
produces,  when  the  stimulation  is  removed,  a  dark  after-image,  which  has 
its  seat  in  the  previously  stimulated  portion  of  the  retina.  If  we  look  stead- 
fastly for  a  minute  in  a  bright  light  at  a  red  disc  on  a  white  ground  and  then 
look  away  at  a  uniform  white  surface,  we  see  an  after-image  of  the  disc  on  the 
sm'face.  This  after-image  is,  however,  green,  and  the  white  background  takes 
on  a  reddish  tinge.  If  the  disc  in  the  first  instance  has  been  a  greenish  blue 
the  after-image  is  red,  and  to  every  colour  in  the  spectrum  we  find  there 
corresponds  another  which  represents  the  after-image  evoked  by  stimulation 
with  the  first  colour.  If  the  first  disc  has  been  green  the  after-image  will  be 
purple,  and  vice  versa.  We  can  therefore  arrange  the  spectrum  into  a  series 
of  pairs  of  colours  which  are  known  as  complementary.  The  following  is  a 
list  of  such  pairs,  with  wave-lengths  of  the  rays  involved,  as  determined  by 
Helmholtz  : 

Colours  Wave-lengths 

Red — ^greenish  blue  ....       656 — 492 

Orange — blue 


Bright  yellow — blue 
Yellow— indigo 
Greenish  yellow — violet 


608—490 
574—482 
567-^65 
564—433 


If  the  retina  be  stimulated  by  any  of  these  pairs  of  colours  simultaneously 
the  effect  is  not  that  of  colour,  but  of  white.  White  light,  or  the  sensation 
of  white,  can  thus  be  due  either  to  simultaneous  stimulation  of  the  retina  by 
all  the  rays  of  the  spectrum,  or  to  stimulation  of  the  retina  by  pairs  of  colours 
which  are  known  as  complementary.  If  these  pairs  be  taken  rather  nearer 
in  the  spectrum  a  colour  is  obtained  representing  a  part  of  the  spectrum 
situated  between  the  two  constituents  of  the  pair.  If  the  rays  are  further 
away  than  would  correspond  to  the  complementary  colours  we  obtain  again 
a  coloured  sensation,  which,  however,  is  unsaturated,  being  mixed  with  a 
certain  amount  of  white  light.  By  taking  three  colours,  such  as  red,  green, 
and  Aaolet,  or  four  colours,  such  as  red,  yellow,  green,  and  violet,  it  is  possible 
by  mixing  them  in  various  proportions  to  form  either  white  light  or  any  colour 
of  the  spectrum,  besides  the  various  purples  which  do  not  occur  in  the  spec- 
trum. 

These  experiments  of  mixing  colours  can  be  carried  out  in  various  ways  : 

In  every  case  we  aim  at  stimulating  the  retina  simultaneously  with  rays  of  different 


VISUAL  SENSATIONS  577 

wave-lengths,  or  successively  at  such  short  intervals  of  time  that  there  is  complete 
fusion  of  the  seasations  resulting  from  the  individual  excitations.  In  order  to  deter- 
mine fine  differences  in  shade  a  coloured  surface  is  always  provided  with  which  a  colour 
produced  by  the  fusion  of  the  different  rays  under  experiment  may  be  compared  : 

(1)  The  most  exact  method  of  mixing  colours  is  to  employ  a  couple  of  spectra 
and  by  means  of  prisms  to  bring  different  parts  of  the  spectra  on  one  and  the  same 
white  surface  on  which  the  result  of  the  mixture  can  be  compared  with  sample  colours. 

(2)  In  Maxwell's  '  colour  top  '  discs  with  a  radial  slit  are  placed  one  over  the  other 
on  a  disc  which  can  be  made  to  revolve  with  considerable  rapidity.  By  means  of  the 
slit  two  or  three  discs  of  different  colours  can  be  slid  one  into  the  other,  so  that  the 
disc  is  composed  of  sectors  of  variable  extent  of  the  two  or  three  colours  wliich  we  wish 
to  mix.  These  discs  are  generally  mounted  on  a  background  of  a  larger  disc,  which 
can  be  used  as  a  sample  colour  to  compare  with  the  result  of  the  mixture  of  the  colours 
in  the  centre.  If  we  are  determining  the  relative  amount  of  different  colours  necessary 
to  produce  white,  the  outside  disc  would  be  partly  white  and  partly  black,  so  that  on 
rotation  the  effect  of  grey  is  produced,  i.e.  a  weak  white.  Thus  in  one  experiment  the 
small  discs  in  the  centre  were  red,  green,  and  blue.  It  was  found  that  when  the  sectors 
were  chosen  in  the  following  proportion  :  165  red,  122  green,  and  73  blue,  a  grey  colour 
was  produced  equal  to  the  grey  obtained  in  the  outer  disc  by  mixing  100  white  with 
260  black. 

These  methods  and  all  others  in  which  coloured  surfaces  are  used  suffer 
from  the  defect  that  no  pigments  give  perfectly  pure  coloiu'-sensations. 
On  looking  at  a  red  painted  surface,  for  instance,  in  a  bright  light  with  a 
spectroscope,  it  will  be  found  that  the  spectrum  contains  yellow  and  green 
rays  as  well  as  red.  On  this  account  no  information  as  to  the  effect  of  mixing 
colour- sensations  can  be  obtained  by  mixing  the  pigments  themselves.  Thus 
a  familiar  way  of  producing  a  green  pigment  is  to  mix  a  blue  and  a  yellow 
pigment.  A  mixture  of  blue  and  yellow  rays  will  give  a  sensation  of  white. 
The  fact  that  blue  and  yellow  pigment  mixed  together  give  a  green  pigment 
is  due  to  the  fact  that  the  blue  pigment  cuts  off  the  red  and  yellow  rays,  and 
reflects,  or  allows  to  pass,  the  blue  and  green  rays,  while  the  yellow  pigment 
retains  the  blue  and  violet  rays,  but  reflects  the  red,  yellow,  and  green  rays. 
When  we  mix  the  two  we  get,  not  an  addition,  but  a  subtraction  ;  the  blue 
pigment  absorbs  the  red  rays  which  the  yellow  pigment  allows  to  pass,  and 
the  yellow  pigment  absorbs  the  blue  rays  which  the  blue  allows  to  pass. 
The  only  rays  left  over  are  the  green,  and  the  mixture  of  pigment  has  a  green 
colour. 

THEORIES  OF  COLOUR  VISION 

These  facts  show  that  in  all  probabiUty  the  primitive  colour-sensations 
are  few  in  number,  and  that  the  various  sensations  excited  by  the  different 
parts  of  the  spectrum  are  not  simple,  but  are  compounded  of  mixtures  of  these 
primary  sensations.  The  two  theories  which  have  obtained  most  vogue,  and 
which  enable  us  to  account  for  a  certain  number  of  the  phenoniona  associated 
with  colour- vision,  are  those  known  as  the  Young-Helmholtz  theory  and  the 
Hering  theory. 

{a)  THE  YOUNG-HELMHOLTZ  THEORY.  This  theory,  which  was 
first  put  forward  by  Young  and  elaborated  by  Helmholtz,  assmnes  that 
there  are  three  primary  colour-sensations— red,  green,  and  violet — which 
are  represented  by  three  separate  sets  of  elements  in  the  retina,  or  in  each 

19 


578 


PHYSIOLOGY 


cone,  or  by  separate  substances,  each  of  which  is  afiected  by  one  of  these 
colours. 

Thus  the  rays  with  a  longer  wave-length  excite  chiefly  the  red  fibres  or 
elements  ;  those  of  medium  wave-length  the  green  percipient  element ;  those 
of  short  wave-length  the  violet  percipient  element  of  the  retina.  The  excita- 
bihty  of  these  three  elements  by  the  rays  of  different  parts  of  the  spectrum 
are  represented  in  the  figure  (Fig.  296).     At  the  extreme  red  and  violet  end 


Gr. 


JBl.  V 

Fig.  296.     Curves  showing  sensitiveness  of  the  three  varieties  of  nerve  fibres  to 

different  parts  of  the  spectrum. 

1,  red  fibres  ;  2,  green  fibres  ;  .3,  violet  fibres. 


of  the  spectrum  alterations  of  the  wave-length  cause  no  alteration  in  colour, 
showing  that  these  rays  only  excite  either  the  red  or  the  violet  fibres.  All 
other  parts  of  the  spectrum  excite  the  three  sets  of  fibres  simultaneously, 
but  to  varying  degrees.  Thus  the  greater  part  of  the  red,  e.g.  about  '  C,' 
excites  the  red  percipient  element  strongly,  the  other  two  only  weakly  ;  the 
result  is  a  sensation  of  red.  The  yellow  rays  at  '  D  '  excite  almost  equally 
the  red  and  the  green  percipient  elements,  but  the  violet  only  shghtly. 
Yellow  is  therefore  a  mixed  sensation.  The  green  rays  excite  the  green  per- 
cipient element  strongly,  the  other  two  shghtly,  with  green  sensation  as  a 
result.  Blue  rays  excite  green  and  violet  percipient  elements  to  a  moderate 
extent,  and  the  red  rays  to  a  somewhat  less  extent ;  blue  is  therefore  a 
mixed  sensation  composed  chiefly  of  green  and  violet.  Simultaneous 
excitation  of  all  three  elements  evokes  a  sensation  of  white  or  grey, 
according  to  the  intensity. 

The  cases  of  defective  colour-vision  which  occur — the  so-called  colouc- 
bhndness— are  regarded  under  this  theory  as  due  to  the  absence  of  one  or 
other  of  the  elements  which  determine  the  primary  colour-sensations.  The 
normal  eye  is  spoken  of  as  trichromatic  since  it  has  three  primary  colour- 
sensations.  Two  kinds  of  dichromatic  eyes  are  described — those  in  which 
the  red  sensation  is  lacking,  and  those  in  which  the  green  sensation  is  lacking. 
In  either  of  these  cases  the  subject  confuses  red  and  green.  The  ripe  cherry 
on  a  tree  they  may  distinguish  from  the  leaves,  not  by  their  colour,  but  by 
form  or  difference  in  their  luminosity.  It  is  only  when  they  are  tested  by 
means  of  the  spectrum  that  we  find  that  whereas  in  the  first  case  (red  blind- 
ness) there  is  insensibihty  to  the  red  end  of  the  spectrum,  in  the  second  case 
the  red  end  of  the  spectrum  is  seen  as  well  as  by  the  normal  person,  so  that 


VISUAL  SENSATIONS  579 

the  defect  must  be  located  towards  the  middle  of  the  spectrmn.  Theoreti- 
cally, of  course,  violet  bhndness  ought  also  to  exist,  but  cases  of  this  nature 
are  so  rare  that  their  very  existence  is  doubted.  Cases  have  also  been  recorded 
with  total  colour-bhndness  (so-called  monochromatic  vision).  Such  cases 
have  been  supposed  to  be  endowed  only  with  vision  similar  to  that  found  in 
the  dark-adapted  eye,  i.e.  with  sensations  only  of  white  and  black  rather  than 
vision  determined  only  by  the  existence  of  the  violet-perceiving  constituent 
of  the  cones.  Indeed  the  phenomena  we  have  studied  under  the  heading  of 
dark  adaptation  would  tend  to  show  that,  if  we  accept  the  Young-Helmholtz 
theory,  we  should  add  to  the  primary  visual  sensations  those  of  hght  and 
dark,  which  have  their  seat  in  the  rods. 

(6)  THE  HERING  THEORY.  According  to  Hering  there  are  four,  and 
not  three,  primary  colour-sensations,  viz.  red,  yellow,  green,  and  blue.  In 
this  theory  the  sensations  of  white  and  black  are  also  regarded  as  primary 
visual  sensations.  These  sensations  are  placed  in  three  groups — ^red  and 
green,  yellow  and  blue,  white  and  black.  For  each  pair  of  sensations  he  con- 
siders that  there  is  a  special  substance  in  the  retina,  dissimilation  or  cata- 
bolism  of  which  gives  rise  to  one  colour-sensation  ;  anabohsm  or  assimilation 
to  the  other.  Thus  if  white  light  falls  on  the  retina,  it  causes  a  breaking 
down  or  cataboUsm  of  the  white-black  substance.  This  breaking  down 
excites  certain  fibres  of  the  optic  nerve,  and  produces  in  consciousness  a 
sensation  of  white.  If  the  light  be  now  removed,  this  breaking  down  gives 
place  to  anabolism  or  building  up  of  the  white-black  substance,  which  excites 
the  same  nerve  fibrils  in  a  different  way,  giving  rise  to  a  sensation  of  black. 
The  white-black  substance  is  affected  not  only  by  white  light  but  also  by  the 
colours  red,  green,  yellow,  blue,  and  their  mixtures.  The  other  two  ^nsual 
substances  are  affected  only  by  red  and  green  or  by  yellow  and  blue  respec- 
tively. Hence  even  the  spectral  colours  do  not  give  rise  to  pure  sensations, 
there  being  always  some  mixture  of  a  sensation  of  white  with  the  proper 
colour-sensation. 

Most  of  the  phenomena  of  colour-^dsion  that  we  have  mentioned  above 
can  be  equally  well  explained  on  either  theory.  Thus  the  fact  that  blue  and 
yellow  together  give  rise  to  a  sensation  of  white  may  be  explained  on  the 
Young-Helmholtz  theory  by  saying  that  the  stimulation  of  all  three  sets  of 
fibrils  is  equal,  as  wiU  be  seen  by  adding  together  the  ordinates  of  each  curve 
in  Fig.  296  at  yellow  and  at  blue. 

Adopting  Hering's  h}^othesis,  we  may  say  that,  anabolism  and  catabo- 
lism  being  equally  excited  in  the  yellow-blue  substance,  no  change  in  it  takes 
place,  and  the  sole  sensation  is  that  produced  by  the  stimulation  of  the  white- 
black  substance.  The  pairs  of  colours  that  we  have  distinguished  are  there- 
fore, according  to  this  theory,  not  in  the  strict  sense  of  the  word  comple- 
mentary, but  antagonistic.  The  fact  that  white  hght  appears  to  us  as  a  simple 
sensation  and  gives  us  no  suspicion  of  the  coloured  rays  of  which  it  may  be 
composed  is  in  favour  of  Hering's  theory.  Cases  of  colom--blindness  would 
be  reduced  by  Hering  to  two  classes,  viz.  those  in  which  the  red-green  sub- 
stance is  lacking  and  those  in  which  the  yellow-blue  substance  is  lacking. 


580  PHYSIOLOGY 

Most  of  the  data  with  regard  to  colour-blindness  have  been  worked  out  with 
reference  to  the  Young-Helmholtz  theory,  and  have  therefore  been  inter- 
preted in  accordance  with  this  hypothesis. 

It  is  very  difficult,  however,  to  harmonise  the  facts  of  colour-blindness 
either  with  this  or  with  Hering's  hypothesis.  It  is  better  therefore  to 
abandon  hypotheses  altogether  and  to  adopt  a  purely  empirical  classification 
of  colour- vision,  as  has  been  done  by  Edridge-Green.  This  observer  points 
out  truly  that  very  marked  colour- bhndness  may  be  present  mthout  any 
interference  with  the  appreciation  of  the  luminosity  of  any  part  of  the 
spectrum.  A  person  may  be  able  to  see  the  spectrum  up  to  its  extreme  red 
end,  and  yet  distinguish  in  the  spectrum  only  two  colours,  which  we  may 
caU  red  and  violet.  We  may,  in  fact,  regard  discrimination  of  colour  differ- 
ence as  superadded  to  and  evolved  later  than  the  appreciation  of  light. 
Discrimination  may  show  various  degrees  of  deficiency  without  any  inter- 
ference with  the  appreciation  of  luminosity.  According  to  Edridge-Green  a 
normal  individual  will  name  six  distinct  colours  in  the  spectrum — red,  orange, 
yeUow,  green,  blue,  violet.  Such  an  individual,  when  made  to  map  out  the 
spectrum  in  the  manner  indicated  on  p.  575,  will  distinguish  about  eighteen 
monochromatic  patches.  A  few  individuals  will  place  another  colour,  which 
has  been  called  indigo,  between  the  blue  and  the  violet,  and  will  mark  out 
from  twenty-two  to  twenty-nine  monochromatic  patches. 

'  Colour-bhndness  '  may  be  brought  about  by  one  of  two  conditions  : 
(a)  a  shortening  of  the  red  or  violet  end  of  the  spectrum ;  (b)  absence  of 
power  to  discriminate  between  the  colours  in  the  spectrum.  The  former 
condition  may  be  present  with  complete  power  of  discrimination  between 
the  different  parts  of  the  spectrum  which  are  visible.  Thus  in  normal 
individuals  the  hmit  of  the  visible  red  spectrum  is  between  X  760  and  X  780. 
In  a  certain  number  of  cases  it  is  foimd  that  the  spectrum  is  not  visible 
beyond  X  700  with  bright  light,  or  beyond  X  620  with  dim  light.  Such  cases 
may  be  said  with  truth  to  suffer  from  red  bhndness,  and  they  will  be  unable 
to  see  a  red  lantern  or  appreciate  its  colom'  imless  the  red  fight  is  mixed  with 
a  considerable  amount  of  orange.  They  may  be  detected  by  testing  their 
power  of  mixing  colours.  A  rose  colour  consists  of  a  mixture  of  a  violet  and 
red  light.  In  an  individual  with  a  shortened  red  end  of  the  spectrum  only 
the  violet  element  of  the  rose  would  be  visible,  so  that  he  would  be  inclined 
to  class  it  with  the  blues  rather  than  with  the  reds.  Cases  also  occiu-  in  which 
there  is  a  shortening  of  the  violet  end  of  the  spectrum,  but  they  have  little  or 
no  practical  importance. 

Of  the  second  class  of  cases,  distinguished  by  deficiency  of  power  of 
discriminating  colours,  all  grades  are  known.  A  very  large  proportion  of 
individuals,  as  much  as  20  per  cent.,  present  a  power  of  distinguishing 
colours  which  is  below  normal,  and  Edridge-Green  distinguishes  these  various 
classes  (calling  the  normal  person  hexachromic)  as  pentachromic,  tetra- 
chromic,  trichromic,  and  dichromic.  If  we  regard  a  spectrum  in  very  dim 
light  it  appears  grey.  With  a  sfight  increase  in  luminosity  we  can  make  out 
two  colours,  red  at  one  end  and  violet  at  the  other.     On  fiuther  increasing 


VISUAL  SENSATIONS  581 

the  luminosity  the  spectrum  appears  trichromic,  being  composed  of  the 
colours  red,  green,  and  violet.  In  colour-blind  individuals  this  limitation 
of  the  colours  distinguished  applies  to  all  strengths  of  luminosity.  Thus 
the  dichromic  sees  only  red  and  violet,  the  trichromic  sees  red,  green,  and 
violet.  It  is  the  dichromic  cases  to  which  the  name  of  '  colour-blind '  has 
been  chiefly  applied,  the  trichromic  cases  being  often  missed,  or  classified 
simply  as  '  colour  weak.' 

The  name  of  ' anomalous  trichoraats  '  has  been  applied  to  people  -who,  while  able 
to  discriminate  most  of  the  spectral  colours,  use  abnormal  proportions  of  the  red 
and  green,  when  they  mix  these  colours  to  form  yellow. 

The  ordinary  '  red-blind  '  person  is  generally  a  dichromic  with  shortening 
of  the  red  end  of  the  spectrum.  The  '  green-blind  '  person  is  a  dichromic 
without  shortening  of  the  red  end.  It  is  an  instructive  experience  to  make 
either  a  dichromic  or  a  trichromic  mark  out  on  a  spectrum  a  monochromatic 
patch.  In  a  dichromic,  such  a  patch  at  the  red  end  will  include  red,  orange, 
yellow,  and  green.  In  a  trichromic,  red,  orange,  and  yellow  will  probably  be 
included  in  the  patch.  This  method  is  the  most  accurate  way  of  determining 
diminution  of  the  power  of  colour  discrimination  and  shows  with  ease  even 
the  minor  degrees  of  colour  blindness. 

CONTRAST  PHENOMENA 

Simultaneous  Contrast.  If  a  grey  disc  be  placed  on  a  piece  of  red  paper, 
and  the  whole  covered  with  tissue  paper,  the  disc  will  take  on  a  greenish  tinge. 
If  the  groimd  colour  be  green,  the  disc  will  appear  red  ;  if  blue,  the  disc  will 
appear  yellow ;  in  fine,  whatever  be  the  ground  colom-,  the  colour  of  the 
disc  wiU  be  complementary  to  it.  These  eftects  are  spoken  of  as  simultaneous 
contrast. 

Successive  Contrast.  If,  after  gazing  steadily  for  some  time  at  a  red  disc 
on  a  white  surface,  the  eyes  be  turned  towards  a  plain  white  sm'face,  a 
negative  after-image  of  the  disc  is  seen  on  the  paper  coloured  green,  i.e.  the 
complementary  colour  of  the  red  disc.  Sm'rounding  this  the  paper  appears 
red.  If  we  look  at  the  sun  for  some  time,  and  then  tm-n  our  eyes  away, 
there  is  at  first  a  positive  after-image,  and  we  see  a  bright  sun  wherever 
we  look.  In  a  short  time  this  disappears  and  gives  way  to  a  black  sun  (a 
negative  after-image).  Thus  we  may  say  that  stimulation  of  any  part  of 
the  retina  with  any  colour  is  followed  by  a  colour  sensation  referred  to  the 
same  part  of  the  visual  field  and  complementary  to  the  first. 

It  has  been  much  discussed  whether  these  phenomena  are  simply  effects 
of  judgment,  or  whether  they  are  produced  by  definite  changes  taking  place 
in  the  retina.  Helmholtz  explains  them  by  the  fii'st  hypothesis,  and  looks 
upon  them  as  cerebral  processes.  Hering,  on  the  other  hand,  has  extended 
his  theory  so  as  to  embrace  these  phenomena,  and  ascribes  them  to  definite 
changes  in  the  retina,  or  at  any  rate  in  the  peripheral  part  of  the  visual 
mechanism.  A  corollary  to  his  theory  that  we  mentioned  above  is  that  if 
dissimilation  of  a  visual  substance  be  excited  at  any  point  of  the  retina, 
assimilation  of  the  same  substance  is  set  up  in  the  carts  of  the  retina 


582 


PHYSIOLOGY 


immediately  adjoining  that  point.  To  this  process  the  name  of '  retinal  induc- 
tion '  has  been  given.  In  this  way  the  phenomena  of  simultaneous  contrast 
may  be  explained.  Thus  if  a  ray  of  red  light  falls  on  any  spot,  it  may  be 
supposed  to  excite  dissimilation  of  the  red- green  substance  at  this  spot.  This 
sets  up  assimilation  of  the  same  substance  in  the  adjoining  parts  of  the 
retina,  and  the  red  object  is  therefore  surrounded  with  a  green  halo,  which 
at  once  becomes  evident  if  we  increase  our  appreciation  for  slight  colour- 
tones  by  diminishing  the  total  amount  of  light  by  means  of  tissue-paper. 

It  has  been  much  debated  whether  the  contrast  phenomena  depend  upon  psychical 
or  retinal  events.  There  is  no  doubt  that  the  question  must  be  answered  in  the  latter 
sense,  and  that  these  phenomena  are  quite  independent  of  the  judgment  of  the 
individual.     This  is  shown  clearly  by  two  experiments.     A  box  (Fig.  297 )  is  di-^dded  into 


Purple 


Purple       Yellow 


Green        Purple 


Purple 

Fig.  297. 

two  long  compartments,  a  h  and  c  d.  At  a  the  compartment  is  closed  by  a  red  glass- 
plate  and  at  c  by  a  blue  glass-plate.  Apertures  are  provided  at  b  and  d  for  the  observer's 
eyes.  At  +  and  -I-  two  small  grey  crosses  are  fixed  about  the  middle  of  the  com- 
partment on  sheets  of  transparent  glass.  On  looking  through  the  openings  b  and  d 
and  converging  the  eyeballs,  so  as  to  fix  the  line  o,  we  get  a  fusion  more  or  less  complete 
of  the  two  colours  red  and  blue,  so  that  the  background  appears  purple  ;  or  there 
may  be  a  struggle  between  the  colours,  at  one  time  blue,  at  another  red  predominating. 
To  the  judgment,  however,  there  is  one  background  and  not  two,  and  therefore,  accord- 
ing to  the  theory  of  Helmholtz,  the  grey  crosses  should  by  contrast  both  acquire  the 
same  induced  colour,  which  would  be  complementary  for  purple.  But  it  is  found  that 
the  two  crosses  are  perfectly  distinct  in  colour,  that  which  is  seen  by  the  eye  against 
the  blue  ground  being  yellow  while  that  on  the  red  ground  is  green,  showing  that  the 
phenomena  of  simultaneous  contrast  are  peripheral  and  not  centra'l  in  their  causation. 
The  same  fact  is  very  definitely  established  by  the  following  experiment  devised  by 
Sherrington.  The  disc  (Fig.  298)  presents  two  rings,  each  half-blue  and  half -black. 
The  outer  ring  is  intensified  when  at  rest  by  simultaneous  contrast,  the  black  half  being 
seen  against  the  surrounding  yellow,  while  the  luminosity  of  the  blue  half  is  increased 
by  the  effect  of  the  surrounding  black.  In  the  inner  ring  the  blue  half  is  darkened 
by  contrast  with  the  surrounding  yellow,  while  the  black  half  is  not  evident  at  all. 
If  the  disc  be  rotated,  we  get  two  concentric  rings  on  an  apparently  homogeneous 
field.  It  is  found,  however,  that  the  outer  ring  flickers  long  after  complete  fusion 
has  taken  place  in  the  inner  ring,  showing  that  the  stimulation  of  the  retina  by  the 
outer  ring  is  increased  under  the  influence  of  contrast. 


VISUAL  SENSATIONS  583 

On  this  theory  successive  contrast  phenomena  are  analogous  to  certain 
phenomena  we  have  already  studied  in  other  tissues.  If  extensive  breaking 
down  of  the  visual  stuff  has  been  occurring,  when  the  stimulus  is  removed 
there  will  be  a  swing-back  of  the  condition  of  the  protoplasm  of  the  nerve- 
endings  in  the  opposite  direction,  and  the  catabolic  will  be  replaced  by 
anabolic  changes  ;  just  as,  on  breaking  a  constant  current  that  has  been 
flowing  through  a  nerve,  the  condition  of  raised  irritabiUty  at  the  cathode 
gives  place  to  a  condition  in  which  the  irritability  is  depressed  below  the 
normal.  The  improving  effect  on  the  heart  of  stimulation  of  the  vagus  is 
also  analogous  to  a  successive  contrast  effect.  During  stimulation  of  the 
vagus  the  breaking  down  of  the  contractile  substance  is  stopped  or  checked, 
so  that  building  up  or  anabohsm  can  go  on  without  interruption.     When 


Fig.  298. 

the  excitation  of  the  vagus  ceases  there  is  an  extra  store  of  contractile 
material  in  the  muscle- cells.  This  causes  the  beat  to  be  more  vigorous,  and 
we  may  say  that  the  increased  anabohsm  has  been  followed  by  a  period  of 
increased  catabolism,  just  as  strong  stimulation  of  a  part  of  the  retina  with 
green  (anabohsm)  gives  rise  to  a  red  after-image  (catabolism). 

It  seems  probable  that,  as  McDougall  has  pointed  out,  the  examples  of 
simultaneous  contrast  depend  on  inhibitory  processes  analogous  to  those 
which  we  have  studied  in  the  spinal  cord  in  deahng  with  reciprocal  innerva- 
tion and  the  conditions  for  the  isolation  of  any  effective  reflex.  Just  as 
the  flexor  reflex,  due  to  nocuous  stimulation  of  the  paw,  inhibits  the  extensor 
or  stepping  reflex,  by  blocking  the  synapses  of  those  elements  on  the  sensory 
path  which  would  pom-  their  impulses  into  the  final  common  path  of  the 
extensors,  so  stimulation  of  any  portion  of  the  retina  will  tend  to  inhibit 
processes  of  a  similar  kind  occurring  in  adjacent  parts  of  the  retina  or  their 
central  connections. 

Stimulation  of  one  part  of  the  intestine  causes  inhibition  of  the  acti\aty 
of  the  intestine  below  the  point  of  stimulation.     If  this  inhibition  occurred 


584  PHYSIOLOGY 

on  both  sides  of  the  stimulated  spot  we  should  have  a  phenomenon  exactly 
analogous  to  the  process  of  simultaneous  contrast.  In  the  same  way  the 
increased  briskness  of  the  antagonistic  reflex  which  foUows  the  temporary 
inhibition  accompanying  the  primary  reflex  can  be  compared  to  the  negative 
after-image  resulting  on  prolonged  stimulation  of  any  point  in  the  retina, 
while  alternating  after-images,  positive  and  negative,  which  may  succeed  a 
single  positive  stimulation,  have  their  analogue  in  the  alternating  rhythmic 
movements  of  flexion  and  extension  of  the  two  legs  which  may  follow  single 
stimulation  of  one  of  them.  The  phenomena  of  binocular  contrast  show 
that  the  retinse  are  not  alone  concerned  in  the  production  of  these  pheno- 
mena, but  that  we  are  dealing  also  with  the  central  connections  of  the  optic 
nerves,  the  activities  of  which  must  be  regulated  by  the  same  laws  as  those 
determined  from  our  study  of  the  more  lowly  activities  of  the  spinal  cord. 


SECTION  IX 

MOVEMENTS   OF  THE  EYEBALLS 

In  order  to  obtain  stinct  vision  of  any  object,  an  image  of  it  must  be 
formed  on  the  fovea  centralis.  Visual  attention,  i.e.  the  fixing  of  the  gaze  on 
any  object,  involves  the  adjustment  of  the  visual  axes  by  movements  of  the 
eyeball,  in  order  that  the  image  of  the  object  of  attention  shall  fall  on  the 
central  spot  in  each  eye. 

The  eyeball  rests  on  a  pad  of  fat  surrounded  by  a  denser  capsule  of  connective 
tissue,  the  capsule  of  Tenon,  from  which  it  is  separated  by  a  lymph  space.  Within 
this  space  it  is  able  to  rotate  around  axes  which  pass  through  a  point  almost  in  the  middle 
of  the  eyeball.  These  movements  of  rotation  are  carried  out  by  the  six  ocular  muscks, 
the  four  recti  and  the  two  oblique.  The  four  recti  musclcs^ — the  superior,  inferior, 
external,  and  internal — arise  from  a  continuous  tendinous  oval  rin^  which  is  attached 
at  the  back  of  the  orbit  to  the  margin  of  the  optic  foramen  and  sphenoidal  fitsure. 
From  this  common  origin  the  muscles  pass  forwards  as  flat  bands  close  to  the  walls 
of  the  orbit  ;  they  come  in  contact  with  the  eyeball  at  its  equator,  passing  through  the 
surromiding  lymph  space,  and  are  attached  to  the  eyeball  about  7  mm.  behind  the 
margin  of  the  cornea,  their  positions  being  indicated  by  their  names.  Of  these  muscles 
the  internal  rectus  is  the  thickest  and  strongest,  the  superior  rectus  is  the  thinnest 
and  weakest. 

The  superior  oblic^ue  muscle  arises  in  a  short  tendon  attacheel  to  the  back  part  of 
the  orbit  in  front  of  and  internal  to  the  optic  foramen.  The  muscle  runs  forward  in 
the  upper  and  inner  angle  of  the  orbit  and  ends  in  a  round  tendon,  which  passes  through 
a  fibrous  pulley  at  the  upper  and  imier  angle  behind  the  anterior  margin  of  the  orbit. 
The  tendon  then  makes  a  sharp  bend  and  passes  outwards,  backwards,  and  down- 
wards between  the  superior  rectus  muscle  and  the  eyeball,  and  is  attached  to  the  latter 
just  below  the  outer  edge  of  the  superior  rectus,  behind  the  attachments  of  the  rectus 
mascles  and  about  half-way  between  the  anterior  and  posterior  poles  of  the  eyeball. 

The  inferior  oblique  muscle  rises  from  the  orbital  plate  of  the  sui^erior  maxilla, 
just  witliin  the  anterior  margin  of  the  orbit.  The  muscle  forms  a  flat  band  and  passes 
upwards,  backwards,  and  outwarels  between  the  inferior  rectus  and  the  wall  of  the  orbit, 
and  ends  in  a  tenelinous  expansion,  which  is  inserted  under  the  external  rectus  muscle 
into  the  posterior  and  outer  part  of  the  eyeball,  somewhat  behind  the  line  of  attach- 
ment of  the  superior  oblique  muscle. 

In  discussing  the  actions  of  these  muscles  we  may  assume  the  eyes  to  be 
in  what  is  known  as  their  primary  position,  i.e.  with  the  visual  axes  parallel 
and  directed  to  a  point  on  the  horizon.  It  is  evident  that  if  the  muscles 
rotate  the  eyeball  about  an  axis  in  a  plane  at  right  angles  to  the  visual  axes, 
the  pupils  will  move  inwards,  outwards,  or  in  any  direction,  but  will  not 
rotate.  On  the  other  hand,  if  the  axis  of  rotation  of  a  movement  produced 
by  any  muscle  lies  in  a  plane  which  is  not  vertical  to  the  visual  axes,  then 

585  19* 


586 


PHYSIOLOGY 


a  movement  of  the  pupil  will  be  associated  with  rotation  of  the  eyeball. 
The  j&rst  of  these  conditions  is  practically  fulfilled  by  the  external  and 
internal  rectus  muscles,  as  is  shown  in  the  diagram  (Fig.  299).  These  muscles 
by  their  contraction  will  move  the  pupil  directly  outwards  or  directly  inwards. 
The  axis  of  rotation  in  the  diagram  would  run  vertically  through  the  eyeball. 
The  other  four  muscles  produce  movements  with  axes  of  rotation  which  are 
not  at  right  angles  to  the  visual  axis.  The  rectus  superior,  for  instance, 
produces  rotation  round  the  axis  joining  r.sup.  and  r.inf.,  and  will  therefore 
produce  movement  of  the  eyeball  upwards  and  inwards  with  a  certain  amount 
of  rotation  of  the  eyeball  on  its  antero-posterior  diameter.  The  rectus 
inferior  in  the  same  way  moves  the  eyeball  downwards  and  inwards  with 


oiLsup. 


r.iTif 


r.ext. 


T.int 


r.ext.    T.snp.  r.inO 
r.ijd:. 

Fig.  299.  Diagram  to  show  points 
of  attachment  and  liens  of  action 
of  extrinsic  ocular  muscles. 


Fig.  300.  Diagram  to  show  direction  in 
which  pupil  will  move  under  the  action 
of  the  various  ocular  muscles. 


rotation.  The  obhquus  superior  moves  the  eyeball  downwards  and  out- 
wards, and  the  obhquus  inferior  upwards  and  outwards,  in  both  cases  with 
some  rotation  on  its  antero-posterior  axis  (Fig.  300).  The  only  movements 
of  the  eyeball  therefore  which  can  be  carried  out  by  the  action  of  one  muscle, 
or  by  the  reciprocal  action  of  a  pair  of  muscles,  are  the  movements  outwards 
and  inwards,  which  are  involved  in  the  common  actions  of  convergence  of  the 
visual  axes  and  conjugate  deviation  of  both  eyeballs.  Movements  upwards 
or  downwards  will  require  the  co-operation  of  at  least  two  muscles.  In  order 
to  direct  the  gaze  upwards  a  contraction  of  the  superior  rectus  which  moves 
the  eyeball  upwards  and  inwards  must  be  associated  with  a  contraction  of  the 
inferior  oblique  muscle  which  rotates  the  eyeball  upwards  and  outwards.  In 
the  same  way  the  inferior  rectus  muscle  will  be  associated  with  the  superior 
obhque. 

As  we  have  seen,  four  out  of  six  muscles  when  acting  singly  cause'rotation 
of  the  eyeball  on  its  antero-posterior  axis.     The  question  arises  whether 


MOVEMENTS  OF  THE  EYEBALLS  587 

these  movements  of  rotation  ever  occur  under  normal  circumstances.  This 
may  be  tested  in  the  following  way  :  The  gaze  is  first  directed  at  a  brilliant 
line  of  light,  e.g.  a  straight  electric  incandescent  filament.  The  gaze  is  then 
directed  to  a  uniform  white  surface.  On  this  white  surface  a  negative  after- 
image of  the  vertical  line  is  seen.  It  is  found  that  in  whatever  direction  the 
eyes  be  tm-ned,  upwards,  downwards,  or  obliquely  to  right  or  left,  the  after- 
image always  retains  its  vertical  direction.  If  there  were  rotation  of  the 
eyeballs  on  their  antero-posterior  diameters,  the  stimulated  portions  of  the 
retina,  i.e.  those  which  are  the  seat  of  the  after-image,  would  lie  obliquely, 
and  the  apparent  direction  of  the  negative  after-image  would  be  also  obHque. 
We  see  therefore  that,  under  normal  circumstances,  no  rotation  of  the  eyeball 
on  its  antero-posterior  diameter  takes  place.  The  actions  of  the  difierent 
muscles  are  always  so  co-ordinated  that  all  movements  of  the  eyeballs  take 
place  round  axes,  which  he  in  a  plane  passing  through  the  centre  of  rotation 
of  the  eyeballs  and  at  right  angles  to  the  visual  axes. 

In  man  movements  of  the  eyes  are  always  bilateral  and  take  place  in  such 
a  way  that  an  image  of  one  and  the  same  object  will  fall  on  the  central  spot 
of  each  retina.  These  movements  are  simple  in  character  and  are  of  only  two 
kinds,  viz.  : 

(1)  Movements  of  both  eyes  with  maintenance  of  parallehsm  of  the  visual 
axes  ;  to  this  class  belong  the  movements  of  conjugate  de\nation  employed  in 
following  the  passage  of  an  object  across  the  field  of  vision  from  right  to  left, 
or  vice  versa,  as  well  as  less  extensive  upward  and  downward  movements 
of  both  eyeballs. 

(2)  The  movement  of  convergence  of  the  axes  of  both  eyes,  which  is 
always  associated  with  accommodation  for  near  objects,  and  therefore  with 
contraction  of  the  cihary  muscles  and  of  the  constrictors  of  the  pupils. 

Other  movements  can  be  effected,  but  only  with  effort.  Thus  we 
can  converge  the  axes  of  the  eyes  so  as  to  look  at  a  near  object  lying  to  one 
side  of  us.  Such  an  action  is,  however,  associated  with  considerable  effort, 
and  in  nearly  all  cases  is  replaced  by  movements  of  the  head.  Whenever 
we  wish  to  examine  an  object  closely  we  turn  the  head  so  that  the  object  lies 
between  the  two  eyes,  and  a  simple  movement  of  convergence  serves  to  bring 
the  image  of  the  object  on  to  the  two  foveas  centrales. 

BINOCULAR  VISION— CORRESPONDING  POINTS 
When  we  fix  om*  gaze  on  any  object,  although  an  image  of  the  object  is 
formed  on  each  retina,  the  object  appears  as  single  and  not  as  double.  On 
the  other  hand,  gentle  pressm-e  on  one  eyeball,  so  as  to  shift  its  gaze  slightly 
from  that  imposed  on  it  by  the  co-ordinated  action  of  the  ocular  muscles,  at 
once  causes  the  object  to  appear  double.  This  shows  that  the  single  appear- 
ance of  an  object  seen  with  the  two  eyes  is  due  to  the  fact  that  the  image 
from  this  object  must  fall  upon  points  in  the  retina,  simultaneous  stimidation 
of  which  produces  only  a  single  sensation.  These  points  are  known  as 
'  corres-ponding  'points.'  It  is  evident  that  to  each  point  in  one  retina  only 
one  point  can  exist  in  the  other  retina  which  corresponds  to  it,  since  for  every 


588  PHYSIOLOGY 

position  of  the  eyes  a  luminous  point  can  only  throw  an  image  on  a  definite 
point  in  each  retina. 

Such  corresponding  points  are,  in  the  first  place,  the  central  spots  in  each 
retina.  When  we  look  at  any  spot  the  axes  of  the  above  eyes  are  so  directed 
that  the  image  of  the  spot  falls  upon  the  fovea  centralis  of  the  two  retinse. 
The  image  of  all  points  to  the  right  of  this  spot  will  fall  on  the  nasal  side 
of  the  right  retina  and  on  the  temporal  side  of  the  left  retina,  and  vice  versa. 
If  the  right  retina  were  cut  out  and  placed  on  the  left,  the  corresponding 
points  of  the  two  retinae  would  be  nearly  over  one  another. 

This  statement  is  not  absolutely  accurate,  as  is  shown  by  a  careful  investigation 
of  the  corresponding  points  by  means  of  the  haploscope.  In  this  instrument  a  white 
screen  is  placed  vertically  at  the  far  point  of  vision  of  the  eyes,  which  are  made  some- 
what myopic  by  means  of  a  convex  lens.  Each  eye  looks  through  a  cylindrical  tube,  the 
axis  of  which  coincides  with  the  visual  axes.  On  each  half  of  the  white  field  is  a  mark 
which,  however,  appears  single,  since  its  image  falls  on  the  fovea  centralis  of  the  two 
retinae.  If  in  the  left  field  of  vision  a  line  be  drawn  vertically  upwards  from  the  mark, 
and  in  the  right  field  of  vision  another  line  vertically  downwards,  the  two  lin:s  appear 
as  a  single  line  passing  through  the  mark.  It  will  be  seen  that  the  upper  half  of  the 
line  is  not  absolutely  continuous  with  the  lower  half,  but  appears  to  form  a  slight  angle 
with  it,  showing  that  the  general  statement  made  above  is  not  absolutely  correct.  By 
means  of  this  instrument  we  can  determine  the  extent  and  situation  of  all  the  points 
in  the  two  retinse  which  correspond.  The  totality  of  all  the  points  in  space,  the  lines 
from  which  to  the  eyes  will  fall  on  corresponding  points,  is  known  as  the  horopter. 
Its  determination  is,  however,  only  of  theoretical  interest. 

It  might  be  thought  that  single  vision  with  the  two  eyes  was  due  to  the 
fact  that  the  nerve  fibres  from  corresponding  points  in  the  two  retinse  pass  to 
and  terminate  in  identical  nervous  structiu'es  in  the  brain.  This  is  not  the 
case.  Single  vision  is  largely  the  result  of  experience,  and  we  can  show  by 
experiment  that  both  elements  are  present  in  the  fused  sensation  obtained 
from  the  two  eyes.  Thus  if  the  left  eye  is  directed  on  to  a  red  surface  and 
the  right  eye  on  to  a  blue  surface,  we  may  obtain  either  a  fusion  of  the  fields 
with  the  production  of  a  purple  colour,  or  a  struggle  of  the  two  fields  so  that  the 
whole  field  appears  sometimes  red  and  sometimes  blue.  In  the  same  way  if 
two  figures,  lying  side  by  side,  one  ruled  with  vertical  lines  and  the  other  with 
horizontal  lines,  be  looked  at  so  that  the  image  of  the  right  figure  falls  on  the 
right  retina  and  of  the  left  figure  on  the  left  retina,  we  do  not  see  a  single 
figure  with  the  lines  crossing  one  another  so  as  to  form  a  network,  but  we 
again  obtain  a  struggle  so  that  first  one  figure  is  seen  with  the  vertical  lines 
prominent,  and  then  this  wanes  and  is  succeeded  by  the  other  figure  in  which 
the  horizontal  lines  are  prominent.  Which  figure  we  see  most  easily  seems 
to  be  dependent  on  the  direction  of  the  eye  movement.  If  the  eyes  are 
moved  vertically  upwards  and  downwards  the  figure  with  the  vertical  lines 
comes  more  into  prominence,  while  the  figure  with  the  horizontal  lines  is  seen 
when  tlie  eyes  are  moved  from  side  to  side. 


SECTION  X 
VISUAL   JUDGMENTS 

LOCALISATION  AND  PROJECTION.  Much  discussion  has  been  wasted  on 
the  question  why  we  see  things  upright  while  the  images  on  our  retina  are 
inverted.  The  answer  is  a  simple  one.  We  do  not  look  at  nor  are  we  con- 
scious of  the  image  on  our  retina.  When  we  say  that  we  see  anything  we 
are  not  expressing  merely  a  sensation,  but  we  are  giving  an  interpretation 
of  certain  sensations  in  the  light  of  long  experience  which  has  involved  a  large 
number  of  sensations  besides  that  of  vision.  Thus  a  new-born  child  sees, 
i.e.  receives  images  on  its  retina  which  excite  impulses  in  the  brain,  but  it  is 
unable  to  interpret  anything  that  it  sees.  In  the  first  few  months  there  is 
indeed  no  connection  between  the  visual  sensations  and  eye  movements  ; 
it  is  only  about  the  third  month  after  birth  that  the  child  will  follow  a  lighted 
candle  or  bright  object  with  its  eyes,  and  this  association  of  ocular  movements 
with  retinal  impressions  gradually  extends  also  to  many  other  movements. 
The  continual  and  at  first  apparently  aimless  movements  of  the  infant  bring 
in  a  flood  of  muscular  and  tactile  impressions  w^hich  only  after  many  trials 
are  recognised  as  corresponding  with  sensations  arriving  from  the  eyes.  It 
at  first  finds  that  with  the  right  hand  it  can  touch  objects  lying  on  the  right 
side  of  the  field  of  vision.  It  becomes  conscious  therefore,  not  of  the  left  side 
of  its  retina,  but  of  a  series  of  objects  which  have  distinct  relations  to  its  right 
hand,  and  of  a  certain  thing  seen  outside  itself.  The  projection  and  localisa- 
tion of  visual  impressions  are  therefore  not  intuitive  or  innate  qualities 
attached  to  stimulation  of  each  point  of  the  retina,  but  are  the  result  of 
experience,  the  testing  and  comparing  of  visual  sensations  with  tactile  and 
muscular  sensations  from  all  parts  of  the  body.  From  these  experiences 
we  learn  to  associate  stimulation,  say,  of  the  right  side  of  the  retina  with 
the  presence  of  objects  lying  in  front  of  and  to  the  left  of  the  body,  and  to 
project  our  visual  sensations  in  this  direction.  If,  for  instance,  we  press  the 
finger,  with  closed  eyelids,  on  the  outer  side  of  the  right  eyeball,  a  luminous 
ring,  or  phosphene,  will  be  seen  apparently  towards  the  left,  i.e.  the  region 
whence  the  pressed-upon  part  of  the  retina  will  be  normally  stimulated  by 
rays  of  light. 

The  projection  of  visual  impressions  is  well  shown  in  Scheiner's  experiment.  Two 
needles  are  placed  one  behind  the  other  on  a  wooden  rod,  one  at  18  cm.  and  the  other 
at  a  distance  of  60  cm.  from  the  eye.  One  eye  is  closed,  and  then  a  card  is  held  before 
the  other.     In  the  card  two  small  holes  are  pierced  by  means  of  a  needle  at  a  distance 

580 


590 


PHYSIOLOGY 


from  one  another  less  than  the  diameter  of  the  pupil.  On  accommodating  now  for  one 
needle,  the  other  needle  appears  double.  Thus  if  the  eyes  are  accommodated  for  the 
distant  needle  F  (Fig.  301,  II),  the  image  of  N  is  formed  behind  the  retina,  and  since 
only  a  very  narrow  bundle  of  rays  can  pass  through  the  holes  in  the  card  two  images 

of  the  needle  are  formed  on  the  retina.  In  the 
same  way,  if  the  eye  be  accommodated  for  the 
near  needle  the  image  of  F  falls  in  front  of 
the  retina,  and  therefore  there  will  be  again 
two  images  of  it  on  the  retina.  In  the  former 
case,  if  the  hole  /3  be  covered  with  a  card,  the 
left-hand  image  disappears.  In  the  latter  case, 
on  covering  ^  the  right-hand  image  disappears, 
showing  that  the  apparent  position  of  the  object 
depends  on  the  relation  of  its  image  in  the 
retina  to  the  point  of  fixation,  i.e.  to  the  fovea 
centralis. 


JUDGMENT  OF  SIZE.  The  apparent 
size  of  an  object  is  determined  in  the 
first  place  by  the  magnitude  of  its  image 
formed  on  the  retina,  and  therefore  by 
the  visual  angle  which  the  object  sub- 
tends at  the  optical  centre  of  the  eye,  as 
will  be  evident  from  the  diagram  (Fig. 
302).  The  apparent  size  of  any  given 
object  varies  inversely  in  proportion  to 
the  distance.  Thus  the  size  of  an  image 
on  the  retina  of  an  object  two  inches 
long  at  a  distance  of  one  foot  is  equal 
to  the  image  of  an  object  four  inches 
long  at  a  distance  of  two  feet.  An 
object  can  be  seen  if  the  visual  angle 
subtended  by  it  (the  angle  AcB  in 
Fig.  302)  is  not  less  than  sixty  seconds. 
This  is  equivalent  to  an  image  on  the  fovea  centrahs  about  4^  across, 
which  is  about  the  diameter  of  a  cone. 

The  visual  angle  is,  however,  by  no  means  the  most  important  factor 
in  our  judgment  of  size.  Thus  as  a  man  walks  away  from  us  his  size  does  not 
appear  to  vary,  although  the  visual  angle  subtended  by  him  on  our  retina 
is  continually  diminishing.  Where  the  size  of  an  object  is  known  to  us,  as  in 
the  instance  just  mentioned,  it  is  used  as  a  means  of  judging  the  size  of 
surrounding  objects.  Where  the  size  of  the  object  is  unknown  our  judgment 
of  its  size  is  determined  by  a  comparison  of  its  apparent  size,  as  judged  from 
the  size  of  the  retinal  image,  with  the  muscular  effort  of  the  convergence  and 
accommodation  which  are  present  at  the  same  time.  Thus  if  we  gaze  at  the 
sun  for  a  minute  so  as  to  gain  a  negative  after-image  the  size  of  this  image  will 
be  constant.  Its  apparent  size,  however,  will  vary  according  to  the  distance 
of  the  surface  on  which  we  direct  our  gaze  :  on  looking  at  a  piece  of  paper  held 
near,  it  may  be  about  one  inch  across  ;  on  looking  at  a  distant  wall,  it  may  be 


Fig.  301.     Diagram  to  illustrate 
Scheiner's  experiment. 

F,  the  far  needle  ;  N,  the  near  needle  ; 
a  andjS,  two  pin-holes  in  a  piece  of  card. 
The  continuous  lines  indicate  the  path 
of  the  rays  for  which  the  eye  is  accom- 
modated. 


VISUAL  JUDGMENTS 


591 


Fig.  302. 


several  feet  across.  If  we  look  through  a  piece  of  coarse  wire  gau^e  at  a  distant 
window,  the  meshes  of  the  gauze  appear  to  be  in  the  neighbourhood  of  the 
window  and  extremely  large ;  on  directing  the  gaze  then  to  an  object  held  just 
in  front  of  the  wire  gauze,  the  mesh  will  look  extremely  small.  On  the  other 
hand,  if  we  cut  out  the  movements  of  accommodation  and  convergence  by 
looking  at  a  piece  of  wire  gauze 
through  a  minute  pinhole  in  a  card,  ^ ' 
the  size  of  the  meshes  will  increase 
as  the  gauze  is  brought  near  to  the 
eye.  In  this  case  we  judge  of  their 
size  entirely  by  the  visual  angle 
they  subtend. 

In  the  muscular  elements  which 
contribute  to  this  judgment  of  size, 

the  convergence  of  the  axes  is  more  important  than  the  accommodation 
of  each  eye,  so  that  judgment  is  but  little  affected  if  we  paralyse  accommoda- 
tion altogether  by  dropping  atropine  into  the  eye.  The  visual  axes  may  be 
regarded  as  practically  parallel  for  any  object  at  a  greater  distance  than  five 
metres  ;  for  such  objects  no  act  of  accommodation  is  necessary.  In  judging 
of  the  size  of  any  object  beyond  this  distance  we  have  only  the  visual  angle 
to  go  by,  which  of  course  gives  by  itself  no  information  unless  we  know  the 
distance  of  the  object.  Here  the  obscuration  of  the  outlines  of  the  object 
in  consequence  of  the  deficient  transparency  of  the  atmosphere  plays  a  large 
part  in  our  judgments  and  may  be  upset  in  either  direction  by  changes  in 
transparency  of  the  atmosphere.  Thus  when  walking  on  the  Downs  in  foggy 
weather  a  gigantic  object  may  be  seen  looming  through  the  mist,  which,  on 
advancing  a  couple  of  paces,  is  seen  to  be  a  sheep.  On  the  other  hand,  in  the 
clear  air  of  the  Alps  the  traveller  continually  under-estimates  the  size  of 
distant  objects,  and  takes  a  mass  of  rocks  of  the  size  of  St.  Paul's  for  a 
traveller  wending  his  way  up  the  snow  arete. 


ILLUSIONS  OF  SIZE 

The  distance  between  two  points  appears  longer  if  a  number  of  points  be 
interposed  between  the  two.     Thus  if  two  equal  quadrilateral  figures  be 

divided  —  one   by  horizontal 

and  the  other  by  vertical  lines 

— the  one  divided  by  horizon- 

- —         tal  lines  will  appear  elongated 

vertically,  and  that  divided  by 

vertical  lines  elongated  hori- 

FiG.  303.  zontally  (Fig.  303).      Appar- 

ently it  requires  a  somewhat 
less  effort  to  pass  directly  from  one  point  to  the  other  than  when  the  gaze 
has  to  follow  an  interrupted  line.  The  eye  muscles  probably  make  a 
separate  effort  of  movement  at  each  interruption  of  the  line.     To  these 


592 


PHYSIOLOGY 


movements  is  due  the  illusion  in  Fig.  304,  where  parallel  lines  seem  to 
diverge  or  converge.  Of  two  equal  lines,  one  of  which  is  vertical  and  one 
horizontal,   the    vertical    line    seems    the    longer.      When    the     eye   is 

moved  upwards,  the  tendency  of  the 
superior  rectus  to  move  the  eye  inwards 
has  to  be  counteracted  by  a  pull  of  the 
inferior  oblique  muscle  turning  the  eye 
outwards.  A  greater  effort  is  therefore 
required  than  when  the  eye  is  moved 
either  inwards  or  outwards,  and  it  has 
been  suggested  that  it  is  this  greater 
muscular  effort  which  is  responsible 
for  our  over- valuation  of  the  length  of 
vertical  as  compared  with  that  of  hori- 
zontal lines. 

It  must  not,  however,  be  imagined 
that  an  actual  movement  of  the  eyes 
is  necessary  in  order  to  judge  of  the 
size  and  distance  of  any  object.  If  a  white  thread  be  hung  up  in  a  dark 
room  and  be  illuminated  for  an  instant  of  time  by  an  electric  spark  it  is 
impossible  for  an  observer  in  the  dark  room  to  move  his  eyes  so  that  the 


r////////////////x 
/////////////////J 
r////////////////x 
/////////////////J 


Fig.  304. 


Fig.  .305.  The  eyes  arc  directed  to  the  point  b.  A  thread  hung  obliquely  at  a 
under  these  circumstances  gives  rise  to  the  images  shown  in  the  ujiper  figures 
• — i.e.  two  images  which  do  not  lie  on  corresponding  points.  Nevertheless  the 
thread  is  seen  as  single. 

image  of  the  thread  shall  fall  on  the  corresponding  points  of  the  two  retinae 
before  the  illumination  has  disappeared.  In  spite  of  the  fact,  however, 
ihat  the  image  of  the  thread  falls  on  non-corresponding  points,  as  will 
be  seen  from  the  diagram  (Fig.  305),  the  thread  is  seen,  not  as  double, 


VISUAL  JUDGMENTS 


593 


Fig.  306. 


but  as  single,  and  a  very  correct  impression  may  be  obtained  of  its  size 
and  position.  In  this  judgment  or  interpretation  a  number  of  separate 
processes  must  be  involved.  The  fact  that  the  eyes  are  not  accommodated 
for  the  thread  evokes  at  once  the  associated  movements  which  would  be 
necessary,  if  time  allowed,  to  bring  the  non-corresponding  images  on  to 
corresponding  points  of  the  retina.  We  do  not  therefore  assume  a  double- 
ness  of  an  object,  even  when  its  images  fall  on  non-corresponding  points, 
unless  our  gaze  is  voluntarily  directed  on  the  object. 

THE  J  UDGMENT  OF  SOLIDITY.  The  fusion  of  non-corresponding  images 
to  a  single  visual  conception  is  responsible  for  our  appreciation  of  solidity. 
If  we  look  at  any  object  which  is  not  too  far 
from  the  eyes,  first  with  the  right  and  then  with 
the  left  eye,  we  shall  see  that  the  images  in 
the  two  eyes  are  not  identical.  If  we  look,  for 
instance,  at  a  truncated  pyramid,  we  shall  see 
with  the  right  eye  rather  more  of  the  right  side 
of  the  pyramid  and  with  the  left  eye  rather  more 

of  the  left  side  (Fig.  306).     If  these  two  images  a 
__  S__^  and  6  bB  so  arranged  that  they  fall   on   corre- 

sponding points  of  the  two  retinae,  there  is  no 
confusion  of  sensation,  but  the  resulting  impres- 
sion is  that  of  a  solid  object.  This  is  the  principle 
involved  in  the  stereoscope,  which  allows  us  to 
combine  two  images  of  this  character  so  that  they 
fall  on  corresponding  points  of  the  two  retinae. 

In  Brewster's  stereoscope  (Fig.  307),  which  is  almost 
invariably  used  at  the  present  time,  the  combination  of  the 
two  pictm'es  is  effected  by  means  of  two  half-lenses  with 
convex  surfaces,  and  their  thimier  margins   directed  in- 
wards so  that  they  act  as  prisms.    A  vertical  black  screen 
is  placed  between  the  two  lenses.      On  looking   through 
the  lenses  towards  the  point  s,  the  direction  of  the  rays 
is  changed  by  the  prisms  so  that  the  image  of  the  pictures 
B  and  b'  fall  on  corresponding  points  of  the  retinae — B  into 
the  left  eye  and  b'  into  the  right  eye.     The  ordinary  photo- 
graphs for  these  stereoscopes  are  taken  by  means  of  a  double  camera  with  lenses  at 
a   distance   apart   considerably  greater  than   that    between  the  two   eyes.      On   this 
account  there  is  actually  an  exaggeration  of  the  solidity  of  the  combined  images. 

When  only  one  eye  is  used  the  external  world  has  a  much  flatter  appear- 
ance. Some  idea  of  solidity  is  still  gained  from  the  fact  that  the  accommo- 
dation has  to  be  altered  in  order  to  bring  different  parts  of  the  solid  objects 
into  focus.  The  judgment  is  also  aided  by  the  eft'ects  of  light  and  shade. 
The  inadequacy  of  such  means  in  default  of  the  stereoscopic  images  in 
binocular  vision  is  at  once  appreciated  when  we  try  to  dissect  or  to  carry 
out  any  fine  manipulation  using  only  one  eye. 


Fio.  307.     Brewster's 
stereoscope. 


SECTION  XI 

THE   NUTRITION   OF   THE   EYEBALL 

The  eyeball  is  protected  in  front  by  the  eyelids.  These  are  Uned  internally 
with  a  delicate  mucous  membrane  continuous  with  the  conjunctiva  covering 
the  anterior  surface  of  the  eyeball.  This  membrane  is  kept  constantly  moist 
by  the  secretion  of  the  lacrymal  gland,  a  small  acino- tubular  gland  built  up  on 
the  type  of  a  serous  gland,  situated  at  the  upper  and  outer  angle  of  the  orbit. 
The  secretion,  '  the  tears,'  has  a  slightly  alkaline  reaction  and  contains  about 
98-2  per  cent,  water  and  1  -8  per  cent,  total  solids,  viz.  0-5  per  cent,  coagulable 
protein  and  1  "3  per  cent,  inorganic  salts,  of  which  sodium  chloride  is  the  most 
important  constituent.  Since  the  tears  are  constantly  flowing  over  the 
eyes  they  serve  not  only  to  moisten  the  surface  but  to  wash  away  any  irritant 
material  or  bacteria  which  may  be  deposited  from  the  air.  The  tears  have  a 
bactericidal  power  which  is  lost  if  the  fluid  be  boiled  for  two  or  three  minutes. 
Our  knowledge  as  to  the  nervous  mechanism  of  the  secretion  of  the  tears  is 
still  incomplete.  Stimulation  of  the  conjunctiva  evokes  an  increased  secre- 
tion of  lacrymal  fluid  which  can  also  be  induced  by  emotional  conditions. 
It  is  stated  that  lacrymal  secretion  can  be  produced  by  the  stimulation 
of  the  cervical  sympathetic  as  well  as  by  stimulation  of  certain  cranial 
nerves,  e.g.  facial  and  fifth  nerve.  Structural  changes  analogous  to  those 
to  be  described  in  the  salivary  glands  have  also  been  found  in  the  lacrymal 
gland  as  a  result  of  secretion.  The  excess  of  fluid  is  drawn  ofl  from  the 
conjunctival  sac  by  the  nasal  duct,  which  leads  to  the  nasal  cavity  on  the 
same  side.  If  the  eyes  be  kept  open  for  some  minutes,  the  conjunctiva 
covering  the  eyeball  becomes  dry  and  irritation  is  set  up.  Normally  the 
membrane,  and  especially  that  over  the  cornea,  is  kept  moist  and  trans- 
parent by  involuntary  movements  of  the  eyelids,  which  close  or  blinlc 
about  twice  a  minute,  so  distributing  the  lacrymal  secretion  over  the 
whole  conjunctival  surface.  This  blinking  is  a  reflex  act,  the  afferent 
channels  being  fibres  of  the  fifth  nerve,  and  the  efferent  the  fibres  of  the 
facial  nerve  supplying  the  orbicularis  palpebrarum.  It  is  spoken  of  as 
the  '  conjunctival  reflex,'  and  is  one  of  the  last  reflexes  to  disappear  in 
chloroform  or  ether  narcosis. 

Just  below  the  mucous  membrane  of  the  lids  we  find  a  series  of  specialised 
sebaceous  glands,  the  '  Meibomian  glands.'  The  fatty  secretion  of  these 
glands  is  poured  out  at  the  edge  of  the  lids,  keeping  these  and  the  eyelashes 
greasy,  and  so  preventing  their  being  wetted  by  the  tears.  Any  overflow  of 
tears  from  the  conjunctival  sac  is  thereby  prevented,  unless  the  secretion 

594 


THE  NUTRITION  OF  THE  EYEBALL  595 

becomes  excessive  ;  so  that  the  whole  of  the  fluid  under  normal  circumstances 
is  kept  within  the  sac  and  flows  away  only  through  the  nasal  ducts. 

INTRAOCULAR  PRESSURE.  The  eyeball  is  formed  of  a  tough  in- 
extensible  capsule,  the  sclerotic,  filled  with  fluid  or  semi-fluid  contents.  In 
order  that  the  eyeball  may  be  sufficiently  rigid  to  maintain  the  normal 
relations  of  the  various  refractive  media,  and  to  afford  a  fixed  point  for  the 
action  of  the  ciliary  muscle,  this  fluid  must  be  under  pressure.     On  connecting 


Fro.  308.     Arrangement  of  apparatus  for  measurement  of  intraocular  pressure. 

(Henderson  and  Starling.) 

G  is  a  piston-recorder  for  recording  graphically  the  changes  in  pressure. 

a  small  manometer  with  the  anterior  chamber,  care  being  taken  to  prevent 
any  escape  of  the  intraocular  fluid,  it  is  found  in  the  normal  eye  that  this 
pressure  is  about  25  mm.  Hg. 

The  problem  of  measuring  intraocular  pressure  is  analogous  to  that  of  measuring  the 
intracranial  pressure.  The  eyeball  represents  a  cavity  into  which  fluid  is  continually 
being  poured  and  from  which  it  is  being  absorbed,  the  intraocular  tension  determining 
the  exact  balance  between  the  processes  of  secretion  and  absorption.  It  is  therefore 
necessary  in  determining  the  amount  of  this  pressure  to  take  care  that  no  fluid  either 
enters  or  leaves  the  eyeball.  For  tliis  purpose  we  can  make  use  of  the  arrangement 
represented  in  the  accompanying  diagram  (Fig.  308).  The  steel  needle  a  is  connected 
to  a  capillary  glass  tube,  cb.  This  has  a  lateral  opening,  through  which  a  bubble  of  air 
can  be  introduced  into  the  tube.  By  means  of  a  T-piece  the  capillary  is  connected 
with  a  water  manometer  e,  and  with  a  reservoir  f,  containing  0-9  per  cent,  salt  solution. 
The  pressure  in  the  apparatus  is  now  raised  to  about  25  cm.  of  water.  Wliile  the 
fluid  is  dropping  from  the  end  of  the  needle,  it  is  tlu-ust  through  the  lateral  part  of  the 
cornea,  so  as  to  lie  in  the  middle  of  the  anterior  chamber.  A  bubble  is  then  intro- 
duced by  the  side  tube,  d,  into  the  capillary  tube,  and  the  reservoir  adjusted  to  such 
a  height  that  the  bubble  remains  stationary.  We  know  then  that  the  pressure  inside 
the  eye  exactly  balances  the  pressure  of  the  fluid  in  the  reservoir,  and  we  have  also 
provided  that  there  shall  be  no  appreciable  escape  of  fluid  from  the  eye  or  entry  of 
fluid  into  the  eye.  If  the  bubble  remains  stationary  for  three  or  four  minutes  we  know 
that  equilibrium  is  attained,  and  we  can  read  off  the  height  of  the  intraocular  pressure 
on  the  manometer  e  comiected  with  the  reservoir. 


596 


PHYSIOLOGY 


On  making  an  opening  into  the  cornea  the  fluid  drains  away  and  the  eye- 
ball becomes  soft  and  collapsed,  the  cornea  being  folded,  and  the  eye  being 
naturally  useless  as  an  optical  instrument.  The  fluid  which  flows  away,  and 
which  forms  the  aqueous  humour  and  also  fills  the  interstices  of  the  gela- 
tinous tissue  of  the  vitreous,  contains  only  a  minute  trace  of  protein,  con- 
sisting, in  every  100  parts,  of  98-7  parts  water  and  1-2  to  1-3  total  solids,  of 
which  only  0-08  to  0-12  part  consists  of  protein.  If  a  cannula  be  kept  in  the 
anterior  chamber  this  fluid  rapidly  alters  its  character,  becoming  coagulable, 
and  containing  3  to  4  per  cent,  of  proteins. 

The  intraocular  fluid  is  continually  being  renewed.  The  eyeball  receives 
a  rich  vascular  supply,  which  forms  a  close  network  of  vessels  and  capillaries 


I.O.P 


mm.  Hg. 


mm.  He 


Art.  B.P. 

mm.  Hg. 
mm.  Hs. 


10  sec. 


Fig.  309.  Curve  showing  effects  on  the  intraocular  pressure  (in  the  dog)  of  mechani 
cal  interference  with  the  circulation.  Blood- pressure  measured  in  left  carotid, 
intraocular  pressure  in  right  eye.  From  p  to  s  the  descending  thoracic  aorta 
was  occluded.  From  q  to  K  the  right  vertebral  and  subclavian  arteries  were  also 
occluded.     (Henderson  and  Starling.) 


in  the  choroid  coat,  with  its  prolongations  the  ciliary  processes  and  iris. 
The  chief  seat  of  formation  of  the  intraocular  fluid  is  the  ciliary  processes. 
Here  there  is  a  constant  transudation  of  fluid  from  the  blood-vessels  into 
the  anterior  part  of  the  vitreous  cavity,  the  amount  of  the  transudation 
varying  with  the  pressure  in  the  blood  capillaries  (Fig.  309),  being  increased 
by  any  rise  in  the  capillary  blood  pressure  or  by  any  fall  in  the  intraocular 
pressure.  Of  the  fluid  poured  out  by  the  ciliary  processes  a  very  small 
proportion  (perhaps  one-fiftieth)  passes  backwards  into  the  vitreous  humour 
and  gradually  drains  out  of  the  eyeball  by  the  lymphatic  spaces  of  the  optic 
nerve.  By  far  the  larger  amount  passes  forward  through  the  fibres  of  the 
suspensory  ligament  into  the  posterior  chamber  (the  annular  cavity  between 
the  iris  in  front  and  the  lens  and  ciliary  processes  behind),  and  thence  round 


THE  NUTRITION  OF  THE  EYEBALL  597 

the  margin  of  the  iris  into  the  anterior  chamber.  From  the  anterior  chamber 
it  passes  into  the  spaces  of  Fontana  at  the  outer  angle  of  the  chamber,  whence, 
under  pressure,  it  can  filter  slowly  between  the  endothehal  cells  lining  the 
canal  of  Schlemm  into  this  vessel  and  so  drain  away  into  the  venous  system. 
A  considerable  resistance  is  offered  to  the  passage  of  fluid  into  the  canal 
of  Schlemm.  Hence  the  constant  transudation  of  fluid  from  the  ciUary 
processes  raises  the  intraocular  pressm-e  to  25.  mm.  Hg,  and  a  con- 
tinuous production  of  about  6  cubic  milhmetres  of  fluid  per  minute  suffices 
to  maintain  the  pressure  at  this  height. 

If  the  formation  of  intraocular  fluid  be  increased  by  rise  of  blood  pressure, 
the  intraocular  pressure  must  also  rise  until  a  point  is  reached  at  which  the 
increased  filtration  through  the  anterior  angle  is  just  equal  to  the  increased 
production  resulting  from  the  rise  of  blood  pressure.  Within  \dde  hmits 
therefore  the  intraocular  pressure  varies  with  the  blood  pressm-e.  This  is 
shown  by  the  following  records   of  both  pressures  in  dift'erent   animals 

(Henderson  and  Starling)  : 

Dog 

Arterial  pressure  Intraocular  pressure. 

128  mm.  Hg.  .  .  26  mm.  Hg. 

158  mm.  Hg.  .  .  34  mm.  Hg. 

180  mm.  Hg.  .  .  40  mm.  Hg. 

70  mm.  Hg.  .  .  23  mm.  Hg. 

Conversely  the  intraocular  pressure  may  be  altered  by  increasing  or 
diminishing  the  ease  with  which  the  fluid  escapes  through  the  filtration  angle. 
If  the  anterior  angle  becomes  blocked  as  the  result  of  inflammatory  changes, 
or  other  causes,  the  intraocular  pressm-e  rises  gradually  mitil  it  attains  a 
height  far  above  normal.  The  eyeball  to  the  finger  feels  stony  hard,  and  the 
increased  pressm-e  affects  seriously  the  circulation  of  blood  through  the 
retinal  vessels,  so  that  atrophy  of  the  retina  is  produced  together  with  dis- 
turbance of  the  nutrition  of  the  whole  eyeball.  This  condition  of  raised 
intraocular  tension  occurs  in  the  disease  known  as  glaucoma. 

The  constant  renewal  of  the  intraocular  fluid  is  important  not  only  for 
the  maintenance  of  the  intraocular  pressure  but  also  for  the  nutrition  of  the 
structures,  such  as  the  lens,  suspensory  ligament,  and  vitreous  humour,  which 
do  not  receive  any  vascular  supply. 


THE   ORGANIC   SENSATIONS 

SECTION  XII   • 

SENSATIONS  OF   MOVEMENT   AND  POSITION 

In  studying  the  phenomena  of  reflex  movements,  as  presented  by  the  spinal 
animal,  om:  attention  was  drawn  to  the  importance  of  the  afferent  impulses 
transmitted  to  the  central  organ  by  means  of  a  special  system  of  sense- 
organs,  called  by  Sherrington  the  proprioceptive  system.  These  afferent 
impressions  intervene  at  a  later  period  in  every  reflex  action  than  do  the 
initiating  sensory  (exteroceptive)  impulses.  They  arise  as  a  result  of  the 
reflex  movement  itself,  and  serve  to  regulate  the  extent  of  this  movement 
as  well  as  the  co-ordinated  changes  in  the  other  muscles  of  the  body. 
Whether  they  be  synergic  or  antagonistic,  the  abolition  of  the  impulses 
arising  in  this  system  has  an  effect  similar  to  that  of  the  destruction  of  the 
governor  of  an  engine.  The  movements  excited  by  peripheral  stimulation 
become  excessive  and  conflicting ;  there  is  no  longer  the  give-and-take  of 
the  antagonistic  muscles  surrounding  the  joint,  and  the  result  is  a  state  of 
disorder  and  inco-ordination,  termed  ataxy. 

Of  the  proprioceptive  impulses  a  certain  proportion  reach  the  cerebral 
cortex  and  arouse  states  of  consciousness  which  we  speak  of  as  sensations  of 
position,  movement,  or  resistance,  and  which  form  the  basis  of  judgments  as 
to  these  conditions.  In  consciousness  they  are  contrasted  with  the  sensa- 
tions arising  from  the  other  sense-organs  in  the  same  way  as  they  are  in  the 
subconscious  regulation  of  the  motor  adaptations  of  the  body.  All  the 
senses  which  we  have  so  far  considered  give  us  information  of  things,  i.e.  of 
a  material  world  which  can  affect  ourselves,  but  which  we  conceive  of  as 
existing  altogether  apart  from  our  sensations  of  it.  Indeed  the  visual  and 
auditory  sensations  we  project  to  distances  remote  from  the  body.  The 
sensations,  on  the  other  hand,  which  are  aroused  through  the  intermediation 
of  the  proprioceptive  system  we  refer  entirely  to  ourselves.  By  them  we 
receive  information  of  the  condition  of  the  material  '  me,'  i.e.  of  ourselves 
as  things  apart  from  the  objects  which  surround  us  and  the  changes  in  which 
ordinarily  excite  our  activity. 

Consciousness  we  have  seen  to  be  developed  in  proportion  to  the  differen- 
tiation of  the  educatable  association  centres,  which  are  responsible  for  our 
powers  of  ideation,  and  by  means  of  which  the  different  reflex  movements 

698 


SENSATIONS  OF  MOVEMENT  AND  POSITION  599 

which  we  call  volitional  are  carried  out,  guided,  augmented,  or  inhibited, 
according  to  the  past  experience  of  the  individual.  Volitional  movement  is 
therefore  a  movement  determined  by  previous  neural  events,  of  which  a  part 
at  any  rate  is  represented  in  consciousness  as  feehng,  emotion,  or  desire. 
Where  an  act  is  involuntary,  i.e.  does  not  need  the  guidance  of  experience, 
individual  or  racial,  for  its  performance,  the  afferent  impulses  which  arouse 
it  are  also,  as  a  rule,  devoid  of  representation  in  consciousness.  Thus  we 
have  no  sensation  of  the  passage  of  a  bolus  along  the  oesophagus.  The 
proprioceptive  impulses  also  only  afiect  consciousness  where  they  are 
necessary  for  the  guidance  of  vohtional  movement.  The  tactile  and  gusta- 
tory impressions  from  the  tongue  have  a  very  full  representation  in  conscious- 
ness. Volition,  however,  only  interferes  for  the  rejection  or  acceptance  of 
the  food  taken  into  the  mouth,  and  is  not  required  for  the  minute  direction  of 
the  movements  of  mastication  and  deglutition.  The  muscular  sensibihty  of 
the  tongue,  and  therefore  our  voluntary  control  of  its  movement,  is  extremely 
slight,  although  there  must  be  a  continual  flow  of  afferent  impressions  from 
the  tongue  to  the  lingual  motor  centres  to  guide  the  complex  movements  both 
of  mastication  and  deglutition.  In  the  case  of  the  palate  muscles,  as  of  the 
oesophagus,  muscular  sensibility  is  entirely  wanting. 

It  has  been  suggested  that  afferent  impressions  from  the  muscles  can  play 
only  a  subordinate  part  in  our  sensations  of  movement,  since  we  are 
not  aware  of  the  part  taken  by  each  individual  muscle  in  any  given  move- 
ment. Such  a  statement  is  absurd.  We  have  no  objective  phenomenal 
experience  of  our  muscles.  All  that  we  are  aware  of  and  can  judge  of  by 
our  other  senses  is  the  movement  as  a  whole,  and  our  sensation  of 
movement  is  therefore  referred  to  the  whole  movement  and  not  to  the 
individual  muscles. 

The  sensations  arising  in  the  proprioceptive  system  can  be  divided 
into  two  main  classes  : 

(1)  The  sensation  of  the  relative  positions  of  parts  of  the  body, 

(2)  The  sensations  which  inform  us  of  the  position  of  the  head,  with 
regard  to  its  surroundings,  i.e.  with  regard  to  the  direction  of  the  pull  of 
gravity,  (It  must  be  remembered  that '  downwards  '  always  means  towards 
the  centre  of  the  earth,  '  upwards '  away  from  the  centre  of  the  earth,  i.e. 
against  the  gravitational  forces.)  This  orientation  sense  depends  on  the  in- 
tegrity of  a  special  sense-organ  contained  in  the  labyrinth  of  the  internal 
ear.     It  is  therefore  sometimes  spoken  of  as  the  labyrinthine  sense. 


THE  SENSE  OF   RELATIVE  POSITION,   INCLUDING  THE 
MUSCULAR  SENSE 

Without  using  our  eyes  we  are  able  at  any  moment  to  tell  the  position  of 
our  limbs.  If  one  arm  be  moved  passively  into  any  position  we  can  without 
difficulty  move  the  other  arm  into  an  exactly  similar  position.  We  thus 
know  the  extent  to  which  we  move  the  limb  and  the  static  position  attained 
as  the  result  of  the  movement.     If  the  movement  is  resisted,  we  are  able  to 


600  PHYSIOLOGY 

adjust  the  force  of  the  muscular  contraction  to  the  resistance,  and  to  form 
therefore  a  fair  idea  as  to  the  strength  of  the  resistance. 

(a)  PASSIVE  MOVEMENTS.  A  large  number  of  different  sense-organs 
contribute  to  the  formation  of  these  judgments.  In  the  appreciation  of 
passive  movement  the  chief  end-organs  involved  are  those  in  connection  with 
the  joints  and  their  ligaments,  though  it  is  probable  that  the  deeper  sense- 
organs  in  the  soft  parts  around  the  joints  also  contribute  to  the  total  sensa- 
tion. Cutaneous  sensations  apparently  play  but  little  part  in  the  judgments 
of  passive  movement.  It  is  true  that  the  alternating  movements  of  the  hind 
hmbs,  which  occur  in  a  spinal  animal  when  it  is  held  up  by  the  hands  under 
the  fore  hmbs,  are  started,  partly  at  any  rate,  by  the  stretching  of  the  skin 
of  the  thighs  ;  but  this  effect  is  one  rather  of  initiation  of  movement,  and  can 
hardly  be  regarded  as  proprioceptive  in  character. 

The  strength  of  the  sensation  of  passive  movement  depends  on  the 
extent  of  the  movement  as  well  as  on  the  rate  with  which  it  is  carried  out. 
The  dehcacy  of  perception  varies  in  different  joints.  Thus  in  some  joints 
a  movement  of  0-25°  per  second  is  appreciated  as  a  movement,  while  in  other 
joints  the  movement  must  be  as  extensive  as  1-4°  per  second.  It  is  more 
easily  appreciated  when  the  joint  surfaces  are  pressed  together  than  when 
they  are  pulled  apart,  showing  that  the  nerve- endings  in  the  joint  surfaces 
play  a  part  in  the  origination  of  the  sensations. 

(b)  THE  SENSE  OF  MOVEMENT  (MUSCULAR  SENSATION).  This  term 
is  applied  to  those  sensations  by  which  we  judge  of  the  extent  and  force  of 
any  active  movement  which  we  may  have  carried  out.  Many  authors  have 
ascribed  an  important  part  in  this  act  of  judgment  to  the  so-called  '  sense  of 
innervation,'  i.e.  a  sense  of  the  actual  energy  which  is  being  discharged 
from  the  motor  cells  of  the  central  nervous  system  to  the  muscles,  and  have 
thought  that  when  we  raise  a  weight  we  judge  of  its  amount,  not  by  the 
degree  of  stretching  of  the  muscle  or  pressure  on  sensory  nerves  in  the  muscle, 
but  by  the  amount  of  force  we  voluntarily  put  out  to  raise  the  weight.  The 
fact,  however,  that  we  can  judge  of  weights,  when  the  muscles  are  made  to 
contract  by  electrical  stimuli  and  not  by  voluntary  impulses,  shows  that  this 
sense  is  in  large  part,  if  not  entirely,  peripheral.  It  is,  however,  very  com- 
plex in  nature,  and  is  served  by  a  whole  array  of  different  end-organs 
in  the  skin,  joints,  tendons,  and  muscles.  The  muscles  themselves  are 
known  to  be  well  supplied  with  afferent  nerves.  Stimulation  of  the  central 
end  of  a  muscular  nerve  may  reflexly  excite  or  inhibit  movements  of  other 
muscles.  Sherrington  has  shown  that,  after  section  of  the  motor  roots, 
over  one-third  of  the  fibres  in  a  muscular  nerve  remain  undegenerated, 
proving  their  connection  with  the  posterior  root  ganglia.  The  sensory  nerve- 
endings  in  the  muscle  are  represented  partly  by  the  tendon  nerve- endings 
and  partly  by  the  muscle-spindles.  The  former  are  richly  branched  end- 
arborisations  of  nerve  fibres  on  the  surface  of  the  tendon  bundles.  The 
muscle-spindles  consist  of  one  or  more  muscle  fibres,  often  continuous  with 
normal  fibres,  enclosed  in  a  sheath  composed  of  several  layers  of  fibrous 
tissue  with  intervening  lymph-spaces.     One  or  more  nerve  fibres  pierce  this 


SENSATIONS  OF  MOVEMENT  AND  POSITION  601 

sheath  and,  after  making  many  spiral  turns  round  the  muscle  fibres,  branch 
freely  and  terminate  in  httle  knobs  on  the  surface  of  the  fibres  (Figs.  310,311 ). 
The  cross-striation  of  the  muscle  fibres  within  the  spindle  is  but  faintly 
marked.  It  is  evident  that  the  continuity  of  these  sense-organs  with  the 
contracting  muscle  ensures  in  the  best  possible  way  that  the  organs  should 


Fig.  310.     A  neuro- muscular  spindle  of  the  cat.     (Ruffini.) 
c,  capsule;    pr.e,  primary  ending;    s.e,  secondary  ending;    'pl.e,  plate  ending 
(all  these  are  probably  sensory  in  function). 


s  a  d  - 

Fig.  311.     Part  of  a  muscle-spindle  more  highly  magnified. 
n,  nerve  fibres  passing  to  spindle  ;  a,  annular  endings  of  axis  cylinders  ;  s.  spiral 
endings;  c?,  dendritic  endings  ;   s/i,  connective-tissue  sheath  of  spindle.     (Ruffini.) 

be  affected  by  the  shghtest  change  of  tension  of  the  muscle,  and  should 
transmit  information  of  the  state  of  tension  to  the  central  nervous  system. 

THE  PSYCHOLOGICAL  SIGNIFICANCE  OF  SENSATIONS  OF  MOVE- 
MENT. Not  only  are  these  organic  sensations  of  importance  as  afi'ording 
us  information  of  the  condition  of  om"  own  bodies  as  distinct  from  the  objects 
in  the  world  around,  but  they  enter  into  and  qualify  om-  judgments  derived 
from  all  the  sensations  which  arise  in  the  special  sense-organs. 

When  we  regard  the  continuous  aimless  activity  of  a  healthy  baby,  we 
see  that  all  ideas  of  space,  of  extension,  of  relative  position  are  wanting,  or  at 
any  rate  are  not  present  to  guide  the  movements.  Bit  by  bit  muscular 
experience  is  acquired.  The  child  learns  that  a  given  movement  of  the  right 
arm  will  bring  the  hand  in  contact  with  something  which  is  exciting  the  left 


602  PHYSIOLOGY 

side  of  his  retina.  The  surface  of  the  thing,  if  of  sufficient  extension,  can 
excite  tactile  sensations  in  all  the  fingers  of  the  right  hand.  By  moving  one 
finger  over  the  object  the  tactile  sensations  are  found  to  be  continuous  ;  by 
moving  the  whole  hand  forwards  the  thing  is  found  to  possess  extension  in 
a  direction  away  from  the  body,  and  therefore  in  the  third  plane  of  space. 
Thus  gradually  are  acquired  not  only  ideas  of  extension,  distance,  and  space, 
but  certain  movements  are  correlated  with  stimulation  of  definite  regions 
of  the  skin  or  of  the  retina.  Tactile  and  retinal  impressions  therefore  acquire 
local  sign,  and  power  is  acquired  of  moving  the  limbs  to  a  degree  and  in  a 
direction  adapted  to  stimuh  arising  from  any  part  of  the  tactile  or  retinal 
surfaces.  The  child  gradually  acquires  the  power  of  following  a  bright 
object  with  its  eyes,  i.e.  of  contracting  the  ocular  muscles  so  as  to  keep 
the  retinal  image  of  the  object  on  the  fovea  centralis,  and  up  to  adult  age 
we  are  still  engaged  in  this  balancing  of  muscular  movement  against  sense 
impressions — a  balancing  in  which  the  muscular  sensations  are  the  constant 
guide  and  criterion  of  success.  Only  by  the  muscular  sensations  are  we 
informed  whether  our  willed  movement  has  been  carried  out  or  not. 
It  is  in  virtue  of  the  muscular  and  alHed  sensations  that  we  are  able  to  clothe 
our  visual  and  tactile  sensations  with  properties  of  extension,  sohdity,  and 
resistance,  which  create  them  in  consciousness  as  parts  of  a  material  world. 


SECTION   XIII 

THE  LABYRINTHINE  SENSATIONS 

Throughout  almost  the  whole  of  the  animal  kindgom,  and  in  practically 
all  freely  moving  metazoa,  we  find  a  sense-organ  which  has  often  been 
designated  as  an  auditory  organ.  This  organ,  which  is  situated  in  the  integu- 
ment, is  in  the  form  of  a  small  sac  generally  open  to  the  exterior,  and  lined 
by  cells  provided  with  hairs  and  richly  supplied  with  nerves.  Resting  among 
the  hairs  is  a  small  concretion,  generally  of  carbonate  of  lime,  which  is  known 
as  an  otolith.  These  sacs  have  generally  been  regarded  as  auditory  in 
function,  hence  the  term  otolith  applied  to  the  concretion.  The  evidence 
for  audition,  i.e.  the  power  of  appreciating  vibrations  in  the  elastic  medium 
surrounding  them,  is  scanty.  Thus  in  fishes  this  power  has  been  stated  to  be 
absent  unless  the  vibrations  are  of  sufficient  amplitude  to  affect  the  sense- 
organs  of  the  skin.*  On  the  other  hand,  there  is  evidence  that  these  otohth 
organs  are  connected  with  equihbration.  Section  of  the  nerves  going  to  them 
in  the  crajl&sh  causes  disturbance  of  locomotion.  Steinach  has  succeeded 
in  the  crayfish  in  replacing  the  concretion  by  a  small  particle  of  iron.  The 
animal's  behaviour  and  movements  were  perfectly  normal  until  it  was 
brought  within  a  powerful  magnetic  field.  Under  the  influence  of  this 
field  the  effect  of  gravity  on  the  iron  particle  was  annulled  and  replaced  by  a 
force  of  attraction  in  another  direction,  and  the  effect  was  at  once  seen  as 
pronounced  disorders  of  locomotion,  the  animal  swimming  in  an  abnormal 
position. 

From  a  sac,  such  as  that  present  throughout  the  lower  animals,  the  organ 
of  hearing  in  the  higher  vertebrata  is  developed.  Arising  as  a  pit  in  the 
epiblast  in  the  neighbourhood  of  the  hind-brain,  the  auditory  sac  becomes 
shut  off  from  the  exterior,  and  then,  by  an  outgrowth  in  various  directions, 
forms  the  complex  membranous  labyrinth  of  the  internal  ear.  This  mem- 
branous lab}T.'inth,  as  we  have  seen,  can  be  divided  into  two  parts,  viz.  the 
canalis  media  of  the  cochlea  in  front,  and  the  saccule,  utricle,  and  semi- 
circular canals  behind.  The  canalis  media  of  the  cochlea  is  concerned  with 
the  reception  and  analysis  of  soimd  waves.  In  the  lower  vertebrates 
in  which  auditory  sensations  are  wanting  the  cochlea  is  absent,  and  in  fishes 
is  represented  merely  by  a  small  diverticulum  knowni  as  the  lagena.  With 
the  development  of  air-breathing  vertebrates  we  see  the  first  signs  of  a  special 

*  On  the  other  hand,  Piper  has  succeeded  in  detecting  an  electrical  variation  in 
the  eighth  nerve  of  fishes  in  response  to  a  sound  stimulus. 

603 


604  PHYSIOLOGY 

organ  of  hearing.  Thus  a  primitive  cochlea  is  present  in  the  amphibia,  and 
especially  in  the  anm-a,  and  in  some  of  the  reptiles  as  well  as  in  birds  it  ac- 
quires a  bend  and  shows  the  beginning  of  a  spiral  arrangement.  Only  in 
the  mammals  does  it  attain  a  degree  of  development  at  all  comparable 
with  that  found  in  man,  and  characterised  by  the  formation  of  one  and  a 
half  to  four  spiral  turns  in  the  cochlea  as  well  as  in  the  canahs  media. 

This  development  of  auditory  functions  cannot  involve  any  abrogation 
of  the  important  part  played  by  the  otolith  organ  throughout  all  the  lower 
classes  of  the  animal  kingdom.     In  man,  as  in  the  crayfish,  it  is  the  otoHth 

organ  which  determines  his 
behaviour  in  relation  to  the 
force  of  gravity,  and  is  there- 
fore responsible  not  only  for 
the  maintenance  of  equilibrium 
but  also  for  the  sensations 
which  enable  him  consciously 
to  orientate  himself  and  to 
know  the  position  in  which  he 
happens  to  be  at  any  given 
moment.  With  the  increasing 
importance  of  visual  sensa- 
tions in  determining  the  be- 
haviour of  the  animal,  close 
connections  are  established  be- 
tween the  central  connections 
of  the  nerves  running  from  the 
otolith  organ  and  the  parts  of 
the  brain  concerned  with  the 
innervation  of  the  eye  muscles. 
By  this  means  the  position  of 
the  eyes  is  constantly  adapted 
to  the  position  of  the  head. 

The  auditory  part  of  the  inter- 
nal ear  has  already  been  described. 
That  part  of  the  labyrinth  which 
represents  the  primitive  otolith  organ  consists  of  a  bony  framework  containing 
perilymph,  in  which  is  contained  the  membranous  labyrinth  with  the  endings  of 
the  vestibular  division  of  the  eighth  nerve.  The  osseous  labyrinth  consists  of  a  cavity, 
thes  vestibule,  into  which  open  behind  the  three  bony  semicircular  canals.  In  the 
vestibule  are  contained  two  little  membranous  sacs,  the  utricle  and  saccule,  the 
cavities  of  which  are  connected  by  means  of  the  saccus  endolymphaticus.  Into 
the  utricle  open  the  three  semicircular  canals,  the  three  canals  having  five  openings. 
These  semicircular  canals  are  arranged  in  three  planes,  each  of  which  is  at  right  angles 
to  the  other  two,  so  that  in  the  organ  are  represented  the  three  planes  of  space.  We 
may  distinguish  on  each  side  an  external  or  horizontal  canal,  an  anterior  or  superior 
vertical  canal,  and  a  posterior  vertical  canal.  The  two  outer  canals  lie  always  exactly 
in  the  same  plane,  which  is  practically  horizontal  in  the  normal  position  of  the  head. 
Each  posterior  vertical  canal  lies  in  a  plane  which  is  parallel  to  that  of  the  superior 
vertical  canal  of  the  opposite  side.     We  thus  see  that  these  semicircular  canals  form 


Fig.  312.  Figure  from  Ewald  showing  the  situ- 
ation of  the  three  semicircular  canals  in  the 
skull  of  the  pigeon. 


THE  LABYRINTHINE  SENSATIONS 


605 


together  three  planes — one  horizontal  and  two  vertical,  the  two  latter  being  at  righ» 
angles  to  one  another  (Fig.  312).  The  membranous  canal  lies  within  the  osseous 
canal,  a  considerable  sjxxce  intervening  between  the  two  canals.  At  one  end  the  osseous 
canal  is  dilated  and  the  membranous  canal  undergoes  a  corresponding  dilatation  so  as 
to  fill  up  the  whole  bony  canal.  In  this  dilatation,  which  is  knowTi  as  the  ampulla, 
we  find  the  ending  of  a  branch  of  the  vestibular  nerve  in  a  special  sense  epithelium 
forming  the  crista  acustica  (Fig.  313).  The  crista  is  composed  of  hair-cells  with  sus- 
tentacular  cells  between  them.     The  fibres  of  the  vestibular  nerve  end  in  arborisations 


Fig.  313.     End-organ  of  vestibular  nerve  in  ampulla  of  semicircular  canal  ('  crista 

acustica  '). 

among  the  hair-cells,  the  hairs  of  which  project  into  the  endolymph  filling  the  ampulla. 
In  the  utricle  and  saccule  we  also  find  sjiecial  sense-organs,  known  as  the  macula  acustica, 
the  structure  of  which  is  very  similar  to  that  of  the  crista  in  the  ampullaj.  Among  the 
hairs,  however,  of  the  macula  is  found  a  small  concretion  of  carbonate  of  lime,  the 
otolith. 

The  first  accurate  experimental  investigation  of  the  functions  of  these 
different  parts  we  owe  to  Flourens.  This  observer  showed  that,  whereas 
extirpation  of  the  cochlea  caused  deafness,  extirpation  of  the  vestibule  and 
semicircular  canals  left  the  auditory  sense  intact,  but  caused  marked  dis- 
orders of  equilibration.  That  the  peculiar  arrangement  of  the  semicircular 
canals  in  the  three  planes  of  space  was  connected  in  some  way  with  the 
functions  of  these  structm-es  was  also  indicated  by  Flourens'  observation  that 
destruction  of  the  horizontal  canals  on  each  side  gave  rise  to  continual 
nodding  movements  of  the  head  in  the  plane  of  the  injured  canals.  By  many 
physiologists  the  results  obtained  by  Flourens  were  ascribed  to  continued 
irritation  of  the  peripheral  sense-organs  or  of  the  central  parts  of  the  brain  in 
consequence  of  the  lesion.     The  accurate  experiments  of  Goltz,  and  especially 


606 


PHYSIOLOGY 


-'F' 


those  of  his  pupil  Ewald,  showed  that  these  effects  might  last  twelve  to 
eighteen  months,  or  be  permanent,  and  must  therefore  be  regarded  as 
an  Ausfallserscheinung,  i.e.  as  due  to  abolition  of  a  function  and  not  to  the 
arousing  of  a  function  by  abnormal  stimulation. 

Most  of  the  experiments  on  this  subject  have  been  carried  out  on  pigeons 
on  account  of  the  easy  accessibility  of  their  semicircular  canals.  Confirma- 
tory observations  have,  however,  been  made  on  mammals.  After  destruc- 
tion of  all  the  canals  or  of  the  whole  membranous  labyrinth  on  both  sides, 
disturbances  of  equihbrium  are  aroused  which  may  last  for  a  considerable 
time.  The  animal  can  neither  stand,  nor  fly,  nor  maintain  any  fixed  attitude, 
but  is  constantly  moving  about  incoherently  and  often  so  violently  that 
it  is  necessary  to  pad  its  cage  in  order  to  prevent  it  from  injuring  itself. 

Although  the  movements  are  so  violent, 
very  Kttle  guidance  sujB&ees  to  stop  them 
altogether.  Any  support  given  by  the 
hand  enables  the  animal  to  rest  quietly. 
After  some  months  these  disorders 
gradually  disappear,  and  the  animal 
learns  to  guide  its  movements  by 
sensations  of  touch  and  sight  alone  ; 
but  they  are  instantly  brought  back 
in  all  their  severity  if  the  eyes  be 
bandaged,  so  as  to  deprive  the  co- 
ordinating centres  of  the  guiding  visual 
sensations. 

The  same  effect  is  produced  if  that 
part  of  the  brain  which  alone  is  edu- 
catable,  viz.  the  cerebral  cortex,  be 
excised.  Extirpation  of  the  cerebral 
hemispheres  in  pigeons  causes  no  dis- 
orders of  equilibrium,  but  extirpation,  after  destruction  of  the  labyrinth, 
brings  back  the  disorders  which  were  noted  during  the  first  days  after  the 
operation,  and  these  disorders  are  now  permanent.  Recovery  even  in  the 
presence  of  the  cerebral  hemispheres  is,  however,  never  really  complete. 
Although  the  animal  may  be  able  to  walk  and  fly  very  fairly,  it  suffers 
from  a  loss  of  power  and  loss  of  tone  which  affect  all  its  muscles,  but 
especially  those  moving  the  trunk  and  neck.  If  the  labyrinth  has  been 
extirpated  only  on  one  side,  then  this  loss  of  tone  is  noticed  chiefly  on 
the  opposite  or  contralateral  side  of  the  body  (Fig.  314).  Loss  of  tone 
after  complete  destruction  is  well  shown  in  the  following  experiment 
devised  by  Ewald  : 

A  small  lead  bullet  is  hung  by  a  thread  to  the  beak  of  the  pigeon.  As 
the  bird  moves  about  the  bullet  swings,  the  head  following  its  movements  ; 
finally  the  bullet  happens  to  fall  over  the  beak  of  the  animal — the  head  is  now 
found  to  be  fixed  in  the  position  shown  in  the  figure  (Fig.  315).  The  anterior 
muscles  of  the  neck  are  too  weak  and  toneless  to  restore  the  head  to  its 


Fig.  314.  Abnormal  posture  of  pigeon, 
in  which  the  labyrinth  had  been  ex- 
tirpated on  one  side  five  days  pre- 
viously.    (Ewald.) 


THE  LABYRINTHINE  SENSATIONS 


607 


normal  position  against  the  weight  of  the  bullet.     No  such  phenomena  aie 
presented  by  a  normal  bird. 

The  same  absence  of  tone  is  seen  in  mammals.  A  dog  with  both  laby- 
rinths destroyed  may  jump  down  from  a  table  once,  but  will  not  repeat  the 
experiment,  since  the  muscles  of  the  fore  hmbs  are  too  toneless  to  support 
the  head  against  the  shock  of  the  jump,  and  he  knocks  his  head  against  the 
ground  as  his  legs  collapse  imder  him.  If  only  one  canal  be  put  out  of  action, 
as,  for  instance,  by  stopping  it  with  dentist's  amalgam,  the  head  is  thrown 
into  oscillations  in  a  corresponding  plane,  or  perhaps  rather  we  should  say 
that  when  the  head  oscillates  in  this  plane  there  are  no  corresponding  sensa- 
tions set  up  which  tend  to  inhibit  the  movements.  The  same  effect  may  be 
produced  temporarily  by  painting  any  one  of  the  canals  with  cocaine  so  as 
to  paralyse  its  nerve-endings.  The  converse  experiment  of  isolated  stimula- 
tion of  one  canal  has  also  been  effected 
by  Ewald.  For  this  purpose  Ewald, 
by  means  of  a  dentist's  bmT,  opened 
one  bony  canal  at  two  spots.  By  the 
hole  furthest  away  from  the  ampulla 
he  introduced  an  amalgam  stopping, 
so  as  to  prevent  any  current  of  fluid 
backwards  through  the  canal.  Over 
the  second  hole  he  fixed,  by  means  of 
plaster  of  Paris,  a  tube  which  was 
connected  by  a  flexible  rubber  tube 
with  a  rubber  ball.  By  this  means, 
while  the  bird  was  sitting  quietly  on 
its  perch,  he  could  suddenly  blow  upon 
the  exposed  membranous  canal  with- 
out disturbing  the  bird  in  any  way. 

By  the  air  pressure  thus  produced  on  the  canal  a  stream  of  endolymph  was 
caused  in  the  direction  of  the  ampulla.  Every  time  this  was  done  he  fomid 
that  the  animal  moved  its  head  and  eyes  in  the  direction  of  the  current  and 
always  exactly  in  the  plane  of  the  canal  which  was  being  stimulated.  By 
this  means  proof  was  brought  of  the  correctness  of  the  theory  put  forward 
by  Breuer  and  Mach,  viz.  that  the  specific  stimulus  of  the  nerve-endings  in 
the  ampulla  is  afforded  by  the  current  of  the  endolymph  in  the  semicircular 
canals. 

Since  the  endolymph  is  a  fluid  with  inertia  it  will  not  immediately  follow 
a  rotational  movement  of  the  bony  walls  of  the  semicircular  canals.  Thus  a 
sudden  tiurning  of  the  head  from  left  to  right  will  cause  movement  of  endo- 
lymph towards,  and  therefore  increased  pressure  on,  the  ampullary  nerve- 
endings  of  the  right  horizontal  canal,  and  movement  of  endolymph  away 
from,  and  therefore  diminished  pressure  on,  the  corresponding  ampulla  of 
the  left  side.  In  this  way,  for  movement  in  any  given  plane,  the  two 
corresponding  semicircular  canals  of  the  two  sides  are  synergic,  and  unite  in 
sending  impulses  which  guide  the  equilibrating  centres,  and  inform  us  of 


Fig.  315. 


608  PHYSIOLOGY 

the  position  of  our  head  in  space.  "  One  canal  can  be  affected  by  and  trans- 
mit the  sensation  of  rotation  about  one  axis  in  one  direction  only  :  and  for 
complete  perception  of  rotation  in  any  direction  about  any  axis  six  semi- 
circular canals  are  required  in  three  pairs,  each  pair  having  its  two  canals 
parallel  (in  the  same  plane),  and  with  their  ampullae  turned  opposite  ways. 
Each  pair  would  thus  be  sensitive  to  any  rotation  about  a  line  at  right  angles 
to  its  plane  or  planes,  the  one  canal  being  influenced  by  rotation  in  the  one 
direction,  the  other  by  rotation  in  the  opposite  direction  "  (Crum  Brown). 
These  reflex  movements  of  head  and  eyes  are  the  invariable  result  of  move- 
ments set  up  in  the  endolymph,  and  occur  equally  well  in  the  absence  of 
the  cerebral  hemispheres.  If  an  animal  or  man  be  placed  on  a  turntable 
and  rotated,  his  first  tendency  will  be  to  turn  his  head  and  eyes  in  the  opposite 
direction  to  that  of  rotation.  If  the  rotation  be  continued,  the  endolymph 
gradually  takes  up  the  movement  of  the  surrounding  parts  of  the  head,  and 
if  the  eyes  be  closed,  no  movement  of  head  or  eyes  is  observed.  If  now  the 
rotation  is  stopped,  the  endolymph  will  tend  to  go  on  moving,  and  the  effect 
will  be  the  same  as  if  a  movement  of  rotation  were  suddenly  begun  in  the 
opposite  direction.  Head  and  eyes  will  now  be  turned,  without  any  volun- 
tary impulse,  in  the  direction  of  the  previous  rotation,  and  in  consciousness 
there  will  be  an  actual  sensation  of  rotation  in  the  opposite  direction.  This 
sensation  is  in  opposition  to  the  sensations  derived  from  other  parts,  and 
hence  the  feehng  of  giddiness  and  the  actual  disorders  of  equilibrium  which 
are  its  concomitants. 

That  this  feehng  of  giddiness  on  rotation  is  due  to  impulses  started  in  the 
semicircular  canals  is  shown  by  the  fact  that,  in  a  large  number  of  deaf-mutes 
where  these  organs  are  imperfectly  developed,  it  is  impossible  to  produce 
giddiness  and  the  associated  eye  movements  by  passive  rotation. 

THE  FUNCTION  OF  THE  OTOLITHS 

The  semicircular  canals  are,  as  we  have  seen,  a  higher  development  of 
the  otolith  organ.  The  primitive  part  of  this  organ  is  represented  by  the 
maculae  in  the  utricle  and  saccule.  It  is  to  these  organs  that  we  must 
ascribe  our  powers  of  appreciating  the  static  position  of  the  head,  as  well 
as,  to  a  slight  degree,  movements,  not  of  rotation,  but  in  one  plane  forwards 
or  backwards. 

A  consideration  of  the  structure  of  the  otolith  organ  shows  at  once  that 
the  incidence  of  the  weight  of  the  otoliths  on  the  hairs  of  the  macula  will  vary 
according  to  the  position  of  the  head.  Thus  in  the  diagram  (Fig.  200,  p.  399) 
in  A  (normal  position)  the  chief  weight  of  the  otolith  falls  on  the  hairs  from 
h  to  c,  whereas,  when  the  head  has  been  rotated  round  a  right  angle  so  that 
the  man,  for  instance,  is  lying  on  his  right  side,  the  chief  weight  of  the  otoliths 
will  fall  on  the  hairs  at  c.  The  nerve-endings  stimulated  by  the  weight  of  the 
otoliths  will  therefore  vary  according  to  the  position  of  the  head.  The 
cerebellum  and  its  associated  structures  represent  a  mechanism  for  the 
regulation  of  the  movements  of  the  trunk  as  a  whole  and  the  position  of  its 
centre  of  gravity  in  relation  to  the  position  of  the  head. 


THE  LABYRINTHINE  SENSATIONS  609 

The  beginning  and  ending  of  all  movements  of  the  head,  or  any  change  in 
the  rate  at  which  it  is  moving,  must  cause  a  momentary  alteration  of  the 
incidence  of  pressure  of  the  otoliths  on  the  sensory  hairs.  Any  translatory 
movements  of  the  head  must  therefore  excite  a  set  of  nerve  fibres  which  will 
be  constant  for  each  direction.  We  are  therefore  justified  in  ascribing  to 
these  organs  the  functions  possessed  by  the  otolith  organ  throughout  the 
animal  kingdom,  viz.  the  transmission  of  impulses  to  the  central  nervous 
system  which  are  aroused  by  the  position  or  movements  of  the  head,  and,  hke 
the  sensations  from  the  muscles,  regulate  and  govern  any  motor  reaction  to  a 
sensory  stimulus.  Of  these  afferent  impulses  a  certain  proportion  will  arrive 
at  the  cerebral  cortex,  and  in  consciousness  will  inform  us  of  our  position  in 
space  and  of  the  direction  and  extent  of  any  movement,  active  or  passive,  of 
the  head. 


20 


BOOK  III 
THE   MECHANISMS  OF   NUTRITION 


CHAPTER   IX 

THE   EXCHANGES   OF   MATTER   AND   ENERGY 
IN   THE  BODY 

GENERAL  METABOLISM 

All  the  energy  which  leaves  the  body  as  heat  or  work  is  derived  from  pro- 
cesses of  oxidation,  the  carbon,  hydrogen,  nitrogen,  and  sulphur  of  the  food- 
stuff's uniting  with  oxygen  in  the  body  and  being  eliminated  in  the  form  of 
carbon  dioxide,  water,  urea  and  other  substances,  and  sulphates.  In  a 
starving  animal  this  discharge  of  energy  must  be  associated  with  a  loss  of 
body  substance.  The  necessity  for  taking  food  is  determined  by  the  need  of 
replacing  this  loss.  The  food-stuSs  cannot,  hke  the  coal  or  fuel  of  a  steam- 
engine,  be  utilised  directly  as  a  source  of  energy,  but  must  be  built  up  to  a 
greater  or  less  degree  into  the  structm'e  of  the  living  protoplasm.  The  total 
amount  of  living  material  in  the  body,  though  maintained  fairly  constant 
in  the  adult  animal,  may  yet  undergo  alterations  under  varying  conditions, 
and  these  alterations  are  naturally  more  marked  in  the  growing  animal.  We 
have  in  this  chapter  to  inquire  into  : 

(1)  The  nature  and  amount  of  the  substances  which  may  serve  as  food- 
stuffs and  are  necessary  for  maintaining  the  weight  of  the  body  constant  or 
providing  for  its  growth  ; 

(2)  The  relation  between  the  total  amount  of  material  taken  up  by  the 
body  and  the  total  amomit  given  out ; 

(3)  The  variations  in  the  total  chemical  exchanges  determined  by 
variations  in  the  output  of  energy  by  the  body  ;  and 

(4)  The  significance  of  the  various  classes  of  food-stuffs  as  sources  of 
energy  and  in  the  replacing  of  tissue  waste. 

We  have  therefore  to  make  balance-sheets  of  two  kinds,  namely  :  (1)  an 
accurate  comparison  of  the  ingesta  (food  and  oxygen)  and  the  egesta  (carbon 
dioxide,  water,  urea,  &c.) ;  and  (2)  one  showing  the  amomit  of  potential 
energy  introduced  into  the  body  c  jmpared  with  the  amount  of  energy  set 
free  in  the  body. 


613 


SECTION  I 

METHODS   EMPLOYED   IN  DETERMINING  THE 
TOTAL  EXCHANGES  OF  THE  BODY 

The  determination  of  the  material  exchanges  of  the  body  involves  an  ac- 
curate comparison  of  its  income  and  output.  The  income  consists  of  the 
food-stuffs  and  oxygen.  The  food-stuffs  may  be  divided  into  two  classes, 
namely,  (1)  the  organic  food-stuffs,  which  on  oxidation  may  serve  as  sources 
of  energy,  and  (2)  the  inorganic  food-stuffs,  such  as  salts  and  water. 

The  latter  class  neither  add  to  nor  subtract  from  the  total  energy  of  the 
organism,  but  their  presence  is  a  necessary  condition  of  all  vital  processes, 
and  as  they  are  contained  in  the  various  excreta  a  corresponding  amount 
must  be  present  in  the  food  in  order  to  make  good  this  loss. 

In  spite  of  the  bewildering  complexity  of  the  nature  of  the  foods  taken 
by  man,  their  essential  constituents  can  always  be  confined  to  the  three 
classes,  proteins,  fats,  and  carbohydrates,  and  any  analysis  of  the  food  must 
give  the  relative  amounts  present  of  these  three  classes  of  substances.  The 
approximate  analysis  of  the  food-stuffs  presents  little  difficulty.  The 
nitrogen  is  determined  by  Kjeldahl's  method.  The  figure  thus  obtained 
is  multiplied  by  the  factor  6-25,  and  the  resulting  figure  is  taken  to  represent 
the  total  protein  in  the  food.  Of  course  such  a  valuation  may  give  too  high 
a  value  when  the  food-stuff  is  one  that  is  rich  in  nitrogenous  extractives. 
The  total  fat  is  determined  by  extracting  the  food  in  a  Soxhlet  apparatus  with 
ether.  It  is  advisable  to  precede  this  extraction  by  an  extraction  with 
boiling  alcohol.  The  total  ethereal  and  alcoholic  extract  obtained  is  reckoned 
as  fat.  The  amount  of  water  is  determined  by  drying  the  food-stuff  at 
110°  C,  and  the  amount  of  inorganic  constituents  by  ashing  the  dried 
remainder.  Carbohydrates  may  be  determined  directly  by  boihng  the  food 
with  dilute  acids  in  order  to  convert  all  its  disaccharides  and  polysaccharides 
into  hexoses,  which  are  then  reckoned  as  glucose,  and  estimated  by  their 
copper- reducing  power.  In  most  cases,  however,  the  total  protein,  fat,  and 
ash  are  subtracted  from  the  dried  weight  of  the  food  and  the  remainder  is 
taken  as  carbohydrate. 

Although  the  methods  for  the  analysis  of  food-stuffs  are  by  no  means  diffi- 
cult, the  total  analysis  of  the  food  during  a  metabolism  experiment  may 
become  extremely  tedious  on  account  of  the  very  large  number  of  analyses 
Avhich  have  to  be  performed.  The  labour  is  lightened  by  the  fact  that  nearly 
all  the  ordinary  food-stuffs  have  been  subjected  to  analysis  and  their  average 

614 


THE  TOTAL  EXCHANGES  OF  THE  BODY  615 

composition  published  by  the  Agricultural  Board  of  the  United  States. 
Since,  however,  the  foods  vary  in  composition,  especially  in  water  content, 
from  time  to  time,  a  calculation  of  the  total  income  of  proteins,  fats,  and 
carbohydrates  from  data  given  by  workers  in  other  lands  must  present  a 
considerable  margin  of  error.  In  order  to  attain  greater  accuracy  some 
observers  have  made  a  complete  food  in  the  form  of  biscuits  or  of  preserve 
which  is  prepared  in  large  quantities  at  the  beginning  of  the  experiment  and 
used  as  the  sole  food  throughout  the  experiment.  Pfliiger,  for  instance,  con- 
verted the  horse-flesh,  with  which  he  desired  to  feed  his  dogs  in  a  metabolism 
experiment,  into  sausage  meat  which  was  sealed  up  in  cases  and  sterihsed. 
The  sausage  meat  having  been  analysed  at  the  begimiing  of  the  experiment, 
it  was  only  necessary  thereafter  to  weigh  the  amount  eaten  by  the  dog  in 
order  to  know  accurately  the  total  amount  of  protein,  fat,  and  carbohydrate 
ingested  by  the  animal.  In  experiments  on  man  it  has  been  endeavoured  to 
obtain  the  same  result  by  limiting  the  food  to  a  few  articles  of  diet  which  could 
be  accurately  analysed  in  each  case.  The  monotony  of  such  a  diet  tends 
to  interfere  with  the  success  of  the  experiment,  since  the  subject  of  the 
experiment  loses  his  appetite  and  his  processes  of  nutrition  are  not  normally 
carried  out.  It  is  usually  possible  to  steer  a  middle  course  between  the  two 
extremes  of  too  much  and  too  little  variation  of  diet,  and  so  to  obtain  values 
for  the  composition  of  the  iugesta  which  cannot  differ  very  largely  from 
their  true  composition. 

The  material  output  of  the  body  consists  of  the  products  of  combustion 
of  the  food-stuffs,  which  are  turned  out  by  the  various  channels  of  excretion, 
namely,  the  kidneys,  the  alimentary  canal,  the  lungs,  and  the  skin.  These 
excreta  must  therefore  be  collected  and  analysed.  In  addition  to  the  main 
sources  of  excretion,  small  quantities  of  material  are  lost  by  the  shedding 
of  the  cuticle,  by  the  growth  and  cutting  of  the  hair  and  nails,  and  so  on.  In 
most  cases  the  losses  in  this  way  are  so  small  that  they  may  be  disregarded. 
The  nitrogen  of  the  food-stuffs  and  that  derived  from  the  disintegration  of 
the  tissues  of  the  body  is  excreted  almost  exclusively  in  the  urine,  a  small 
amount  being  thrown  out  by  the  alimentary  canal.  The  total  nitrogen  must 
be  therefore  determined  both  in  the  faeces  and  in  the  urine.  The  nitrogen  in 
the  fa3ces  is  derived  from  two  sources.  Part  represents  those  nitrogenous 
constituents  of  the  tissues  which  have  resisted  the  digestive  processes  of  the 
alimentary  canal.  There  is  in  addition  a  certain  amount  derived  from  the  in- 
testine itself.  During  complete  starvation  faecal  masses  are  formed  in  the 
intestine,  and  it  has  been  calculated  that  in  a  normal  individual  about  one 
gramme  of  nitrogen  a  day  is  excreted  by  the  mucous  membrane  of  the  gut  and 
contributes  to  the  formation  of  the  faeces.  It  is  usual  therefore  to  regard 
one  gramme  of  the  nitrogen  of  the  faeces  as  belonging  to  the  output  of  the 
body  and  representing  the  result  of  nitrogenous  metabolism,  while  the 
balance  is  taken  as  belonging  to  undigested  food-stuifs,  and  is  subtracted 
from  the  total  nitrogen  of  the  latter  in  reckoning  the  real  income  of  the  body. 
A  small  amount  of  nitrogen  is  also  lost  by  sweat,  but  this  can  be  disregarded 
unless  the  sweating  is  profuse,  when  the  loss  of  nitrogen  by  this  channel  may 


616 


PHYSIOLOGY 


rise  to  as  much  as  4  per  cent,  of  the  total  nitrogenous  output  of  the  body. 
Although  a  trace  of  ammonia  has  been  described  as  occurring  in  the  expired 
air,  the  amount  is  so  minute  that  any  loss  of  nitrogen  by  the  lungs  can  be 
neglected.  That  the  loss  both  by  lungs  and  skin  under  ordinary  circum- 
stances can  be  disregarded  is  shown  by  the  fact  that  it  is  possible  to  account 
directly  for  the  whole  nitrogen  of  the  body  by  a  comparison  of  the  compo- 
sition of  food  with  that  in  the  urine  and  faeces.  If,  for  instance,  an  animal 
is  kept  on  a  sufficient  diet  which  contains  a  perfectly  regular  amount  of 
nitrogen,  after  a  few  days  a  condition  known  as  nitrogenous  equilibrium  is  set 
up,  i.e.  the  total  nitrogen  of  faeces  and  urine  is  exactly  equal  to  the  total  nitro- 
gen of  the  food.  The  same  thing  apphes  to  the  sulphur,  as  is  shown  in  the 
following  Table  (quoted  by  Tigerstedt)  : 


Days  of 
experiment 

Nitrogen 
of  food 

Nitrogen 
excreted 

Per  cent, 
difference 

Sulphur 
ingested 

Sulphur 
excreted 

1-7 

8-17      . 

154-81 
213-72 

153-02 
213-26 

-0-51 
-0-21 

12-77 

12-79 

In  order  to  express  the  nitrogenous  metabolism  in  terms  of  protein, 
we  use  the  factor  employed  in  estimating  the  amount  of  protein  in  the 
food,  i.e.  we  multiply  the  total  nitrogen  of  the  excreta  by  6-25.  This  will 
give  the  total  protein  which  has  been  broken  down  during  the  period  of  the 
experiment.  Much  more  important  from  the  energy  standpoint  is  the  deter- 
mination of  the  total  processes  of  oxidation  of  the  body,  information  on  which 
is  given  by  a  comparison  of  the  oxygen  intake  with  the  output  of  carbon 
dioxide  and  water.  The  estimation  of  these  substances  presents  much 
greater  difficulties  than  the  investigation  of  the  nitrogenous  exchange  and 
involves  the  use  of  some  form  of  respiration  apparatus. 

The  follov/ing  are  the  chief  methods  which  have  been  employed  for  this  purpose  : 
I.  THE    METHOD   OF    HALDANE.      This  method  is  extremely  convenient  when 
dealing  with  the  gaseous  exchanges  of  small  animals,  such  as  mice,  rats,  guinea-pigs 


Soda  Lime     H^SC, 


Fig.  316.     Haldane-Pembrey  respiration  apparatus, 
c,  chamber  for  animal ;    m,  gas  meter. 

or  rabbits.  The  animal  is  placed  in  the  chamber  c,  which  may  be  simply  a  wide- 
mouthed  bottle  (Fig.  316).  This  chamber  is  supplied  with  a  thermometer,  and  can 
be  kept  at  any  desired  temperature  by  immersion  either  in  warm  or  cold  water. 
On  the  inlet  .side  of  the  bottle  is  a  series  of  tubes  or  bottles,  some  of  which  contain 
sulphuric  acid  and  pumice-stone,  while  the  others  contain  soda  lime.     On  the  outlet 


THE  TOTAL  EXCHANGES  OF  THE  BODY 


617 


^W 


L 


WATER 
ADDED 


WATER 
eSORBED 


1_J 

n 


^CARBON  DIOXIDE 
AB50fiB£0 


hi 

n 


Fig.  317. 


Air  circuit  in  Benedict's  respiration 
apparatus. 


side  of  the  vessel  is  a  corresponding  series  of  vessels  for  the  absorption  of  water  and  of 
carbon  dioxide.  On  the  further  side  of  these  vessels  is  a  gas  meter.  During  an  ex- 
periment air  is  sucked  through  the  wliole  apparatus  by  means  of  an  aspirator  or  a  water 
pump,  the  amount  of  air  passing  througli  the  apparatas  being  measured  by  the  meter. 
The  animal  is  thus  supplied  with  pure  air  freed  from  water  vapour  and  from  carbon 
dioxide.  Any  water  or  carbon  dioxide  produced  by  the  animal  is  absorbed  by  the 
vessels  interposed  in  the  course  of  the  outgoing  air.  These  vessels  are  weighed  at  the 
beginning  of  the  experiment  and  at  the  end,  and  the  difference  in  weights  will  there- 
fore give  the  amounts  of  carbon  dioxide  and  water  which  have  been  discharged  by  the 
animal. 

The  intake  of  oxygen  by  the  animal  is  determined  indirectly.  Since  it  gives  off 
only  carbon  dioxide  and  water,  and  absorbs  only  oxygen  during  its  stay  in  the  chamber, 
the  loss  of  weight  of  the  animal  during 
its  stay  in  the  chamber,  subtracted  from 
the  total  amount  of  carbon  dioxide  plus 
water  it  gives  off,  will  represent  the 
amount  of  oxygen  absorbed. 

The  advantage  of  this  apparatus  is 
that  it  can  be  fitted  up  in  any  labora- 
tory, and  is  accurate  for  the  purposes 
to  which  it  is  applied.  It  is  not,  how- 
ever, appropriate  for  long-continued 
experiments  or  for  experiments  on 
larger  animals  or  on  man  *liimself. 
Most  of  the  data  with  regard  to  the 
respiratory  exchange  under  various  cir- 
cumstances have  therefore  been  obtained 
by  one  of  the  three  following  methods  : 

II.  THE  METHOD  OF  REGNAULT  AND  REISET.  The  principle  of  this  method 
consists  in  placing  the  animal  that  is  to  be  the  subject  of  investigation  in  a  closed 
chamber  containing  a  given  volume  of  air.  The  carbon  dioxide  produced  bj^  the  animal 
is  absorbed  by  means  of  caustic  alkali,  and  the  oxygen  consumed  by  the  animal  is  made 
good  by  allowing  oxygen  to  flow  into  the  chamber  from  a  gasometer.  The  inflow  of 
oxygen  is  regulated  so  as  to  keeji  the  pressure  of  air  in  the  chamber  constant.  At 
the  end  of  the  experiment  the  alkali  is  titrated  and  the  amount  of  carbon  dioxide 
absorbed  thus  determined.  The  air  in  the  chamber  is  also  analysed  so  as  to  be  certain 
that  it  contains  an  excess  neither  of  carbon  dioxide  nor  of  oxygen.  The  amomit  of 
oxygen  absorbed  by  the  animal  is  knoAvn  already,  the  oxygen  which  has  been  allowed 
to  flow  in  having  been  measm'ed. 

A  modification  of  this  method  has  been  devised  by  Benedict  and  is  especially 
applicable  to  clinical  pm-poscs.  In  this  method  the  individual  who  is  the  subject  of 
the  experiment  breathes  through  a  nose-piece  into  a  wide  metal  tube,  the  mouth  being 
kept  closed.  The  metal  tube  forms  part  of  a  closed  system  tlu-ough  which  a  current 
of  air  is  maintained  by  means  of  a  ])ump.  In  the  course  of  the  current  of  air  are  inter- 
posed vessels  for  the  absorption  of  carbon  dioxide  and  of  water,  and  the  volume  of 
gas  in  the  system  is  maintained  constant  by  admitting  oxygen  to  it  in  projiortion  as 
the  oxygen  of  the  system  is  used  up  in  respiration.  In  Fig.  317  is  given  a  diagrammatic 
scheme  of  the  air  circuit,  and  in  Fig.  318  a  diagram  of  the  arrangement  of  the  whole 
respiration  apparatus,  showing  the  nose-piece  for  breathing,  the  tension  equaliser, 
the  air-purifying  apparatus,  and  the  oxygen  cylinder.  The  tension  equaliser,  A,  is 
attached  to  the  ventilating  pipe  near  the  point  of  entrance  of  the  air  into  the  Imigs. 
It  consists  of  a  pan  with  a  rubber  diaphragm  (which  may  be  conveniently  made  from 
a  lady's  bathing-cap).  As  the  air  is  dra\\ii  into  the  hmgs  the  rubber  diaphragm  sinks, 
to  rise  again  with  expiration.  The  respiratory  movements  can  thus  proceed  without 
altering  appreciably  the  jiressure  within  the  closed  system  of  tubes.  By  the  admission 
of  oxygen  the  supply  of  oxygen  iis  adjusted  so  as  to  keep  the  bag  from  becoming  either 
too  much  distended  or  too  uuich  flattened.      As  the  air  leaves  the  lungs  and  passes 

20* 


INTRODUCED 


618 


PHYSIOLOGY 


into  the  constantly  moving  current  of  air,  it  is  carried  along  by  the  pump  and  flows 
through  two  Wolff's  bottles  containing  strong  sulphmic  acid  and  pumice  for  the  removal 
of  water  vapour.  It  then  passes  through  a  brass  cylinder,  c,  filled  with  soda  lime 
for  the  absorption  of  carbon  dioxide.  From  here  it  passes  again  through  sulphuric 
acid  in  a  Kipp  generator  for  the  absorption  of  water  given  off  by  the  soda  lime.  Since 
the  air  so  deprived  of  moisture  would  be  uncomfortable  to  breathe,  it  is  then  carried 
through  another  Kipp  generator  containing  water  with  a  trace  of  sochum  carbonate 
for  the  neutralisation  of  any  acid  fumes  which  may  be  given  off  by  the  sulphuric  acid. 
It  then  passes  back  to  the  tube  from  which  the  subject  is  breathing.  In  tin's  way  it  is 
possible  to  determine  very  accurately  the  amount  of  oxygen  used  up  and  the  amount 

of  carbon  dioxiele  given  off  in  the  course 
of  an  experiment  lasting  one  to  three  hours 
or  longer.  The  oxygen  consumption  is 
measm'cd  by  weighing  the  cylinder  of  this 
gas,  chosen  small  for  this  purpose,  before 
anel  after  the  experiment. 

III.  PETTENKOFER'S  METHOD.  In 
the  apparatus  designed  by  Pettenkofer 
the  animal  or  man  was  placed  in  a 
chamber  through  which  a  constant  cur- 
rent of  fresh  air  was  passed.  The  amount 
of  air  passing  through  the  chamber  was 
measured  by  means  of  a  meter.  Through- 
out the  experiment  continuous  samples 
both  of  the  air  entering  the  chamber 
and  of  the  air  leaving  the  chamber  were 
taken.  The  analyses  of  these  samples 
served  to  show  the  composition  of  the 
whole  air  entering  and  leaving  the  cham- 
ber, and  therefore  the  changes  in  the  air 
caused  by  the  presence  of  the  animal. 
The  advantage  of  this  apparatus  is  that 
an  adequate  ventilation  can  be  kept  up, 
and  the  apparatus  can  be  built  of  any  size. 
In  the  apparatus  of  Tigerstedt  built  on 
this  plan  the  chamber  had  a  capacity 
of  100-6  cubic  metres,  and  was,  in  fact, 
a  small  room.  A  small  respiratory 
apparatus  has  been  built  by  Atwater. 
IV.  ZUNTZ  AND  GEPPERTS  METHODS.  For  mtny  purposes  the  methods 
devised  by  Zuntz  and  Geppert  present  many  aelvantages,  especially  when  it  is  desired 
to  take  the  respiratory  exchanges  in  man  or  any  animal  during  a  limited  perioel  of  time. 
The  subject  of  the  experiment  has  his  nostrils  clamped  and  breathes  into  and  out  of 
a  face-piece.  This  face-piece  is  provided  with  valves  either  of  aluminium  or  of  animal 
membrane,  which  serve  to  separate  the  in-going  from  the  out-going  current  of  air. 
In  the  course  of  the  out-going  current  is  placed  a  very  delicate  gas  meter  which  presents 
practically  no  resistance  to  the  air  current.  A  branch  from  the  efflux  tube  passes  to  a 
gas  analysis  apparatus.  By  an  ingenious  method  it  is  arranged  that  an  aliquot  part 
of  the  whole  of  the  out-going  air  is  drawn  off  into  this  apparatus,  so  that  the  experiment 
can  be  interrupted  at  any  time,  and  the  analysis  of  this  sample  will  give  the  average 
composition  of  the  expired  air,  and  therefore,  on  multiplicaticn  by  the  total  gas  passing 
through  the  gas  meter,  the  total  output  of  carbon  dioxide  eluring  the  course  of  the 
observation.  One  advantage  of  this  method  is  that  the  apparatus  is  portable,  and  can 
be  applied  to  the  investigation  of  the  respiratory  exchanges  of  ])atients  in  hospitals 
or  of  man  or  animals  while  they  are  walking  about.  It  has  been  ufed,  for  instsnce, 
by  Zuntz  and  his  pupils  in  an  interesting  series  of  researches  on  the  gaseous  metabolism 
of  men  at  high  altitudes. 


Fig.    318.      Arrangement  of   apparatus  in 
Benedict's  method  for   determination  of 
respiratory  exchange. 
N,  tubes  inserted  into  nostrils  of  patient ; 
A,  tension  equaliser  ;   c,    cyhnder    contain- 
ing soda  lime  for  absorbing  002- 


THE  TOTAL  EXCHANGES  OF  THE  BODY 


619 


By  means  of  one  or  more  of  these  methods  we  may  arrive  at  a  correct 
idea  of  the  total  income  and  output  of  an  individual  for  periods  of  many 
days.  The  following  details  by  Tigerstedt  may  serve  as  an  example  of  the 
results  obtained  in  such  an  experiment.  The  experiment  lasted  two  days. 
The  subject  was  a  man  of  twenty-six  years  of  age,  weighing  about  65  kilos, 
who  had  previously  taken  no  food  for  five  days.  The  following  Tables 
represent  his  material  income  and  output. 

Total  Income 


Food 

3  3 

N. 

c. 

a 

'3 
2 

P4 

Fat 

5| 

Ash 

Brccad      . 

373 

7-3 

36 

337 

46 

4 

278 

9 

_ 

Butter    . 

388 

0-4 

37 

351 

3 

337 

4 

7 

— 

Cheese     . 

116 

4-3 

56 

60 

27 

35 

— 

5 

— 

Salt  meat 

26 

11 

16 

10 

9 

— 

— 

2 

— 

Milk 

2313 

11-3 

2047 

266 

71 

85 

95 

16 

— 

Broth      . 

658 

11-8 

580 

78 

74 

— 

— 

9 

— 

Beer 

1413 

1-2 

1273 

77 

8 

— 

67 

b 

59 

Beef  steak 

700 

20-6 

533 

167 

129 

33 

— 

7 

— 

Potatoes 

452 

0-9 

359 

93 

6 

1 

82 

5 

— 

Water 

2335 

— 

2335 

— 

— 

— 

— 

— 

— 

Totals 

8773 

59-3 

831-6 

7275 

1439 

371 

497 

525 

61 

59 

Total  Output 


Total 
amount 

N. 

C. 

Water 

Solids 

Protein 

Fat 

Carbo- 
hydrate 

Ash 

Respiration 

Urine 
Faeces 

2701 

2564 

455 

41-5 

4-8 

-!5:-0 
32-5 
43-8 

2248 

2490 

363 

91-6 

30 

20 

27 

21 
15 

Totals     . 

5720 

46-3 

529-3 

5101 

91-6 

30 

20 

27 

36 

As  we  should  expect  in  a  man  who  had  fasted  five  days,  this  balance-sheet 
shows  a  marked  retention  of  the  food  taken  in,  i.e.  a  marked  excess  of  income 
over  output.  Thus  of  the  nitrogen  ingested,  1.3  grm.,  which  is  equivalent 
to  81-3  grm.  of  protein,  was  retained  ;  of  the  carbon,  302  grm.  was  retained. 
Of  this  302  gi'm.,  42-7  grm.  would  be  contained  in  the  81-3  grm.  of  protein, 
so  that  the  rest  of  the  carbon,  namely,  259-6  grm.,  was  probably  laid  down 
in  the  form  of  fat.  This  would  correspond  to  339  grm.  of  fat.  Of  the  salts 
contained  in  the  ash  of  the  food,  25  grm.  were  retained  in  the  body.  The 
carbon  and  nitrogen  reappearing  in  the  excreta  serve  as  an  index  of  the 
amount  of  metabolism  of  the  food-stuffs  which  had  occurred  during  the 
two  days.  In  order  to  supply  the  energy  requirements  of  the  body  during 
the  time  of  the  experiment,  -498  grm.  of  carbohydrate,  59  grm.  of  alcohol, 


620 


PHYSIOLOGY 


and  138  grm.  of  fat  had  been  completely  oxidised.  The  amount  of  protein 
used  up  during  this  time  can  be  obtained  by  multiplying  the  nitrogen  of 
the  urine  plus  1  grm.  of  nitrogen  of  the  faeces  by  the  factor  6-25,  and  is  found 
to  amount  to  271-9  grm. 


THE  ENERGY  BALANCE-SHEET  OF  THE  BODY 

The  energy  income  of  the  body  is  measured  by  the  potential  energy  of  the 
food-stujEEs,  i.e.  the  amount  of  energy  which  can  be  evolved,  either  as  heat, 
work,  or  in  any  other  form,  by  the  oxidation  of  the  food-stufis  to  the  end- 
products  which  occur  in  the  body.  Since  it  is  convenient  to  have  a  uniform 
method  of  expressing  the  total  potential  energy  of  a  food-stuff,  we  generally 
express  it  in  calories,  and  speak  of  the  heat-valae  of  a  food-stuff.  The 
heat- value  of  any  given  food  is  the  amount  of  large  calories  *  which  it  evolves 
on  complete  combustion  with  oxygen,  and  is  determined  by  burning  a 
weighed  quantity  of  the  dried  food-stuff  in  oxygen  in  the  bomb  calorimeter. 
The  following  heat  values  have  been  obtained  for  different  food-stuffs  : 


Substance 

Heat  value 

Lean  meat 

.     5-656  (or  5-345  Rubner) 

Lard          .          .          .          . 

.     9-423 

Butter       .... 

.     9-231 

Grape  sugar 

.     3-692 

Cane  sugar 

.     4-116 

Starch      .          .          .          . 

.     4-191 

In  the  case  of  some  food-stuffs  it  is  necessary  to  draw  a  distinction  be- 
tween the  absolute  heat-value  and  the  physiological  heat-value.  Since 
carbohydrates  and  fats  undergo  complete  oxidation  in  the  body  to  carbonic 
acid  and  water,  their  physiological  heat- values,  i.e.  the  values  of  these  food- 
stuffs to  the  organism,  are  identical  with  their  absolute  heat- values.  Pro- 
teins, however,  do  not  undergo  complete  oxidation.  When  they  are  oxidised 
in  the  bomb  calorimeter  the  nitrogen  is  set  free  in  a  gaseous  form.  In  the 
animal  body  no  nitrogen  is  eliminated  in  the  gaseous  form,  the  whole  of  it 
being  excreted  as  urea  and  allied  substances  still  endowed  with  a  considerable 
store  of  potential  energy,  which  can  be  set  free  when  their  oxidation  is  com- 
pleted in  a  calorimeter.  In  order  to  determine  the  physiological  heat- value 
of  protein  we  must  subtract  from  its  absolute  heat- value  the  heat- value  of 
the  excretory  products  in  the  form  of  which  it  leaves  the  body.  The 
physiological  heat  value  of  proteins  has  been  determined  by  Rubner  in  the 
following  way  :  A  dog  was  fed  with  the  same  protein  which  had  served  for 
the  determination  of  the  absolute  heat- value.  While  the  dog  was  receiving 
this  food  its  urine  was  collected,  dried,  and  its  heat-value  determined  by 
combustion  in  the  calorimeter.  It  was  fomid  that  for  each  gramme  of 
protein  which  had  undergone  disintegration  in  the  body  an  amount  of  urine 
was  passed  corresponding  to  a  heat- value  of  1  -0945  calories.     The  heat- value 

*  A  calorie  is  the  amount  of  heat  necessary  to  raise  a  gramme  of  water  from 
0°C.  to  1°  C.  A  large  calorie  is  the  heat  required  to  raise  a  kilogramme  of  water  from 
0"  C.  to  1°  C,  and  is  therefore  equal  to  1000  small  calories. 


THE  TOTAL  EXCHANGES  OF  THE  BODY 


621 


of  the  faeces  formed  under  the  same  diet  was  0  •  1854  calorie  for  each  gramme  of 
protein.  Rubner  fiuther  reckoned  that  a  certain  amomit  of  heat  would  be 
required  for  the  solution  of  the  proteins  and  of  the  urea,  and  reckoned  this 
at  0-05  calorie.  The  reduced  or  physiological  heat- value  of  protein  is  there- 
fore equal  to  5-345  —  (1-0945  +  0-1854  +  0-05)  =  4-015  calories. 

A  determination  of  the  heat-values  of  the  various  food-stuifs  shows 
minute  differences  between  individual  members  of  the  same  class.  Since  it 
is  impossible  to  reckon  out  accurately  the  relative  amounts  of  the  different 
kinds  of  protein,  carbohydrate,  &c.,  contained  in  each  diet,  Rubner  has 
calculated  the  average  physiological  heat- values  of  the  three  classes  of  food- 
stuffs.    These  figures  have  been  universally  adopted,  and  are  as  follows  : 


1  grm.  protein 

=  4-1  calories 

1  grm.  fat 

=  9-3      „ 

1  grm.  carbohydrate 

=  4-1      „ 

Careful  experiments  have  shown  that  just  as  there  is  no  loss  of  matter 
in  the  body,  so  also  the  sum  of  the  energies  put  out  by  the  body  is  equal  to 
the  sum  of  the  energy  obtained  by  the  oxidation  of  the  tissues  and  of  the 
food-stuffs  in  the  body  during  the  same  time.  In  an  earlier  chapter  I  have 
quoted  the  results  of  an  experiment  by  Rubner  on  a  dog,  which  demonstrated 
this  equivalence,  as  proving  the  important  fact  that  the  fundamental 
doctrine  of  the  Conservation  of  Energy  applies  to  the  organised  as  to  the 
inanimate  world.  Similar  results  have  been  arrived  at  by  Atwater  in  a 
series  of  experiments  with  a  special  calorimeter  on  man.  It  may  be  sufficient 
here  to  give  the  figures  from  one  such  experiment : 


a 

b 

C 

d 

e 

f 

cr 

0 

h 

i 

Date 

Cals. 

Gals. 

Cals. 

Cals. 

Cals. 

Cals. 

Cals. 

Cals. 

% 

Dec.  9-10  . 

2519 

110 

142 

-85 

+  3 

2349 

2414 

-1-65 

+  2-8 

10-11   . 

2519 

110 

133 

-25 

-44 

2345 

2386 

-f-41 

+  1-7 

11-12  . 

2519 

no 

132 

-21 

-93 

2391 

2413 

+  22 

-t-0-9 

12-13  . 

2519 

110 

1.33 

-14 

-55 

2345 

2375 

-1-30 

4-1-3 

Total  4  days 

10076 

440 

540 

-145 

-189 

9430 

9588 

-f-158 

Average             \ 

one  day  1 

2519 

110 

135 

-3G 

-47 

2357 

2397 

-f-40 

+  1-7 

3 

a  -i- 

^--j 

"o 

o 

J2  ^ 
St3 

O  w 

•a 

§^ 

^    ^ 

r  g 

a 
o 

3 

.a 

a 

8 

a 
o 

1 

-a 
g 

3 

p 

d  licat  of  CO 
protein  gainc 

d    lieat    of 
of  fat  gaine 

°5 

eo  s  ^ 
S       + 

■3  -S  " 

B 

§3 

tc  - 

1? 

=5   a 

i  - 

u 

o  a 

°« 

o 

=3    O  "ot 

S  .2  "S 

a  0 .3 

•3 

^  s 

gS 

t^ 

s-g 

H  a  .2 
5  2^ 

"■S    3    i. 

a  _  -' 

1 

9  "Z  ■ 

If  " 

a  « 

■^^  ° 

w-  = 

.f;  ^  3 

a  °  " 

;^  — 

622  PHYSIOLOGY 

It  we  take  into  account  the  great  difficulties  of  such  an  experiment,  we 
cannot  but  be  impressed  with  the  closeness  of  agreement  between  the  total 
output  of  energy  reckoned  as  heat  and  measured  by  the  warming  of  a  given 
volume  of  water  and  the  total  income  of  energy  as  estimated  from  the  chemi- 
cal reactions  involved  in  the  metabolic  changes  which  had  taken  place  during 
four  days  of  the  experiment.  The  important  result  which  comes  out  in 
such  experiments  is  that  the  food-stuffs  produce  the  same  amount  of  energy 


'  iiijiiiiiiiiiiiiiiiiiiiimiiiiniiiiiiiii 


i 


Double 
Window 


illllllllllllllllllllllllllllllllllllllllll 


vC. 


Calorimeter 
Chamber. 


I    -A, 

i^ — 


mw^^": 


T 


j      CO^       I  f   Water 
'  removed  ' '  removed 

/r L    ''■>'      f 1      ''->' 

poda-Lime  H;S04. 


WatertCOj:  deficient  in  Onygen 

\J 


Air  minus  CO,  and  Water;  deficient  in  Oxyge 


Oxygen  enters.* 

Fig.  319.     Diagram  to  show  the  principle  of  the  Atwatcr  -Benedict  calorimeter. 
(After  Halliburton.) 

when  oxidised  in  the  body  as  when  burnt  to  the  same  end-products  outside 
the  body,  so  that  it  becomes  easy  in  any  given  research  to  sum  accurately  the 
energy  income  of  the  body. 

The  Atwater  calorimeter  has  been  improved  to  such  an  extent  by 
Benedict  and  his  fellow  workers  that  it  has  practically  replaced  all  other  forms 
for  physiological  purposes.  It  consists  of  a  room  or  chamber  with  double 
non-conducting  walls.  All  round  the  inner  wall  of  the  room  are  fitted  coils 
of  pipes  through  which  a  stream  of  water  flows.  The  pipes  are  fitted  with 
discs  so  as  to  take  up  rapidly  heat  produced  in  the  room.  The  current  of 
water  is  accurately  adjusted  so  as  to  maintain  the  temperature  of  the  inner 
wall  constant.  As  the  inner  wall  and  outer  wall  are  kept  at  the  same  tempera- 
ture, no  heat  is  lost  to  the  exterior,  the  whole  of  the  heat  produced  by  the 
animal  or  individual  in  the  chamber  being  communicated  to  the  water 
passing  through  the  chamber.  The  temperatures  of  the  entering  and  leaving 
water  are  taken  by  accurate  thermometers  reading  to  a  hundredth  or  a 
thousandth  of  a  degree  Centigrade.  Knowing  the  amount  of  water  that  has 
passed  through  in  a  given  time  and  the  difference  in  temperature  during  the 
same  time,  it  is  easy  to  calculate  the  amount  of  heat  given  off  by  the  animal 
under  investigation.  It  is  generally  convenient  to  maintain  a  constant 
difference  of  temperature  between  the  entering  and  leaving  water  by  appro- 
priate adjustment  of  the  amount  of  water  passing  through  the  apparatus. 
The  equality  of  temperature  between  the  inner  and  outer  casing  is  recorded 


THE  TOTAL  EXCHANGES  OF  THE  BODY  623 

by  electric  thermo  couples,  any  difference  of  temperature  being  at  once 
compensated  by  electrically  warming  the  cooler  part.  The  chamber  con- 
tains a  bicycle  or  other  arrangement  for  the  performance  of  mechanical 
work.  It  is  adequately  ventilated  by  a  current  of  air  passing  through  an 
apparatus  similar  to  that  of  Benedict,  described  on  p.  617.  It  is  thus  possible 
to  estimate  simultaneously  the  total  heat  production  of  an  individual  as  well 
as  the  respiratory  exchanges,  including  both  carbon  dioxide  output  and 
oxygen  intake.  The  general  principle  of  the  calorimeter  is  shown  in  the 
diagram  (Fig.  319).  The  calorimeter  is  also  supplied  with  bed,  table, 
chair,  &c.,  and  food  can  be  introduced  through  a  double  window  so  that 
an  experiment  may  be  continued  over  two  or  three  days  on  one  and 
the  same  individual. 


SECTION   II 

THE  METABOLISM  DURING  STARVATION 

It  will  tend  to  simplify  our  task  if  we  deal  first  with  the  results  of  the 
experiments  which  have  been  made  on  the  metaboHc  exchanges  of  animals 
during  starvation,  i.e.  dming  a  period  when  the  whole  energy  involved  in  the 
maintenance  of  the  movements  of  respiration  and  circulation,  and  in  the 
maintenance  of  the  body  temperature,    &c.,  is  derived  from  the  animal's 
own  tissues.     It  must  be  remembered  that  the  tissues  of  an  animal  comprise 
two  distinct  classes.     In  the  first  class  must  be  placed  the  Hving  machinery 
of  the  body,  generally  composed  of  proteins  or  their  near  alhes.     In  the 
second  class  are  the  fatty  tissues  of  the  body,  which  form  no  part  of  the 
ordinary  machinery,  but  function  simply  as  a  storehouse  of  material  which 
can  be  utihsed  for  the  production  of  energy.     In  addition  to  the  store  of  fat 
there  is,  in  a  well-fed  animal,  a  certain  reserve  of  carbohydrate  in  the  form 
of  glycogen,  deposited  in  the  liver  and  muscles  of  the  body.     This  store  of 
glycogen  is  drawn  upon  to  a  large  extent  at  the  beginning  of  a  period 
of  starvation.      The  total  amount  of  glycogen  present  at  any  time  is  so 
small  in  comparison  with  the   possible   amount    of   fat    that  it   cannot 
provide  the  energy  necessary  for  the  prolonged  period  during  which  the 
maintenance  of  hfe  is  possible  in  a  complete  state  of  inanition,  although 
it  plays  an  important  part  during  the  first  one  or  two  days  of  a  period 
of  starvation. 

Contrary  to  general  belief,  the  condition  of  an  animal  which  is  completely 
deprived  of  food  is  not  a  painful  one.  For  this  statement  we  have  not  only 
such  evidence  as  can  be  derived  from  inspection  of  animals  placed  in  this 
condition,  but  also  evidence  derived  from  men  who  have  voluntarily  or 
involuntarily  been  deprived  of  food  for  considerable  periods.  Especially 
instructive  in  this  connection  are  the  cases  of  the  so-called  professional 
'  fasting  men,'  two  of  whom,  Succi  and  Cetti,  have  been  subjected  to  complete 
metabohc  investigation  during  the  period  of  their  starvation.  During  the 
first  day  or  two  there  is  a  craving  for  food  at  meal-times.  This,  however, 
passes  off,  and  during  the  later  portions  of  the  experiment  even  the  desire  for 
food  may  be  entirely  absent.  As  might  be  expected,  the  restriction  of  food 
is  followed  by  a  diminution  in  the  amount  of  water  required  by  the  animal. 
The  essential  characteristic  of  the  state  of  inanition  is  an  ever-increasing 
weakness,  accompanied  by  a  strong  disinclination  to  undertake  any  mental 
or  physical  exertion  whatsoever.     The  animal  passes  its  time  in  a  state  of 

624 


THE  METABOLISM  DLHING  STARVATION 


625 


sleep  or  semi-stupor.  In  the  case  of  Succi,  who  fasted  for  thirty  days, 
considerable  muscular  exertion  was  undertaken  on  the  twelfth  and  on  the 
twenty-third  day  of  starvation  without  any  appreciable  ill-effects.  A  strong 
effort  of  the  will  must  have  been  necessary  in  his  case  to  overcome  the  auto- 
matic instinct  to  preservation  of  life  by  the  utmost  economy  in  the  expendi- 
ture of  energy.  The  pulse-rate  and  the  body  temperature  remain  nearly 
normal  until  a  few  days  before  death,  which  is  ushered  in  by  an  increase  in 
the  somnolent  condition  of  the  animal  and  by  a  gi-adual  slowing  of  respiration 
and  fall  of  temperature.  The  urine  is  naturally  diminished  with  diminution 
in  the  output  of  urea  and  in  the  amount  of  water  consumed.  Some  faeces 
are  formed,  and  may  be  voided  during  or  at  the  close  of  the  starvation 
period.  In  Succi  their  amount  varied  from  9-5  to  22  grm.  a  day  and 
contained  from  0-3  to  1-0  grm.  nitrogen.  On  microscopic  examination 
they  consisted  of  an  amorphous  material  enclosing  a  number  of  crystals  of 
fatty  acids. 

During  the  whole  of  the  starvation  period  energy  is  being  used  up  in  the 
body  for  the  maintenance  of  its  temperature  and  the  Aatal  movements  of 
respiration  and  circulation.  Since  this  energy  is  derived  from  the  destruction 
and  oxidation  of  the  tissues  of  the  body,  it  is  evident  that  starvation  must 
be  associated  with  a  constant  and  steady  loss  of  body  weight.  In  experiments 
on  man  the  daily  loss  of  weight  during  the  first  ten  days  amounts  to  between 
1  and  1  -5  per  cent,  of  the  original  total  weight.  This  loss  of  weight  does  not 
affect  all  parts  of  the  body  alike.  It  might  be  imagined  that,  since  the  loss 
of  weight  is  determined  by  the  using  up  of  the  tissues  of  the  body  for  the 
production  of  energy,  those  organs  which  are  most  active  should  show  also 
the  greatest  loss  of  weight.  The  very  reverse  of  this  is  the  case,  as  will  be 
seen  from  the  following  Table  : 


Percentage  Loss  of  Weight  of  Different  Organs  and  Tissues  during 

Starvation.     (Voit.) 


Ti?=ue 

Percentage  loss 

of  weight  of  fresh 

tissue 

Percentage  loss 
of  dry  tissue 

Fat 

97 

Spleen 

67 

G3 

Liver  . 

54 

57 

Testes 

4(1 

— 

Muscles 

31 

30 

Blood 

27 

IS 

Kidneys 

20 

21 

Skin  and  lia 

rs 

21 

— • 

Intestineii 

IS 

— 

Lungs 

18 

19 

Pancreas 

17 

— 

Heart 

3 

— 

Brain  and  spinal  cord 

3 

0 

626  PHYSIOLOGY 

Those  organs  of  the  body  which  are  most  necessary  for  the  maintenance 
of  hfe,  the  brain,  the  heart,  the  respiratory  muscles,  such  as  the  diaphragm, 
undergo  very  httle  loss  of  weight.  Of  the  other  tissues  the  fat,  which  is  a 
mere  reserve  to  provide  for  such  contingencies,  is  drawn  upon  first,  and 
during  starvation  97  per  cent,  of  the  total  fat  of  the  body  may  be  consumed. 
The  nitrogen  needs  of  the  body  during  starvation  seem  to  be  supphed  chiefly 
at  the  expense  of  the  muscles  and  glands,  which  waste  to  a  very  marked 
degree.  The  muscles  being  used  simply  as  reserve  material,  it  is  easy  to 
understand  the  condition  of  lethargy  and  muscular  inactivity  which  charac- 
terises the  state  of  inanition.  During  starvation  all  tissues  of  the  body 
undergo  a  process  of  autolysis  or  disintegration,  giving  up  the  products  of 
this  process  to  the  common  circulating  fluid.  The  nutritional  demands  of 
a  tissue  are  determined  by  its  activity.  Hence  the  active  tissues  of  the 
body  take  up  the  material  set  free  from  all  the  other  cells  of  the  body  and  so 
maintain  their  weight  at  the  expense  of  all  other  parts.  A  similar  pre- 
dominance of  the  nutrition  of  active  over  inactive  tissues  is  to  be  observed 
in  cases  of  partial  starvation,  i.e.  where  the  deprivation  of  food  only  applies 
to  a  single  food  constituent.  Thus  Voit,  in  a  series  of  experiments,  fed 
pigeons  on  a  food  which,  while  normal  in  all  other  respects,  contained  a 
deficiency  of  calcium  salts.  On  kilhng  the  birds  after  a  certain  length  of  time, 
it  was  found  that  while  the  bones  used  in  the  necessary  movements  of  the 
animals  presented  a  normal  appearance,  the  others,  such  as  the  sternum  and 
skull,  showed  a  marked  deficiency  of  lime  salts  and  had  undergone  a  process 
of  rarefaction  giving  rise  to  the  condition  known  by  pathologists  as  osteo- 
porosis. Many  other  instances  of  the  sacrifice  of  a  temporarily  useless  tissue 
on  behalf  of  tissue  of  high  physiological  value  are  known.  Thus  the  salmon 
and  its  congeners,  which  five  part  of  the  year  in  the  sea,  lay  their  eggs  and 
undergo  their  early  development  in  the  fresh  water  of  the  upper  reaches  of 
rapid  streams.  An  adult  salmon  leaves  the  sea  in  the  early  summer  months 
in  a  magnificent  state  of  muscular  development,  fit  to  perform  the  prodigious 
feats  of  swimming  which  are  required  in  order  to  get  it  over  the  rapids 
of  the  river  which  it  has  to  ascend.  It  takes  no  food.  In  the  upper 
reaches  of  the  stream  or  river  there  is  a  growth  of  the  genital  glands, 
ovaries,  or  testes.  The  whole  material  for  the  growth  of  these  large  organs 
is  derived  from  the  atrophy  of  the  skeletal  muscles.  In  this  case  we 
have  the  growth  of  an  active  tissue  at  the  cost  of  an  inactive  one,  the 
activity,  however,  being  determined,  not  by  the  direct  call  upon  it  from 
the  environment,  but  by  what  we  may  speak  of  as  the  '  physiological 
habit '  of  the  animal. 

The  animal  organism,  in  the  complete  absence  of  food,  deals  with  the 
resources  of  its  bodily  tissues  with  the  utmost  possible  economy.  The  total 
metabolism  therefore  sinks  rapidly  during  the  first  two  days  of  starvation, 
and  then  remains  practically  constant.  There  is  indeed  a  shght  continuous 
diminution  with  the  fall  in  body  weight,  but  if  we  reckon  out  the  total 
metabohsm  per  kilo  body  weight,  we  find  that  till  within  a  day  or  two  before 
death  it  is  a  constant  quantity.     This  fact  is  shown  in  the  following  Table  of 


THE  METABOLISM  DURING  STARVATION  627 

the  output  of  energy  in  man  during  a  five    days'  period  of  starvation 
(Tigerstedt)  : 

Metabolism  durdjg  Starvation  (]VIa>-) 


Day  of  experiment 

Xitrogen  output 

Fat  oxydised 

Total  calories 

Calories  per  kilo 
body  weight 

1         .            .            . 

12-16 

2U4-8 

2231 

33-3 

2       .         .         . 

12-85 

190-3 

2112 

32-1 

3       .         .         . 

13 -02 

179-9 

2032 

31-3 

4       .          .          . 

13-67 

176-4 

2003 

31-3 

5       .          .          . 

11-44 

180-0 

1979 

31-4 

Although  in  one  and  the  same  individual  the  total  metabolism  during 
hunger  varies  directly  with  the  body  weight,  this  rule  does  not  apply  when 
we  compare  the  metabolism  of  different  animals  or  different  examples  of 
the  same  species.  We  find,  in  fact,  that  in  larger  animals  the  metabolism 
is  relatively  less  than  in  smaller  animals,  so  that  if  we  take  the  evolution 
of  calories  per  kilo  body  weight  the  result  is  inversely  proportional  to  the 
body  weight.  This  is  shown  in  the  following  Table,  which  represents  the 
total  metabolism  of  a  number  of  animals  of  diff'erent  sizes  (Rubner)  : 


Body  weight, 

Calories  per  kilo 

klos 

body  weight 

Man 

70-6 

32-9 

Dogl       . 

30-4 

35-3 

Dog  2       . 

17-7 

45-0 

Dog  3       . 

3-1 

85-3 

Rabbit  1 

2-9 

50-2 

Rabbit  2 

2-05 

58-5 

Guinea  pig 

0-672 

223-1 

On  account  of  the  gi-eater  relative  metabolism  of  smaller  animals,  their 
resistance  to  starvation  is  less  than  that  of  larger  animals.  A  rat  or  a  mouse 
will  only  stand  total  abstinence  from  food  for  two  or  three  days.  The  differ- 
ence is  determined  by  the  fact  that  a  smaller  animal  has  a  relatively  larger 
surface  per  unit  body  weight  than  is  the  case  with  a  larger  animal.  The 
greater  part  of  the  energy  set  free  during  starvation  is  required  for  the  main- 
tenance of  the  body  temperature.  A  larger  amount  of  energy  per  kilo  is 
required  in  those  animals  with  a  relatively  larger  body  surface  through  which 
heat  loss  may  occur.  That  the  difference  in  relative  surface  is  the  deter- 
mining factor  for  the  differences  in  total  metabolism  per  kilo  body  weight 
is  shown  by  the  fact  that,  if  we  reckon  out  the  amount  of  surface  presented 
by  each  of  the  animals  in  the  above  list,  we  find  that  the  output  of 
energy  per  square  metre  of  body  surface  is  approximately  identical  in 
all  cases.      This  is  shown  in  the  following  Table,  in  which  the  calorie 


628 


PHYSIOLOGY 


output  per  square  metre  of  surface  has  been  reckoned  for  a  number  of 
animals  of  different  weight : 


Body  weight 

Calories  per  square 
metre  body  surface 

Animal  1 
2 
'„      3 
„       4 
„       5 
„       6 
„      7 

30-40 
23-70 
19-20 
17-70 
10-90 
6-45 
3-10 

977 
1069 
1135 
1040 
1109 
1054 
1091 

Speaking  roughly,  we  may  say  that  a  warm-blooded  animal  during 
starvation  requires  the  daily  expenditure  of  1000  calories  per  square  metre 
body  surface  in  order  to  maintain  its  temperature  and  carry  out  such  motor 
processes  as  are  essential  to  life. 


THE  METABOLISM  OF  CARBOHYDRATE,   FAT,   AND 
PROTEIN   DURING  STARVATION 

Since  during  starvation  no  energy  is  supplied  to  the  body  from  without 
in  the  shape  of  food-stuffs,  we  can  regard  the  whole  expenditure  of  the 
animal  during  its  period  of  starvation  as  occurring  at  the  expense  of  its 
capital.  The  amount  of  carbohydrate  which  can  be  stored  up  as  glycogen  or 
other  forms  is  strictly  limited.  In  many  experiments  the  glycogen  meta- 
bolism has  therefore  been  entirely  disregarded,  and  it  has  been  estimated  that 
the  chemical  capital  of  the  body  consisted  entirely  of  proteins  and  fats. 
The  glycogen  metabolism,  however,  during  the  first  day  of  a  period  of  starva- 
tion may  form  a  considerable  fraction  of  the  total  metabohsm  of  the  body, 
and  can  hardly  be  excluded  without  introducing  serious  errors.  The 
relative  parts  played  by  protein,  carbohydrate,  and  fat  respectively  in  the 
chemical  exchanges  of  a  starving  animal  may  be  determined  in  the  following 
way  :  The  amount  of  protein  consumed  is  given  by  estimating  the  total  nitro- 
gen of  the  excreta  by  Kjeldahl's  method  and  multiplying  the  result  by  the 
factor  6-25.  The  loss  of  weight  of  the  body  minus  the  protein  consumed  may 
be  roughly  taken  as  equivalent  to  the  fat  plus  carbohydrate  consumption. 
But  this  is  only  a  rough  method,  since  the  quantity  of  water  in  the  tissues 
may  undergo  considerable  variations,  and  so  affect  the  total  weight  of  the 
body.  For  any  accurate  results  the  respiratory  exchanges  must  be  measured 
including  both  oxygen  intake  and  carbon  dioxide  output.  After  deducting 
the  carbon  dioxide  due  to  the  combustion  of  the  carbon  of  the  proteins  which 
does  not  appear  in  the  urine  in  combination  with  nitrogen,  the  remainder  of 
the  carbon  dioxide  is  derived  entirely  from  carbohydrate  and  fat  metabolism. 
Knowing  the  respiratory  quotient  and  the  total  amount  of  carbohydrate  and 
fat  metabolism,  it  is  possible  to  come  to  a  conclusion  as  to  how  much  of  the 


THE  METABOLISM  DURING  STARVATION 


629 


carbon  dioxide  is  derived  from  oxidation  of  glycogen  and  how  much  from  the 
oxidation  of  fat.  A  very  efficient  check  on  this  calculation  is  furnished 
if  the  individual  or  animal  can  be  placed  at  the  same  time  in  an  accurate 
calorimeter,  as  in  Benedict's  experiments,  o^^dng  to  the  fact  that  a  gramme 
of  fat  when  converted  into  carbon  dioxide  and  water  produces  more  than 
double  the  amount  of  heat  which  would  be  evolved  by  the  complete  oxidation 
of  glycogen.  In  Benedict's  experiments  the  heat- value  of  the  metaboUsm 
calculated  by  the  above  method  agreed  with  the  heat  as  actually  measured 
by  the  calorimeter  within  0-5  per  cent.,  whereas  if  the  total  carbon  of  the 
first  day  had  been  reckoned  as  fat,  the  discrepancy  would  have  been  as  high 
as  5  per  cent,  in  many  cases.  The  influence  of  glycogen  metaboHsm  on  that 
of  protein  during  the  first  and  second  days  of  fasting  is  shown  in  the  following 
experiments  (Benedict)  : 


First  day 

Second  day 

Glj'cogcn  metabolised 

X. 

eliminated 

Glycogen  metabolised 

X. 

eliminated 

Total 

Per  kilo 

Total 

Per  kilo 

S.A.B. 
S.A.B. 
S.A.B. 
H.C.K. 
H.R.D. 

181-6 
135-3 

64-9 
165-6 

32-8 

3-15 
2-31 
1-09 
2 -.33 

0-59 

5-84 
10-29 
12-24 

9-39 
13-25 

29-7 
18-1 
23-1 
44-7 
41-6 

0-52 
0-31 
0-39 
0-64 
0-76 

11-04 
11-97 
12-45 
14-36 
13-53 

The  total  metabolism  per  kilo  body  weight  very  soon  attains  a  constant 
level.  The  relative  part  taken  in  the  production  of  the  total  energy  by  fats 
and  proteins  respectively  may  vary  from  animal  to  animal  according  to  the 
amount  of  fat  available  in  the  body.  If  the  animal  has  been  receiving 
previous  to  the  experiment  a  diet  rich  in  protein  the  excretion  of  nitrogen 
and  urea  in  the  urine  diminishes  rapidly  during  the  first  days  of  starvation. 
During  the  first  two  days  therefore  a  considerable  proportion  of  the  necessary 
energy  is  obtained  at  the  expense  of  protein.  Between  the  third  and 
fifth  day,  however,  the  nitrogenous  excretion  reaches  a  minimum,  at  which 
point  it  remains  approximately  constant  to  within  a  day  or  two  before  death. 
If  the  animal  has  been  receiving  a  diet  very  poor  in  protein  the  excretion 
of  nitrogen  may  be  low  throughout  the  whole  course  of  the  experiment. 
These  facts  are  illustrated  by  the  curves  in  Fig.  320,  which  show  the  output 
of  urea  in  three  experiments  on  a  dog  under  different  conditions  of  nutrition. 
In  the  first  experiment  the  dog,  before  the  experimental  period,  had  been 
receiving  25(30  grm.  of  meat  daily  ;  in  the  second  it  had  been  receiving 
1500  grm.  of  meat,  and  in  the  third  only  a  small  quantity,  which  was  not 
accurately  measured.  Although  there  is  a  great  difference  between  the 
urea  output  during  the  first  day  of  the  experiments,  the  urea  output  during 
the  sixth  to  eighth  davs  is  identical.     In  many  cases  for  a  few  davs  before 


630 


PHYSIOLOGY 


death  there  is  a  rise  of  protein  metabolism.  This  rise  is  synchronous  with  a 
practically  complete  disappearance  of  fat  from  the  body.  The  animal  now 
has  to  supply  all  its  requirements  at  the  expense  of  the  protein  tissues,  which 


.ol 


CM, 
UREA 


Fig.  320.     Three  experiments  on  the  output  of  urea   during  starvation  (dog). 
(TiGERSTEDT  after  VoiT.) 
In  (1)  (thin  line),  the  dog  received  2500  grm.  meat  per  day  before  the  ex- 
periment ;  in  (2)  (thick  line),  the  diet  was  1500  grm.  meat ;  and  in  the  third 
experiment  the  meat  was  reduced  to  a  minimum. 

therefore  waste  rapidly  and  account  for  the  increased  excretion  of  nitrogen. 
This  is  shown  in  the  following  experiment  of  Rubner  on  a  rabbit : 


Days 
1-3 
4-5 
6-8 


Average  daily  out- 
put of  nitrogen 

1-67  grm. 
.        1-46      „ 
.       3-21      ., 


Average  amount  of 
fat  oxidised  daily 

lC-3  grm. 
10-3     „ 
2-4     „ 


We  see  therefore  that  during  starvation,  apart  from  the  first  day  or  two, 
the  animal  derives  the  main  portion  of  its  necessary  energy  from  the  com- 
bustion of  fats,  provided  that  there  is  a  sufficient  store  of  these  substances  in 
the  body.  A  certain  consumption  of  protein  is  unavoidable.  Since  protein 
comes  from  the  working  tissues  of  the  body  they  are  spared  so  far  as  possible, 
and  it  is  only  when  the  stored  fat  is  used  up  that  any  large  call  is  made  on 
the  tissue-protein. 


SECTION  III 

THE   EFFECT   OF  FOOD   ON  THE   METABOLISM 
OF  THE  BODY 

A  MARKED  contrast  exists  between  protein  and  the  other  two  classes  of 
food-stuffs  in  relation  to  nutrition.  Whereas  it  is  possible  in  the  case  of 
many  animals  to  maintain  life  with  a  diet  consisting  of  proteins,  salts,  and 
water,  such  as  is  contained  in  the  leanest  possible  meat,  a  diet  of  pure  fat 
or  carbohydrate,  or  a  mixture  of  the  two,  is  almost  equivalent  to  an  absolute 
abstinence  from  food,  the  animal  on  such  a  diet  surviving  only  a  few  days 
longer  than  during  complete  starvation.  The  primary  importance  of  pro- 
teins in  nutrition  therefore  indicates  that  it  is  advisable  to  deal  first  with 
the  effects  on  metabolism  of  a  diet  consisting  of  this  food-stuff  alone.  In  an 
animal  which  has  been  starved  for  five  or  six  days  the  nitrogenous  output  of 
the  body  has  attained  a  practically  constant  level,  varying  with  the  size 
of  the  animal  and  with  the  relative  content  of  its  body  in  fat.  Let  us  assume 
that  such  an  animal  is  excreting  5  grm.  of  nitrogen  daily,  corresponding  to  a 
protein  metabohsm  of  31-25  grm.  of  protein.  It  might  be  thought  that 
this  loss  of  protein  to  the  body  would  be  met  if  we  administered  to  the  animal 
as  food  a  similar  amount,  i.e.  31-25  grm.  of  protein.  On  trying  the  ex- 
periment, however,  we  find  the  effect  of  giving  protein  food  is  to  increase 
largely  the  nitrogenous  output  of  the  body,  so  that  after  receiving  this  amount 
of  protein  the  animal's  nitrogenous  excretion  will  amount  to  nearly  10  grm. 
The  waste  of  tissue-protein  in  the  body  therefore  proceeds.  In  order  to  stop 
this  waste,  i.e.  to  ensure  that  the  animal  does  not  lose  more  nitrogen  than  it 
receives  in  its  food,  we  must  give  an  amount  of  protein  corresponding  to  be- 
tween two  and  a  half  and  five  times  the  amount  of  protein  which  undergoes 
disintegration  during  starvation.  The  reason  for  this  is  obvious  on  reference 
to  p.  G27.  There  we  see  that  a  man  on  the  fifth  day  of  starvation  excreted 
11-44  grm.  of  nitrogen,  corresponding  to  71-5  grm.  of  protein.  This  protein 
metabolism  did  not,  however,  represent  the  sole  source  of  the  energv  output 
of  the  body.  The  total  energy  output  was  1979  calories.  Of  this  amount 
only  293  calories  could  be  obtained  from  the  combustion  of  the  71  grm.  of 
protein,  the  balance  being  due  to  the  oxidation  of  fat  stored  up  in  the  body. 
This  signifies  that  only  one-fifth  of  the  total  energy  requirements  of  the  body 
were  suppHed  at  the  expense  of  protein.  We  cannot  therefore  expect  to 
stop  loss  of  bcxly  substance  by  giving  an  amount  of  protein  food  which  would 
correspond  only  to  one-fifth  of  the  energy  requirements.     lu  most  cases, 

G31 


632  PHYSIOLOGY 

if  we  are  dealing  with  an  animal  with  a  considerable  store  of  fat  in  its  body, 
nitrogenous  equilibrium,  i.e.  an  equivalence  between  income  and  output 
of  nitrogen,  is  attained  with  a  quantity  of  protein  in  the  food  which  is  less 
than  five  times  the  amount  lost  during  starvation.  In  such  a  case  the 
total  energy  requirements  of  the  body  are  met  not  only  at  the  expense  of 
the  protein  food  but  also  at  the  expense  of  the  fat  of  the  tissues.  The  animal 
will  continue  to  lose  weight  and  to  become  thin,  although  he  is  in  a  state  of 
nitrogenous  equihbrium. 

The  protein  taken  in  with  the  food  on  a  pure  protein  diet  has  a  twofold 
function  to  perform.     In  the  first  place,  every  functional  activity  of  the 
living  tissues  is  probably  associated  with  a  certain  amount  of  wear  and  tear, 
and  results  in  the  production  of  disintegration  products  which  are  not  in  a 
condition  to  be  resynthetised  into  living  working  protoplasm.     We  know, 
for  instance,  that  from  every  mucous  surface  dead  cells  are  being  continually 
cast  off  and  that  a  constant  disintegration  of  red  blood  corpuscles  goes  on, 
resulting  in  the  production  of  the  bile  pigments  ;   and  we  are  warranted  in 
extending  the  operation  of  these  changes  of  which  we  have  ocular  evidence 
to  the  case  of  other  cells,  such  as  those  of  the  liver  and  of  the  muscles, 
where  direct  proof  of  destruction  of    tissue    during    normal  metabolism 
is   more    difiicult  to   obtain.     It   is    certain   that    some   portion    of   the 
nitrogen  excreted  during  complete  starvation  must  come  from  this  source, 
and  that  one  of  the  functions  of  protein  food  is  the  replacement  of  tissue 
which  has  been  lost  in  this  way.     When,  however,  we  are  feeding  an  animal 
on  a  pure  protein  diet,  by  far  the  larger  portion  of  the  food  is  utihsed  for 
meeting  the  energy  requirements  of  the  body.     In  this  function  protein  food, 
apart  from  accidents  of  digestibility  and  structural  adaptation  of  the  animal's 
digestive  arrangements  to  its  habits  of  fife,  presents  no  apparent  advantages 
over  the  other  two  classes  of  food-stuffs.     Its  value  to  the  animal  is  repre- 
sented by  its  physiological  heat- value.     It  may  be  represented  therefore 
numerically  as  4-1,  and  is  equivalent  to  the  value  of  carbohydrate  *  and  is 
far  inferior  to  the  value  of  fats  with  a  heat  equivalent  of  9-3.     If,  instead  of 
giving  to  the  starving  animal  a  pure  protein  diet,  we  administer  a  mixed  diet 
containing  a  sufficient  quantity  of  fat  or  carbohydrate,  or  of  both  substances, 
to  meet  the  normal  energy  requirements  of  the  body,  we  can  restrict  the 
utilisation  of  protein  more  nearly  to  the  replacement  of  tissue  waste  in  the 
body,  and  are  therefore  able  to  attain  nitrogenous  equihbrium  with  a  much 
smaller  proportion  of  protein  than  is  possible  when  this  substance  furnishes 
the  whole  diet.     In  carnivora,  which  have  the  habit  of  supplying  a  large 
proportion  of  their  energy  needs  at  the  expense  of  protein,  the  amount  of 
carbohydrate  and  fat  which  must  be  added  to  protein  in  order  to  attain  nitro- 
genous equihbrium  with  a  nitrogenous  output  equal  to  that  in  starvation  is 
very  large  and  corresponds  to  an  energy- value  in  excess  of  the  total  energy 
expenditure  during  starvation.     In  omnivora,  such  as  man,  it  is  easy  to  attain 
nitrogenous  equilibrium  on  a  mixed  diet  with  a  smaller  nitrogen  turnover 

*  This  may  be  expressed  by  saying  that  protein  is  isodynamic  with  an  equal  weight 
of  carbohydrate. 


THE  EFFECT  OF  FOOD  ON  METABOLISM 


633 


than  is  found  during  starvation.  In  the  experiment  given  on  p.  627  the 
average  nitrogen  output  during  starvation  was  about  12  grm.  of  nitrogen. 
In  Succi,  the  fasting  man,  the  nitrogen  output  varied  from  11-19  grm.  on  the 
fifth  day  to  2  -82  grm.  on  the  twenty-first  day. 

Daily  Nitrogen  Excretion  of  Succi  in  Starvation 


Day 

N. 

Day 

N. 

Day 

N. 

1 

17-0 

8     . 

9-74 

15       . 

505 

2       . 

11-2 

9     . 

10-05 

16       . 

4-32 

3       . 

10-55 

10     . 

7-12 

17        . 

5-4 

4 

10-8 

11      . 

6-23 

18       . 

3-6 

5       . 

1119 

12      .       •  . 

6-84 

19 

5-7 

6       . 

1101 

13     . 

5-14 

20       . 

3-3 

7 

8-79 

14     . 

4-66 

21 

2-82 

Chittenden  has  shown  that  in  man  a  perfectly  normal  nutrition  may  be 
maintained  on  a  mixed  diet  containing  about  7  grm.  of  nitrogen  daily. 
In  the  cases  investigated  by  Chittenden  the  energy  output  of  the  men  could 
be  regarded  as  normal,  corresponding  to  32-35  calories  per  kilo  body  weight. 
If  the  amount  of  fat  and  carbohydrate  be  very  largely  increased  it  is  possible 
to  maintain  nitrogenous  equilibrium  on  even  smaller  quantities  of  protein. 
Thus  nitrogenous  equilibrium  was  attained  by  Siven  on  a  diet  containing 
33  grm.  of  protein  daily  (=  5  grm.  of  nitrogen),  but  in  this  case  the  carbo- 
hydrates and  fats  were  increased  to  such  an  extent  that  the  man  was  taking 
in  78-5  calories  per  kilo  per  day.  These  results  suggest  that  the  quahtative 
metabolism  of  the  body  is  determined  by  the  relative  amount  of  food-stuff 
supplied  to  the  body  and  circulating  in  its  juices  at  any  given  time,  and  that 
preponderance  of  one  food-stuff  will  tend  to  excite  the  cells  of  the  body  to 
the  utilisation  of  this  food-stuff  at  the  expense  of  the  other  two.  That  such 
is  the  case  is  shown  by  a  study  of  the  effect  of  increasing  each  class  of  food  on 
the  metabolism  of  the  body  as  a  whole. 


EFFECTS  OF  VARIATIONS  IN  PROTEIN 
Most  of  the  experiments  on  the  influence  of  variations  in  the  quantity 
of  protein  food  have  been  made  on  carnivora,  such  as  the  dog  and  cat.  Within 
very  wide  limits  the  output  of  nitrogen  is  proportional  to  the  intake.  This 
is  shown  in  the  Tables  (p.  634)  by  Voit,  representing  two  experiments  on 
dogs. 

In  Experiment  I  the  animal  had  been  fed  for  some  days  with  500  grm.  of 
meat  per  diem.  The  fact  that  he  was  excreting  nitrogen  corresponding  to 
547  grm.  shows  that  this  amount  was  insufficient  and  that  he  was  not  yet  in 
a  condition  of  nitrogenous  equilibrium.  Each  day  he  was  using  up  47  grm. 
of  the  protein  of  his  body  in  addition  to  the  500  grm.  supplied  in  the  food. 
On  increasing  his  food  three-fold  to  1500  grm.  the  nitrogenous  output  was 
also  increased,  but  a  state  of  nitrogenous  equilibrium  was  not  reached  until 
the  eighth  day  of  the  experiment.  During  the  six  days  intervening  778  grm. 
of  meat  had  been  retained  in  the  body,  i.e.  there  had  been  a  retention  of 


634 


PHYSIOLOGY 


protein,  probably  in  the  form  of  increased  muscular  substance.  The  amount 
is  too  great  to  be  accounted  for  by  retention  of  the  disintegration  products  of 
the  protein  in  the  body.  It  must  have  been  stored  up  in  the  form  of  protein 
and  probably,  to  a  large  extent  at  any  rate,  as  actual  living  tissue. 


Experiment  I 

EXPERIMENT  II 

Day 

Daily  meat 
ration 

riesl)  loss 
per  day 

Day 

Daily  me^t 
ration 

Flesh  loss 
per  day 

1  . 

2  . 

3  . 

4  . 

5  . 

6  . 

7  . 

8  . 

500 
1500 
1500 
1500 
1500 
1500 
1500 
1500 

547 
1222 
1310 
1390 
1410 
1440 
1450 
1500 

1.  . 

2 

3  . 

4  .          . 

5  . 

6  . 

1500 
1000 
1000 
1000 
1000 
1000 

1500 
1153 
1086 
1088 
1080 
1027 

In  the  second  experiment  the  diminution  of  the  protein  of  the  food  was 
followed  by  a  loss  of  protein  from  the  body,  the  output  being  greater  than 
the  income.  The  excess,  however,  was  rapidly  diminishing  and  equilibrium 
had  been  practically  attained  on  the  last  day  of  the  experiment.  During  this 
time  the  animal  had  excreted  14-8  grm.  of  nitrogen  more  than  it  had  received 
in  its  food,  which  would  correspond  to  a  diminution  of  the  protein  store  of  its 
body,  reckoned  as  muscular  substance,  by  434  grm.  Many  such  experiments 
have  been  performed,  and  they  all  agree  in  showing  that  in  carnivora  a  very 
appreciable  storage  of  nitrogen  can  take  place  in  the  body.  In  cats  it  is 
sometimes  possible  to  double  the  body  weight  by  administration  of  a  large 
protein  diet.  Since  no  fat  is  laid  on  at  the  same  time  and  the  animals  are  in 
a  fine  healthy  condition,  one  must  conclude  that  the  greater  portion  of  the 
storage  takes  place  by  a  growth  of  muscle  substance.  The  degree  to  which 
the  storage  can  take  place  is,  however,  variable  and  is  generally  smaller  in 
dogs  than  in  cats.  However  much  protein  is  given,  the  limit  is  finally  arrived 
at  where  no  further  laying  on  of  protein  tissues  of  the  body  is  possible,  and  the 
animal  then  enters  into  a  state  of  nitrogenous  equihbrium,  when  he  excretes 
a  quantity  of  nitrogen  exactly  equal  to  that  taken  in.  This  equivalence  of 
income  and  output  signifies  that  the  extent  of  the  total  metabolism  of  the 
body  is  affected  by  the  amount  of  protein  supplied  in  the  food,  and,  as  a 
matter  of  fact,  the  total  energy  output  of  the  body  rises  and  falls  with  the 
quantity  of  protein  in  the  food.  This  is  shown  in  the  Table  (p.  635)  by 
Pettenkofer  and  Voit,  in  which  the  figures  have  been  recalculated  by 
Pfliiger. 

We  see  therefore  that  carnivorous  animals  can  satisfy  their  total  energy 
requirements  at  the  expense  of  protein.  When  the  protein  income  is  in 
excesss  of  their  requirements  a  small  amount  is  laid  on,  probably  in  the  shape 
of  increased  muscular  tissue.     The  most  marked  effect  is,   however,   an 


THE  EFFECT  OF  FOOD  ON  METABOLISM 


635 


increased  metabolism  which  rises  in  proportion  to  the  nitrogenous  income. 
The  hmit  to  this  increase  is  set  by  the  powers  of  the  alimentary  canal  to 
digest  the  protein.  The  rise  in  metabolism  consequent  on  protein  food  is 
very  rapid  and  afi'ects  the  gaseous  exchanges  as  well  as  the  output  of  nitrogen. 
Magnus  Le\y  and  Falk  found  that  a  large  protein  meal  might  increase  the 
respiratory  exchanges  40  per  cent.,  an  increase  which  lasted  seven  hours. 


Xitrogcnin  food 

Nitrogen  output 

Fat  gain  or  loss 

Total  calorics 

1 

0 

5-61 

-98 

1067 

2       . 

17 

20-37 

-61 

1106 

3       , 

34 

36-69 

-43 

1360 

4 

51 

51-00 

-24 

1552 

5 

61 

59-74 

-36 

1893 

6       . 

68 

69-50 

+   8 

1741 

7       . 

85 

85-41 

+   4 

2181 

The  nitrogenous  output  also  rises  immediately  after  a  protein  meal,  so  that 
50  per  cent,  of  the  nitrogen  of  the  ingesta  may  appear  in  the  urine  within 
seven  hours  after  the  meal. 

The  whole  of  these  results  cannot  be  strictly  applied  to  omnivorous 
animals,  such  as  man.  In  these  it  is  impossible  to  supply  all  the  energy 
requirements  of  the  body  on  a  pure  protein  diet.  Even  if  a  man  eats  as 
much  meat  as  he  can,  he  will  be  unable  to  obtain  sufficient  energy  for  his 
daily  requirements.  Whereas  the  average  daily  requirements  of  a  man 
amount  to  about  3000  calories,  1  lb.  of  meat  would  yield  only  about  400 
calories,  and  even  if  he  took  4  lb.  of  meat  daily,  an  amount  which  is  im- 
possible for  most  individuals,  he  would  only  be  obtaining  about  1600  calories. 
The  cures  for  obesity,  in  which  a  large  protein  diet  plays  an  important  part, 
owe  their  efficiency  to  this  fact.  They  are  in  all  cases  practically  equivalent 
to  a  state  of  semi-starvation.  Many  experiments  have  been  made  on  the 
influence  of  variations  in  the  quantity  of  protein  in  a  mixed  diet.  Within 
wide  limits  the  output  of  nitrogen  is  strictly  proportional  to  the  intake. 
A  normal  adult  man  seems  to  be  unable  to  store  up  protein  in  any  form,  and 
differs  in  this  respect  from  carnivora,  such  as  the  dog  or  cat.  The  only  way 
in  which  protein  can  be  laid  on  in  the  body  is  by  furnishing  a  physiological 
stimulus  to  the  growth  of  muscle,  i.e.  by  constant  exercise.  Without  this  it 
is  not  possible  to  produce  growth  of  the  muscles  of  the  body,  however  much 
protein  we  may  give  in  the  diet.  The  conditions  are,  however,  different 
when  dealing  with  an  individual  in  whom  from  some  cause  or  other  the 
muscular  tissues  have  not  attained  their  full  development.  Thus  in  growing 
individuals  a  certain  amount  of  the  protein  of  the  food  is  always  retained  in 
the  body  and  laid  on  as  tissue-protein.  In  convalescence  after  severe  fever, 
during  which  a  great  wasting  of  the  muscles  has  taken  place,  forced  feeding 
with  large  amounts  of  protein  has  been  found  to  give  rise  to  a  considerable 
retention  of  protein  in  the  body.  This  process  only  goes  on  until  the  muscles 
have  attained  their  normal  condition  of  development.     When  the  tissues 


636  PHYSIOLOGY 

have,  so  to  speak,  reached  '  par,'  the  possibihty  of  laying  on  protein  tissues 
ceases.  On  the  other  hand,  protein  food  has  in  man,  as  in  animals,  a  specific 
stimulating  effect  on  metabolism,  so  that  the  respiratory  exchanges  are 
largely  increased  as  a  result  of  a  heavy  protein  meal.  This  effect  has  been 
named  by  Rubner  the  '  specific  dynamic  effect '  of  protein.  We  shall  have 
occasion  later  to  discuss  its  significance. 

THE  INFLUENCE  OF  FATS   AND  CARBOHYDRATES 

If  either  fats  or  carbohydrates  be  given  to  a  starving  animal  a  certain 
sparing  of  the  fat  of  the  body  takes  place,  but  this  effect,  according  to  some 
observers,  is  accompanied  by  a  distinct  increase  in  the  metabolic  exchanges 
of  the  body.  As  regards  the  protein  metabolism,  Cathcart  finds  that  while 
administration  of  fat  increases  the  nitrogen  output  during  starvation, 
carbohydrate  food  causes  a  diminution  in  the  nitrogen  output,  and  thus 
exercises  a  marked  sparing  effect  on  the  proteins  of  the  body.  Voit  found 
that  during  starvation  or  with  an  insufficient  protein  diet  addition  of  fat 
to  the  food  increased  the  total  metabolism.  When  sufficient  protein  was 
being  supplied,  the  addition  of  fat  caused  no  increase  in  the  total  metabolism, 
the  whole  of  the  fat  in  the  food  being  laid  on  as  fat  in  the  body.  The 
stimulating  effect  of  fat  on  metabolism  is  but  slight.  Magnus  Levy  found 
that  the  increase  in  the  metabolism  on  the  administration  of  fat  to  a  starving 
animal  was  minimal  and  never  exceeded  10  per  cent. 

Carbohydrates  have  a  somewhat  greater  influence  on  metabolism. 
The  administration  of  a  large  meal  of  carbohydrates  to  a  starving  animal 
may  raise  the  respiratory  exchanges  from  20  to  30  per  cent.,  and  the  increase 
may  last  four  hours  after  the  meal.  This  stimulating  influence  on  metabolism 
is,  however,  much  less  than  that  observed  on  the  administration  of  large 
doses  of  protein.  If  carbohydrate  be  given  in  excess  of  the  daily  energy 
requirements  the  greater  proportion  of  it  remains  in  the  body,  being  stored 
up  to  a  small  extent  as  glycogen,  but  mainly  in  the  form  of  fat. 


SECTION  IV 

THE  EFFECT  OF   MUSCULAR  WORK  ON 
METABOLISM 

When  an  animal  performs  muscular  work  its  total  output  of  energy  must  be 
increased,  and  this  must  take  place  at  the  expense  either  of  an  increased 
intake  of  food  or  an  increased  destruction  of  the  tissues  of  the  body.     For 
many  years  a  theory  put  forward  by  Liebig  received  universal  acceptance 
among  physiologists.     According  to  this  view  the  food- stuffs  could  be 
divided  into  two  classes,  namely,  the  proteins,  which  were  the  plastic  food 
substances  and  were  concerned  in  the  building  up  of  tissues,  and,  secondly, 
the  fats  and  carbohydrates,  which  took  no  part  in  the  building  of  the  tissues, 
but  were  oxidised  for  supplying  heat  to  the  body.     Muscular  work  was  sup- 
posed to  be  attended  with  a  breakdown  of  the  muscular  tissue,  and  therefore 
to  be  performed  at  the  expense  of  an  increased  protein  metabolism,  which  had 
to  be  made  good  by  adding  to  the  protein  intake  in  the  food.     If  this  view 
were  correct  one  would  expect  to  find  a  great  increase  in  the  nitrogenous 
metaboHsm  of  the  body  with  every  increase  in  muscular  work.     Such  an 
increase  has,  in  fact,  been  found  by  Pfliiger  in  dogs  which  were  nourished  on 
a  purely  protein  diet.     In  these  animals  the  sole  source  of  energy  to  the 
organism  w^as  protein,  and  therefore  any  additional  call  on  the  energies  of 
the  body  must  be  associated  with  an  increased  intake  of  food  or  an  increased 
loss  of  material  from  the  body  in  the  shape  of  protein.     In  an  animal  which 
is  enjoying  a  normal  mixed  diet,  or  has  a  store  of  carbonaceous  material  in  its 
tissues  in  the  shape  of  fat,  there  is  no  increase  of  nitrogenous  metabolism 
during  muscular  w^ork  w^hich  w^ould  correspond  in  any  way  to  the  amount 
of  work  done.  This  was  shown  long  ago  by  Voit  in  experiments  on  the  dog. 
The  following  Table  represents  the  nitrogenous  metabolism,  i.e.  the  amount 
of  muscular  material  in  the  shape  of  protein  metabolised  during  the  day, 
under  varying  conditions  of  rest  and  activity,  during  starvation  and  after 
food  : 

Doc.  I 
Food  Flesh  metabolism         Condition  of  dog 

Gnu. 
0  ....  164  .  .  Rest 

0         ....         167  Work 

0         ....         149  ..  Rest 

637 


638 


PHYSIOLOGY 

Dog  II 

Food 

Flesh  metabolism 
Grm. 

Condition  of  dog 

1500  grm.  lean  meat 

1522 

Eest 

1500     „       „ 

1625 

Work 

1500     „       „ 

1526 

Rest 

1500     „       „ 

1583 

Work 

1500     „       „ 

1535 

Rest 

During  the  work  days  the  animal  performed  about  1500  kilogramme 
metres  in  the  day.  The  differences  in  the  protein  metabolism  between  the 
rest  and  the  work  days  are  thus  practically  insignificant,  the  nitrogenous 
output  being  determined,  not  by  the  work  done,  but  by  the  amount  of 
protein  administered  in  the  food.  In  the  second  experiment  there  is  an 
average  increase  of  protein  metabohsm  during  the  work  days  amounting  to 
86  grm.  of  flesh,  a  quantity  which  is  insufficient  to  furnish  the  energy  of  the 
work  done.  The  same  results  were  arrived  at  in  a  classical  experiment 
performed  by  Fick  and  Wishcenus  on  themselves,  in  which  they  measured 
their  total  nitrogenous  metabohsm  during  an  ascent  of  the  Faulhorn  from 
the  Lake  of  Brienz.  The  vertical  distance  traversed  was  1956  metres. 
During  the  seventeen  hours  before  the  experiment,  the  six  hours  of  the  ascent, 
and  the  seven  subsequent  hours  they  ate  food  practically  free  from  nitrogen. 
The  urine  passed  during  the  ascent  and  during  the  next  seven  hours  was 
collected  in  each  case  and  its  nitrogen  determined.  Fick  passed  5-74  grm. 
of  nitrogen,  which,  if  the  energy  of  the  protein  were  totally  converted  into 
work,  would  correspond  to  63,378  kilogramme  metres.  In  Wislicenus  the 
amount  was  5-55  grm.  of  nitrogen,  equivalent  to  61,280  kilogramme  metres. 
Fick,  who  weighed  66  kilos,  in  raising  himself  to  a  height  of  1956  metres, 
had  performed  129,096  kilogramme  metres,  and  Wislicenus,  with  a  weight 
of  76  kilos,  had  performed  148,656  kilogramme  metres.  Even  if  we  assume 
the  possibihty  of  a  conversion  of  the  total  energy  of  the  protein  metabolised 
during  the  experiment  into  mechanical  energy,  we  cannot  account  for  more 
than  half  of  the  total  work  done.  All  subsequent  experimenters  have  con- 
firmed the  deductions  which  were  drawn  from  these  two  researches,  namely, 
that  muscular  work,  while  practically  without  influence  on  nitrogenous 
metabolism,  increases  enormously  the  carbonaceous  metabolism  of  the 
body,  so  that,  except  in  the  rare  cases  where  the  diet  consists  of  pure  protein 
and  the  body  is  practically  free  from  fat,  the  additional  energy  output  during 
work  is  derived  from  the  oxidation  of  carbon  and  hydrogen  to  carbon  dioxide 
and  water. 

The  general  nature  of  the  changes  in  the  metabolism  of  the  body  during 
work  is  well  illustrated  by  the  results  obtained  by  Atwater  on  man.  The 
total  energy  output  of  a  man  was  reckoned  as  heat  by  means  of  the  calori- 
meter. The  heat  equivalent  of  the  external  muscular  work  performed  by 
the  man  was  also  reckoned  as  heat.  In  the  Table  (p.  639)  we  give  the 
total  output  of  energy  per  day  during  rest  and  work,  the  latter  being  also 
expressed  in  calories.* 

*  One  large  calorie,  or  '  kilo-calorie,'  is  equivalent  to  425  kilogrammetres. 


EFFECT  OF  MUSCULAR  WORK  ON  METABOLISM 

Energy  per  Day 


639 


Nature  of  experiment 

Heat  eliminated 

External 
worl£  in 
calories 

Total 

in 

calories 

By  radiation 
and 

conduction 

In  urine 

and 

faeces 

In  water 
vaporised 
from  lungs 
and  skin 

Rest  with  food  (average 
of  four  daj's) 

Rest  fasting  (four  experi- 
ments)    (average     of 
five  days) 

Work   (fourteen   experi- 
ments)    (average     of 
forty-six  days) 

1850 
1005 

3802 

26 
21 

29 

521 
561 

743 

546 

2397 
2187 

5120 

If  we  compare  the  energy- value  of  the  work  done  with  the  excess  of  the 
total  expenditure  of  the  body  over  that  found  during  the  rest  experiments, 
we  find  that  the  performance  of  muscular  work  involves  an  increase  in  the 
total  energy- expenditure  of  the  body  by  an  amount  equal  to  about  five  times 
that  of  the  work  done.  Of  course  a  certain  proportion  of  this  excess  of 
energy  over  work  done  is  accounted  for  by  the  increase  in  the  work  which 
must  be  performed  by  the  respiratory  muscles  and  heart  in  the  state  of 
greater  activity  which  is  imposed  upon  them  by  the  external  work,  and  is 
necessary  for  the  proper  provision  of  the  active  muscles  with  increased  food- 
supply  and  oxygen.  Even  if  we  neglect  these  factors  altogether,  we  see  that 
the  efficiency  of  the  body  as  a  machine  corresponds  to  between  16  and  20  per 
cent.,  an  efficiency  which  exceeds  that  of  the  best  of  our  steam- engines  and 
is  only  equalled  by  certain  internal- combustion  engines. 

A  comparison  of  the  excreta  of  the  same  individual  whose  energy  ex- 
changes are  given  in  the  above  Table  during  rest  and  activity  will  ^ive  us 
information  as  to  the  source  of  the  increased  energy  put  out  during  the  per- 
formance of  muscular  work.  Thus  during  a  period  of  rest  and  starvation 
the  average  output  of  carbon  dioxide  during  six  hours  amounted  to  189-6 
grm.  ;  during  a  rest  experiment  with  food  the  average  output  for  a  period 
of  six  hours  was  230-4  grm.  of  carbon  dioxide.  During  work  the  averat^e 
output  in  the  same  individual  during  six  hours  rose  to  705  grm.  of  carbon 
dioxide  on  a  carbohydrate  diet,  and  to  634-8  grm.  on  a  diet  containing  a  large 
amount  of  fat.  The  oxidation  of  carbon  was  therefore  increased  more  than 
threefold  as  a  result  of  muscular  work.  If  we  compare  in  the  same  wav 
the  protein  metabolism  of  the  same  individul  during  these  experiments  no 
such  alteration  is  observed.  Thus  the  average  output  per  day  during  rest 
and  starvation  corresponded  to  82  grm.  of  protein.  During  rest  and  with 
an  approximately  sufficient  amount  of  food  the  average  amount  of  protein 
consumed  was  98-8  grm.     During  a  work  day  in  which  he  received  practically 


640 


PHYSIOLOGY 


the  same  amount  of  protein  in  the  food  and  a  somewhat  insufficient 
amount  of  carbohydrates  and  fats,  his  consumption  of  protein  amounted 
to  109-4  grm.  Here,  as  against  a  three-  to  fourfold  increase  of  the  gaseous 
metabohsm  of  the  body,  we  have  only  a  10  per  cent,  increase  of  the  protein 
metabohsm. 

A  still  larger  difference  between  the  respiratory  changes  in  the  resting  or 
working  condition  is  found  when  the  exchanges  are  taken  over  shorter 
intervals.  The  following  Table  represents  the  respiratory  exchanges  in  a 
trained  muscular  subject  during  complete  rest  and  when  doing  moderate 
or  severe  work,  namely,  riding  a  bicycle  with  a  brake.  Each  observation 
lasted  from  10  to  15  minutes. 


Condition 

COg  eliminated 
per  minute 

Oxygen  absorbed 
per  minute 

Respiratory 
quotient 

Pulse  rate 

Rate 

Lying 

Moderate  work 
Severe  work 

200 
1720 

2227 

243 
1834 
3265 

.83 

.94 

■     .98 

56 
150 
166 

20 
32 
38 

These  last  figures  represent  a  maximum  since  the  subject  worked  with 
great  difficulty  and  was  exhausted  when  he  came  off  the  machine. 

There  is  another  method  by  which  we  can  arrive  at  some  idea  of  the  nature 
of  the  material  which  is  furnishing  by  its  oxidation  the  necessary  energy 
for  the  performance  of  muscular  work.  It  is  evident,  if  we  compare  the 
formulae  of  a  carbohydrate  and  a  fat  respectively,  that  it  will  require  a 
relatively  larger  amount  of  oxygen  to  oxidise  the  fat  than  is  necessary  in  the 
case  of  the  carbohydrate.  In  the  latter  there  is  sufficient  oxygen  to  combine 
with  all  the  hydrogen  present  and  form  water.  The  whole  of  the  oxygen 
therefore  which  is  taken  in  is  employed  in  the  oxidation  of  the  carbon, 
and  one  volume  of  oxygen  will  produce  one  volume  of  carbon  dioxide.  Thus  : 
CgHiaOs  +  6O2  =  6H2O  +  6CO2.  If  the  whole  of  the  animal's  energy 
requirements  were  furnished  by  the  oxidation  of  carbohydrates,  the  output 
of  carbon  dioxide  expired  would  be  exactly  equal  in  volume  to  the  oxygen 

inspired,  and  the  respiratory  quotient  of  the  animal,  namely,  ■  _  ^ . — —. — -, 

O2  inspired 

would  be  equal  to  unity.  In  fats  the  amount  of  oxygen  is  only  sufficient  to 
combine  with  four  atoms  of  the  hydrogen  of  the  molecule.  When  fats 
undergo  oxidation,  of  the  oxygen  used  only  a  portion  is  devoted  to  the 
formation  of  carbon  dioxide,  the  rest  being  employed  in  the  oxidation  of 
hydrogen  to  water.  In  an  animal  using  only  fats  the  carbon  dioxide  output 
of  the  body  would  be  considerably  less  than  the  oxygen  intake  and  its  respira- 
tory quotient  would  be  less  than  unity.  The  respiratory  quotients  for  pro- 
tein, fats,  and  carbohydrates  are  given  in  the  following  Table  (Atwater)  : 


EFFECT  OF  MUSCULAR  WORK  ON  METABOLISM 


641 


Material 


Respiratory  quotient 


CO. 


Starch 

10 

Cane  sugar 

10 

Glucose 

10 

Animal  fat 

0-711 

Protein 

0-809 

The  respiratory  quotient  in  an  animal  at  any  given  time  is  therefore 
determined  by  the  nature  of  the  substances  which  are  undergoing  oxidation 
in  its  body.  If  the  performance  of  muscular  work  involved  special  chemical 
processes,  a  metabolism  of  one  of  the  main  constituents  of  the  body  in 
preference  to  either  of  the  others,  this  sudden  change  in  the  quality  of  the 
metaboUsm  should  show  itself  in  the  respiratory  quotient. 

According  to  Speck  and  Lowy,  moderate  muscular  work  which  is  not 
associated  with  dyspnoea,  although  attended  by  a  large  increase  in  the 
carbon  dioxide  output  and  the  oxygen  intake  of  the  body,  does  not  alter  the 
respiratory  quotient.  This  is  probably  correct  if  the  respiratory  changes 
are  taken  over  a  sufficient  length  of  time,  when  the  respiratory  quotient 
must  depend  on  the  food  which  is  furnished  to  the  body  however  the  energy 
of  this  body  is  expended.  When  however,  as  in  Benedict's  and  Cathcart's 
experiments,  the  observations  are  of  short  duration,  muscular  exercise  is 
almost  always  fomid  to  be  associated  with  a  rise  in  the  respiratory  quotient, 
which  lasts  too  long  to  be  accounted  for  by  a  mere  washing  out  of  the  carbon 
dioxide  from  the  blood  and  the  body  tissues.  After  the  cessation  of  the 
exercise  the  respiratory  quotient  sinks  below  normal.  The  respiratory 
quotient  however  rarely  rises  even  during  exercise  to  1  as  it  would  if  the 
muscular  work  were  performed  solely  at  the  expense  of  carbohydrates. 

These  results  suggest  that  while  muscular  work  can  be  performed  at  the 
expense  of  any  of  the  food-stuffs  or  of  the  three  classes  of  constituents  of 
the  body,  carbohydrate  is  the  immediate  or  the  most  readily  available  source 
of  muscular  energy.  When  the  body  passes  suddenly  from  a  resting  to  an 
active  condition  the  first  call  is  therefore  on  the  carbohydrates  of  the  blood 
and  those  stored  up  in  the  muscles  and  liver,  whereas  after  exercise  these 
carbohydrate  stores  are  slowly  replenished  probably  at  the  expense  of  the 
proteins.  The  fact  that  the  body  can  draw  on  its  fat  stores  for  the  perform- 
ance of  muscular  work  suggests  that  this  substance  may  also  serve  as  a  source 
of  muscular  energy,  but  there  is  no  evidence  that  the  body  is  able  to  convert 
fats  under  any  circumstances  into  carbohydrates,  so  that  we  must  assume 
that  under  certain  conditions  the  fats  or  their  decomposition  products  may 
be  directly  utihsed  by  the  muscles. 


21 


SECTION   V 

THE  SIGNIFICANCE  OF  THE  FOOD-STUFFS 

When  the  proteins  are  taken  as  food  they  are  rapidly  and  ahnost  completely 
metabolised,  so  that  the  energy  output  of  the  body  increases  fari  passu 
with  the  increased  protein  food.  With  a  large  excess  of  protein,  a  certain 
Hmited  storage  of  this  material  is  possible,  but  the  stored-up  protein  rapidly 
disappears  on  deprivation  of  food.  On  this  account  the  course  of  the  meta- 
bolism during  starvation  is  the  same  after  the  first  two  or  three  days,  whether 
the  animal  has  previously  received  large  or  small  amounts  of  protein  in  its 
diet.  In  man,  even  this  limited  power  of  storing  nitrogen  is  apparently 
absent.  Under  no  circumstances  can  we  produce  a  laying  on  of  fat  in  the 
body,  even  in  carnivora,  however  much  the  protein  income  is  increased. 

The  metabolism  of  fats  and  carbohydrates,  on  the  other  hand,  is  deter- 
mined, not  by  the  amount  of  these  substances  in  the  food,  but  by  the  energy 
requirements,  i.e.  the  functional  activity  of  the  living  tissues.     Any  excess  * 
of  either  of  these  foods  simply  gives  rise  to  their  storage  in  the  body  almost 
entirely  in  the  form  of  fat.     How  are  we  to  regard  the  particular  position 
taken  up  by  the  proteins  in  metaboHsm  ?     Voit,  whose  laborious  observa- 
tions form  the  foundation  of  all  our  present  knowledge  of  metabolism,  drew 
a  sharp  contrast  between  the  proteins  which  were  built  up  to  form  parts  of 
the  living  cells,  the  tissue  or  morphotic  protein,  and  those  which  underwent 
rapid  oxidation  in  the  tissue  juices  without  ever  forming  an  integral  con- 
stituent of  the  living  protoplasm.     The  latter  he  designated  circulating 
protein.     The  rapid  fall  in  the  nitrogenous  excretion  during  the  first  two 
days  of  starvation  he  ascribed  to  the  using  up  of  the  circulating  protein. 
As  soon  as  this  was  exhausted  the  animal  was  reduced  to  living  on  its  own 
tissues,  so  bringing  into  the  metabohc  cycle  the  tissue-proteins  themselves. 
This  theory  has  been  energetically  attacked  of  late  years  by  Pfliiger,  according 
to  whom  the  whole  of  the  protein,  which  is  broken  down  and  oxidised  to  urea, 
must  at  one  time  have  formed  an  integral  part  of  a  living  cell,  so  that  tissue- 
protein  would  be  the  sole  source  of  the  urea.     He  explains  the  rapid  excretion 
of  nitrogen  which  follows  the  ingestion  of  a  protein  meal  by  the  special 
avidity  of  the  animal  cell  for  protein.     When  enough  of  this  is  presented  to  it 
it  feeds  upon  nothing  else,  and  only  when  there  is  a  comparative  lack  of  pro- 
tein will  it  make  use  of  carbohydrate  or  fat  for  its  needs.     Thus  while  a  dog 

*  That  is,  assuming  that  the  animal  is  able  to  digest  and  absorb  the  excess. 
On  this  factor  probably  depends  the  possibility  of  fattening  an  animal. 

642 


THE  SIGNIFICANCE  OF  THE  FOOD-STUFFS  G43 

is  fed  on  a  rich  mixed  diet  it  lives  practically  on  protein  alone,  storing  up  the 
fats  and  carbohydrates  of  the  food  as  fat.  If  food  be  now  withdrawn  the 
animal  must  live  either  at  the  expense  of  its  own  living  tissue  (proteins) 
or  must  attack  the  stored-up  fats  in  its  body.  The  latter  alternative,  as  a 
matter  of  fact,  takes  place.  The  animal  spares  the  precious  protein  and  lives 
on  the  fat  of  its  own  body.  Hence  comes  the  great  fall  in  the  excretion  of 
urea  that  is  observed  in  starvation,  the  consumption  of  proteins  sinking  to  the 
indispensable  minimum.  If  now  a  protein  meal  be  given,  the  cells  of  the 
body  return  to  their  former  way  of  living,  and  satisfy  as  much  of  their  needs 
as  possible  at  the  expense  of  protein,  so  that  the  urea  excretion  rises  almost 
in  proportion  to  the  food  given.  In  order  to  attain  nitrogenous  equilibrium 
on  a  purely  protein  diet,  it  is  necessary  to  give  the  cells  enough  protein 
for  their  total  requirements,  i.e.  three  to  five  times  as  much  as  would  corre- 
spond to  the  nitrogenous  excretion  during  hunger.  If  a  larger  amount  of 
protein  be  given  than  is  necessary  for  the  maintenance  of  nitrogenous 
equilibrium,  a  certain  amount  of  nitrogen  is  retained  in  the  body,  probably 
as  protein,  giving  rise  to  an  increase  in  the  total  living  material  of  the  body, 
and  the  animal  increases  in  weight.  The  amount  of  urea  excreted  by  an 
animal  is  proportional  not  only  to  the  quantity  of  protein  taken  in  with  the 
food  but  also  to  the  weight  of  the  animal ;  so  the  animal  which  has  grown 
heavier  in  consequence  of  increased  supply  of  nitrogenous  food  will  need  a 
larger  amount  of  protein  to  maintain  its  nitrogenous  equilibrium,  which  will 
be  produced  with  the  same  amount  of  protein  as  soon  as  the  animal  has 
increased  in  weight  to  a  certain  extent.  In  order  therefore  to  maintain  the 
increase  in  weight,  it  is  necessary  to  give  ever-increasing  quantities  of  protein, 
and  the  stuffing  process  is  finally  put  an  end  to  by  the  refusal  of  the  digestive 
organs  to  digest  any  more. 

There  can  be  little  doubt,  however,  that  Voit  was  substantially  correct 
in  assigning  a  twofold  fate  to  the  ingested  protein,  and  that,  as  Speck  has 
pointed  out,  we  can  consider  protein  metabolism  under  two  headings,  viz. 
tissue  or  nutritional  metabohsm  and  energy  metabolism.  Since  the  proteins 
form  the  main  constituent  of  living  protoplasm,  the  death  and  destruction 
of  cells,  which  are  constantly  going  on  in  the  body,  nmst  result  occasionallv 
in  the  production  of  substances  which  are  not  available  for  resynthesis,  and 
are  therefore  turned  out  of  the  body  with  the  urine.*  A  certain  proportion 
of  the  proteins  of  the  food  must  therefore  be  applied  to  replacing  this  waste  of 
tissue.  The  proportion  will  be  larger  in  cases  where  a  growth  of  the  nitrogen- 
ous tissues  is  occurring,  as  in  the  young  animal  or  during  convalescence  from 
a  wasting  disorder.  On  the  other  hand,  a  certain  proportion  of  the  nitrogen 
in  the  urine  will  be  derived  from  the  breakdown  of  tissues,  and  this  in  its  turn 

*  Tiger&tedt  suggests  that  the  irreducibk^  minimal  protein  consumption  may  be 
due,  not  to  a  special  metabolic  cycle  of  the  protein  on  its  way  into  and  out  of  the  living 
cell,  but  to  the  fact  that  the  circulating  fluids  of  the  body  contain  large  amounts  of 
protein  as  essential  and  constant  ingredients,  and  the  living  cells  therefore,  which  are 
bathed  by  these  fluids,  cannot  refrain,  even  in  times  of  protein  scarcity,  frrm  feeding 
to  a  certain  extent  on  these  the  predominant  constituents  of  their  nutrient  medium. 


644  PHYSIOLOGY 

will  be  increased  under  any  conditions  which  bring  about  an  augmented  tissue 
disintegration,  such  as  the  toxaemia  of  fevers,  poisoning  by  arsenic  or  phos- 
phorus, or  partial  asphyxia  by  deprivation  of  oxygen,  as  after  inhalation  of 
carbon  monoxide  gas.  In  this  function  protein  cannot  be  replaced  hj  either 
of  the  other  food-stuffs.  With  regard  to  its  second  fate,  viz.  the  furnishing 
of  energy  to  the  body,  protein  stands  on  the  same  level  as  carbohydrates  or 
fats,  its  relative  value  as  compared  with  these  two  classes  of  substances  being 
represented  by  its  physiological  heat- value.  Owing  to  the  inability  of  the 
body  to  store  protein  to  any  marked  extent,  any  protein  which  is  absorbed 
in  the  alimentary  canal  in  excess  of  the  nutritional  requirements  of  the  body 
is  at  once  broken  down  and  oxidised  to  satisfy  the  energy  requirements  of  the 
cells.  The  NH  and  NHg  groups  in  the  protein  molecule  add  little  or  nothing 
to  its  chemical  or  potential  value.  The  energy  value  of  the  protein  depends 
on  its  carbon  and  hydrogen  content,  and  it  seems  probable  that  the  greater 
part  of  the  nitrogen  is  split  off  as  ammonia  from  the  protein  molecule  during 
or  shortly  after  its  absorption  from  the  alimentary  canal.  It  is  on  this  account 
that  an  increased  excretion  of  urea  is  the  almost  immediate  consequence  of 
the  ingestion  of  protein.  The  point  made  by  Pfliiger  against  Voit,  viz.  that 
no  oxidation  occurs  in  the  lymph  or  blood,  is  really  beside  the  mark.  The 
living  cell  is  a  complex  system  which  may  include  food  in  all  degrees  of  oxida- 
tion or  chemical  change,  without  this  food  material  necessarily  forming  part 
of  the  living  framework.  Every  histologist  distinguishes  the  paraplasma 
from  the  more  active  and  essential  protoplasm,  and  we  mast  assume  that 
it  is  in  the  ultra-microscopic  interstices  of  the  foam-like  protoplasm  that  the 
chief  processes  of  chemical  change  and  oxidation  occur.  A  proof  therefore 
that  oxidation  depends  on  the  condition  of  the  cells  and  not  on  that  of  the 
blood  does  not  justify  the  conclusion  that  the  whole  nitrogenous  metaboHsm 
of  the  body  is  confined  to  the  living  protoplasm  itself. 

Polin  has  lately  brought  forward  a  number  of  facts  which  point  not  only 
to  a  twofold  origin  of  the  nitrogen  of  the  urine  but  also  to  a  qualitative 
difference  in  the  two  orders  of  protein  metabolism.  Whereas  in  the  urine 
of  man  on  a  normal  diet  the  urea  nitrogen  forms  85  per  cent,  or  more  of  the 
total  nitrogen,  a  reduction  of  the  protein  ration  to  the  minimum  necessary  to 
meet  the  nutritional  requirements  of  the  body  causes  not  only  an  absolute 
diminution  of  the  urea  but  a  large  relative  diminution  when  compared  with 
the  other  constituents  of  the  urine,  such  as  creatinin.  He  concludes  therefore 
that  the  nitrogenous  end-products  of  nutritional  metabolism  are  different 
from  those  of  the  energy  metabolism.  As  Speck  has  pointed  out,  there  is 
also  a  difference  in  the  time-relations  of  the  two  orders  of  metabolism. 
Whereas  the  nitrogen,  which  furnishes  no  energy  to  the  body,  is  rapidly 
eliminated  when  protein  is  being  utilised  for  the  supply  of  energy  to  the 
body,  the  occurrence  of  increased  tissue  waste  causes  a  rise  of  nitrogenous 
excretion,  which  comes  on  slowly,  often  after  the  lapse  of  a  day,  and  may 
last  two  or  three  days.  The  process  of  protoplasmic  disintegration  appears 
therefore  to  occur  in  a  series  of  stages,  which  occupy  a  considerable  time 
and  end  in  the  production   of  substances  qualitatively  distinct  from  that 


THE  SIGNIFICANCE  OF  THE  FOOD-STUFFS  645 

substance,  urea,  which  is  the  almost  exclusive  nitrogenous  end-product  of 
the  energy  metabolism  of  protein. 

THE  FOOD-VALUE  OF  CERTAIN  SUBSTANCES   ALLIED 
TO  PROTEINS 

PROTEOSES  AND  PEPTONES.  In  the  digestion  of  the  naturally  oc- 
curring proteins  the  first  products  of  hydration  consist  of  a  mixture  of 
substances  known  as  proteoses  and  peptones.  In  the  further  processes  of 
digestion,  under  the  influence  of  the  ferments  of  the  pancreas  and  small 
intestine,  these  substances  are  converted  into  the  amino-acids  which  we  have 
learnt  to  regard  as  the  proximate  constituents  of  the  protein  molecule. 
Many  experiments  have  been  performed  in  order  to  determine  the  nutritive 
value  of  these  digestive  products.  In  nearly  all  cases  it  has  been  found 
that  the  meat  in  the  diet  of  an  animal  can  be  replaced  by  a  corresponding 
quantity  of  the  products  of  digestion  of  the  same  meat  without  interfering 
with  the  nitrogenous  equilibrium  of  the  animal,  and  Loewi  and  others  have 
shown  that  the  same  result  may  be  attained  by  feeding  an  animal  on  the 
products  of  pancreatic  digestion  of  protein,  i.e.  a  mixture  consisting  almost 
entirely  of  amino-acids.  Since  the  proteins  of  the  body  differ  in  their 
composition  from  the  majority  of  the  proteins  of  the  food,  it  is  evident  that 
each  food-protein  molecule  has  to  be  taken  to  pieces  and  reconstructed  before 
it  can  take  its  place  in  the  body  fabric,  and  it  is  therefore  only  natural  that, 
so  far  as  metabolism  is  concerned,  the  results  should  be  identical  whether 
we  feed  the  animal  with  the  ordinary  food- protein  or  with  the  products 
of  its  metabolism.  This  mode  of  feeding  cannot,  however,  be  regarded  as 
presenting  any  advantages.  Under  normal  circumstances  the  food  molecules 
are  broken  down  by  degrees.  Their  products  of  hydrolysis  are  set  free  in 
small  quantities  at  a  time  and  can  be  therefore  absorbed  and  disposed  of  in 
proportion  as  they  are  set  free.  On  the  other  hand,  a  sudden  flooding  of  the 
alimentary  canal  with  a  large  quantity  of  the  products  of  digestion  intro- 
duces an  abnormal  factor  which  must  tend  to  produce  wastage  of  nitrogen 
in  the  body  and  to  disturb  the  normal  chain  of  processes  involved  in  the 
regular  course  of  digestion. 

COLLAGEN  AND  GELATIN,  Among  the  various  sclero-proteins  or  albu- 
minoids which  occur  as  normal  constituents  of  our  foods  these  two  are  the 
only  substances  which  undergo  digestion  and  solution  in  the  alimentary 
canal  to  any  appreciable  extent,  other  substances,  such  as  elastin  and  keratin, 
reappearing  for  the  greater  part  in  the  fseces.  As  we  have  seen,  gelatin,  the 
flrst  product  of  hydration  of  collagen,  represents,  so  to  speak,  an  imperfect 
protein.  When  it  is  hydrolysed  by  acids  its  disintegration  products  include 
the  ordinary  amino-acids  of  the  fatty  series,  including  a  considerable  amount 
of  glycine  and  also  a  certain  amount  of  phenyl  alanine  and  proline.  The  oxy- 
phenyl  group  which  occurs  in  all  the  food-proteins  in  the  form  of  tyrosine,  as 
well  as  the  indol-containing  group  tryptophane,  are  absent.  On  this  account 
purified  gelatin  does  not  give  either  Millon's  test  or  the  Hopkins-Adam- 
kiewicz  test  with  glyoxylic  acid.     As  might  be  expected  from  its  composition. 


646  PHYSIOLOGY 

gelatin  cannot  entirely  replace  the  proteins  of  the  food,  but  is  able  to  take  the 
place  of  part  of  the  proteins.  If  nitrogenous  equilibrium  has  been  attained 
on  a  certain  amount  of  protein  together  mth  a  mixed  diet,  a  considerable 
proportion  of  the  protein,  but  not  all,  can  be  replaced  by  gelatin.  In  an 
experiment  on  a  dog,  in  nitrogenous  equilibrium  on  a  mixed  diet  containing 
0-6  grm.  protein  per  kilo,  it  was  found  that  fully  five-sixths  of  the  protein 
could  be  replaced  by  gelatin  without  any  disturbance  of  the  nitrogenous 
metabohsm.  Physiologists  have  succeeded  in  maintaining  animals  for  a 
short  time  in  a  state  of  nitrogenous  equilibrium  on  a  diet  containing  no 
protein,  but  in  its  place  a  mixture  of  gelatin  with  tyrosine  and  tryptophane. 
It  is  doubtful,  however,  whether  such  experiments  could  be  continued 
indefinitely.  In  most  cases  the  animal  after  a  time  refuses  to  eat  the 
gelatin.  A  somewhat  similar  behaviour  is  found  in  the  case  of  zein,  the 
crystallised  protein  from  maize,  which  yields  no  tryptophane  or  tyrosine  on 
hydrolysis.  Hopkins  has  shown  that  animals  fed  with  zein,  together  with 
a  small  proportion  of  tryptophane,  live  longer  than  those  fed  with  zein  alone. 
But  in  no  case  could  he  maintain  life  on  this  diet  for  a  period  greater  than 
forty-five  days.  There  are  evidently  other  groups  in  the  protein  molecule 
which  are  essential  for  the  maintenance  of  life  and  which  were  not  represented 
in  the  mixture  of  zein  and  tryptophane. 

Experiments  have  been  carried  out  in  order  to  ascertain  whether  asparagine,  which 
forms  so  important  a  nitrogenous  constituent  of  young  plants,  can  be  directly  utilised 
by  animals.  There  is  evidence  that  this  substance  has  a  real  nutritive  value  for  certain 
herbivora.  The  utilisation  is  not,  however,  a  direct  one.  The  asparagine  appears  to 
be  taken  up  by  the  bacteria  which  swarm  in  the  paunch  or  caecum  of  these  animals. 
It  is  built  up  by  these  micro-organisms  into  protein,  and  it  is  the  protein  of  the  micro- 
organisms and  not  the  asparagine  itself  which  is  digested,  absorbed,  and  utilised  by  the 
mammal. 

OTHER  CONSTITUENTS  OF  THE  FOOD 
CELLULOSE.  This  substance,  which  forms  the  cell  walls  of  plants, 
furnishes  an  important  food-supply  to  the  herbivora.  Its  digestion  is  not, 
however,  carried  out  by  the  action  of  juices  secreted  by  the  intestinal  canal 
itself.  The  solution  of  the  cellulose  is  effected  partly  under  the  influence 
of  a  cellulose  or  cytase  present  in  the  plant  cell  themselves,  partly  under  the 
influence  of  the  micro-organisms  living  in  the  paunch  or  caecum.  Under  the 
influence  of  these  bacteria  cellulose  is  dissolved  with  the  production  of 
carbon  dioxide,  methane,  and  butyric  and  acetic  acids.  In  man  the  greater 
part  of  the  cellulose  of  the  food  is  undigested,  and  its  chief  value  appears  to 
be  that  of  lending  bulk  to  the  indigestible  material  and  so  aiding  the  normal 
movements  of  the  intestines.  In  the  case  of  young  plant  cells,  such  as  those 
of  lettuce  or  carrots,  a  certain  percentage  of  the  cellulose  undergoes  solution 
in  the  intestine.  Here,  again,  the  digestion  is  probably  effected  by  the 
agency  of  putrefactive  organisms. 

ALCOHOL.  When  alcohol  is  taken  by  man  in  moderate  quantities  the 
greater  part  of  it  undergoes  oxidation,  and  leaves  the  body  as  carbon  dioxide 
and  water.     About  10  per  cent,  which  escapes  oxidation  is  excreted  unaltered 


THE  SIGNIFICANCE  OF  THE  FOOD-STUFFS  647 

by  the  lungs  and  urine.  This  oxidation  of  alcohol  is  a  result  of  true  utihsa- 
tion,  since  the  addition  of  a  certain  amount  of  alcohol  to  the  food  does  not 
result  in  an  increase  of  the  output  of  carbon  dioxide.  In  small  quantities 
therefore  alcohol  can  act  as  a  food.  This  function,  however,  is  quite  un- 
important, and  is  overshadowed  by  the  poisonous  action  of  this  substance. 
A  man  unaccustomed  to  its  action  cannot  take  more  than  16  to  25  grm. 
without  experiencing  its  poisonous  effects.  This  amount  of  alcohol  only 
represents  a  total  heat- value  of  112  to  175  calories,  i.e.  only  about  5  per  cent, 
of  the  total  energy  requirements  of  the  body.  Only  very  rarely  therefore 
can  we  be  justified  in  administering  alcohol  as  a  food.  Its  value  in  a  diet 
is  entirely  that  of  an  accessory  or  adjuvant  in  exciting  appetite  by  its  taste 
and  smell,  an  advantage  which  is  largely  counterbalanced  by  the  danger 
of  introducing  a  poison  into  the  body  which  on  long  continuance  tends  to  set 
up  various  degenerative  changes  in  the  tissues,  and  if  taken  in  any  quantity 
at  one  time  causes  a  temporary  abolition  of  those  processes  of  inhibition  and 
control  which  have  been  the  determining  factors  in  the  survival  of  the  race 
throughout  the  struggle  for  existence. 

THE  INORGANIC  FOOD-STUFFS 

If  an  animal  be  fed  with  the  proper  quantities  of  fats,  proteins,  and 
carbohydrates,  from  which  all  the  salts  have  been  removed  as  completely 
as  possible,  it  rapidly  shows  a  distaste  for  the  food,  becomes,  ill,  and  dies  in 
a  shorter  time  than  if  it  were  receiving  no  food  at  all.  Part  of  the  symptoms 
which  occur  in  these  cases  are  due  to  the  production  of  acid  substances,  e.g. 
sulphuric  acid,  in  the  course  of  metabolism  of  the  proteins.  It  is  possible 
to  obviate  this  acid  intoxication  by  administering  sodium  carbonate  with  the 
food.  This  admixture,  however,  only  suffices  to  prolong  the  life  of  the 
animal  for  a  short  time.  It  is  evident  therefore  that  the  inorganic  constitu- 
ents of  the  food,  although  yielding  no  energy  to  the  body,  are  as  essential  for 
the  maintenance  of  fife  as  the  energy-yielding  food-stuffs,  namely,  proteins, 
carbohydrates,  and  fats.  In  the  course  of  this  work  we  shall  have  occasion  to 
study  the  intimate  dependence  of  the  functions  of  various  tissues,  such  as 
skeletal  and  heart  muscle,  on  the  presence  of  salts  in  normal  proportions  in 
the  fluids  with  which  they  are  bathed.  Animals  in  a  state  of  salt  hunger  show 
by  the  disorders  of  digestion  which  occur  that  the  presence  of  salts  is  equally 
requisite  for  the  due  performance  of  the  processes  of  secretion  and  absorption. 
Towards  the  end  of  the  experiment  the  animal  vomits  its  food,  which  shows 
no  signs  of  digestion  even  when  it  has  lain  some  hours  in  the  stomach. 
Forster  has  shown  that  in  salt-hunger  the  body  is  continually  giving  ofi 
inorganic  constituents  in  the  urine.  The  amount  of  these  is  smallest  when 
it  is  supplied  richly  with  organic  food-stuffs.  It  seems  that  the  salts  of  the 
body  exist  in  a  state  of  unstable  combination  with  the  tissue  constituents, 
especially  the  proteins.  If  tl\e  amount  of  food  supplied  is  insufficient,  the 
animal  fives  on  its  own  tissues,  thus  setting  free  salts  which  appear  in  the 
urine.  The  loss  of  salts  to  the  body  will  therefore  be  in  direct  proportion  to 
the  degree  in  which  the  animal  is  living  at  the  expense  of  its  own  tissues. 


SECTION  VI 

THE  NORMAL  DIET  OF  MAN 

The  adult  man  has  to  take  a  certain  quantity  of  food  every  day  in  order 
to  furnish  an  amount  of  energy  equal  to  that  lost  from  the  body  as  heat  and 
mechanical  work,  and  to  replace  the  waste  of  tissue.  This  income  is  repre- 
sented, not  by  the  total  food  taken  into  the  ahmentary  canal,  but  by  the  pro- 
portion of  the  food  which  is  absorbed  from  the  canal.  This  will  vary  with 
the  digestibihty  and  nature  of  the  diet,  and  in  any  experiments  instituted  to 
determine  the  metabohsm  of  man  the  first  question  that  must  be  decided 
is  as  to  the  proportion  of  food-stuSs  actually  utihsed.  Food  which  is  not 
absorbed  will  be  excreted  from  the  body  in  the  faeces.  The  degree  of  utihsa- 
tion  of  food-stuffs  will  therefore  be  given  by  an  analysis  of  the  fseces  passed 
daily  on  any  given  diet.  In  order  to  be  certain  that  the  faeces  passed  during 
a  given  time  correspond  to  and  are  derived  from  the  food  taken  in  at  the  same 
time,  it  is  usual  to  give  at  the  beginning  and  end  of  the  experiment  a  capsule 
of  lampblack,  so  as  to  colour  the  faeces  and  dehmit  those  formed  during  the 
period  of  the  experiment.  The  faeces  during  starvation  contain  a  certain 
proportion  of  nitrogen,  carbohydrates,  and  fats,  and  in  judging  of  the 
degree  of  utihsation  of  any  given  food-stuff  the  amounts  of  these  substances 
excreted  by  the  alimentary  canal  during  starvation  must  be  deducted  from 
the  total  amount  found  in  the  faeces. 

The  excretion  of  nitrogen  by  the  intestines  varies  between  0-54  and  1  -36 
grm.  per  day.  If  we  find  an  amount  of  nitrogen  in  the  faeces  not  exceeding 
these  figures,  we  are  justified  in  concluding  that  the  utihsation  of  the  nitro- 
genous constituents  of  the  food  is  practically  complete.  This  is  the  case 
when  the  man  receives  as  food  the  animal  proteins,  such  as  meat,  eggs,  or 
milk.  In  experiments  carried  out  with  these  materials  the  amount  of  nitro- 
gen of  the  faeces  varied  between  0-14  and  1-9  grm.  Only  when  excessive 
amounts  of  milk  are  given  is  the  utihsation  less  complete  and  the  nitrogen  in 
the  faeces  increased  above  this  amount.  If,  however,  the  protein  be  given 
in  the  form  of  vegetable  food,  the  wastage  of  nitrogen  by  the  faeces  is  much 
greater.  It  may  rise  as  high  as  48  per  cent,  and  amount  to  9  grm.  per  day. 
Nearly  always  it  exceeds  15  per  cent.  This  greater  wastage  of  the  nitrogen 
of  vegetable  food  depends  partly  on  the  fact  that  certain  non-protein  and 
indigestible  nitrogenous  constituents  of  seeds  and  grains  are  reckoned  as 
protein,  partly  on  the  fact  that  a  considerable  proportion  of  the  protein  may 
be  enclosed  in  indigestible  envelopes,  and  partly  on  the  greater  stimulant 

648 


THE  NORMAL  DIET  OF  MAN  r,49 

action  of  the  vegetable  diet  on  the  movements  of  the  ahmentary  canal,  so 
that  the  food  is  hurried  through  the  intestine  before  the  processes  of  digestion 
and  absorption  have  had  time  to  attain  their  Hmit.  This  last  factor  may 
interfere  also  with  the  digestion  of  animal  protein  on  a  mixed  diet.  The 
fats  and  carbohydrates  of  the  ordinary  diet  of  man  are  also  utilised  to  a 
very  large  extent.  The  fteces  passed  on  a  fat-free  diet  always  contain 
between  3  and  6  grm.  of  ethereal  extract  which  is  reckoned  as  fat.  When  the 
fat  of  the  food  consists  largely  of  olein  and  is  fluid  at  the  temperature  of  the 
body,  it  is  almost  totally  absorbed,  the  absorption  becoming  less  as  the 
melting-point  of  the  fat  rises.  Ordinary  carbohydrates  are  also  very  well 
absorbed,  but  here  very  large  variations  may  be  produced  by  altering  the 
condition  in  which  they  are  presented  in  the  food.  The  following  lable 
shows  the  relative  digestibihty  of  the  different  food-stuffs  in  a  healthy 
individual  on  a  normal  diet : 

Percentage  of  Food-stuff  Absorbed 

Protein  Fat       Carbohydrate         Ash  Total  energj' 

Average  of  fivej      ^^.^^  g^  g^.^  ^„.^  g^.. 

experiments     ( 

In  judging  therefore  of  the  sufficiency  of  any  given  dietary,  it  is  important 
to  remember  that  on  the  average  only  about  90  per  cent,  of  the  total  energy 
of  the  food  is  available  for  use  by  the  body.  If,  for  instance,  the  body 
requires  an  amount  of  energy  equivalent  to  3000  calories  per  day,  it  would 
be  necessary  to  give  food  corresponding  to  3333  calories  per  day.  If,  as 
is  the  case  with  the  poorer  classes,  the  food  consists  mainly  of  vegetable  pro- 
ducts it  may  be  necessary  to  increase  still  further  this  allowance,  since  on 
a  diet  such  as  rye  bread  the  loss  of  energy  in  the  faeces  may  amount  to  as 
much  as  35  per  cent,  of  the  total  energy  of  the  food. 

The  quantity  of  food  which  is  necessary  to  keep  an  adult  man  in  a  state 
of  health,  without  loss  or  gain  of  weight,  is  represented  by  that  amount  which 
is  sufficient  after  absorption  to  supply  the  total  daily  output  of  energy.  This 
output  will  vary  considerably  not  only  from  individual  to  individual  but  also 
with  the  weight  and  size  of  the  man,  and  above  all  with  his  state  of  muscular 
activity.  Thus  in  the  case  of  a  woman  weighing  4945  kilos,  in  a  state  of 
hysterical  sleep,  the  total  output  of  energy  during  twenty- four  hours 
amounted  to  1228  calories,  i.e.  24-8  calories  per  kilo  body  weight.  Under 
more  normal  conditions,  with  the  increased  tone  of  muscle  which  is  present 
during  waking  hours,  the  evolution  of  energy  by  the  body  is  increased  above 
this  amount.  Pettenkofer  and  Voit  found  that  a  resting  individual  had  an 
output  of  2300  calories  during  starvation  and  2G70  calories  on  a  normal  diet. 
A  series  of  experiments  by  Tigerstedt  on  individuals  kept  in  a  state  of  rest, 
but  on  normal  diet,  gave  results  varying  between  26  and  36  calories  per  kilo 
for  the  twenty-four  hours.  We  may  take  therefore  30  calories  per  kilo  body 
weight  as  the  average  requirements  of  a  man  in  a  state  of  rest.  This  would 
correspond  to  2100  calories  for  a  man  weighing  70  kilos.  When  muscular 
work  is  performed  the  energy  output  is  at  once  largely  increased,  and  with 
it  the  food  requirements  of  the  body.     The  attempts  which  have  been 

21* 


650  PHYSIOLOGY 

made  to  arrive  at  some  idea  of  the  average  amounts  of  food  required  by  a 
working  man  have  been  based  not  so  much  on  scientific  experiment  as  on  an 
analysis  and  comparison  of  the  diets  in  general  use  among  different  classes  of 
men,  the  amounts  of  which  are  determined  by  the  instinct  of  the  man  himself, 
while  its  quahty  is  hmited  by  his  daily  earnings.  Tigerstedt  divided  the 
different  diets  which  have  been  investigated  into  six  classes,  according 
to  the  total  amount  of  energy  which  each  of  them  represents.  These  are 
as  follows  : 


Group 

Protein 

Fat 

Carbo- 
hydrate 

Calories 

gross 

Calories 
net 

Calories  per 

kilo  body 

weight 

I 

II  . 

III  . 

IV  . 
V 

VI      . 

84 
88 
130 
141 
167 
152 

56 
39 
64 
71 
89 
139 

599 
512 
520 

677 

774 

1062 

2483 
2825 
3257 
4020 
4685 
6269 

2235 
2538 
2932 
3618 
4218 
5642 

32 
36 
42 
52 
60 
81 

In  view  of  this  great  variation  among  the  diets  of  different  individuals  it 
becomes  difficult  to  arrive  at  any  conclusion  as  to  the  diet  which  should  be 
regarded  as  the  average  and  should  guide  us  in  drawing  up  dietary  scales  for 
pubUc  institutions.  Voit,  from  experiments  on  ordinary  workmen  per- 
forming eight  or  nine  hours'  labour  a  day,  such  as  a  bricklayer  or  carpenter, 
has  laid  down  the  following  as  an  average  diet,  namely  : 


Protein 

Pat 

Carbohydrate 


118  grm. 

56      „ 

500     „ 


This  would  correspond  to  a  total  calorie  value  of  3055,  or,  subtracting 
10  per  cent,  for  the  food  which  is  not  utihsed  in  the  ahmentary  canal,  to 
2749  calories.  The  fat  in  this  diet  is  rather  low,  preference  being  given  to 
the  carbohydrate  on  account  of  its  greater  cheapness.  It  is  not  advisable 
to  reduce  the  fat  below  this  limit,  since  the  human  body  has  a  need  for  a 
certain  proportion  of  fat,  in  the  absence  of  which  the  utihsation  of  the  other 
food-stuffs  does  not  proceed  normally.  The  presence  of  fat  in  the  diet  is 
especially  important  in  the  case  of  infants  and  young  children,  many  of  the 
disorders  of  nutrition  prevalent  among  the  children  of  the  lower  classes  being 
largely  determined  by  the  absence  of  the  proper  quantity  of  fat  from  the 
diet.  In  the  case  of  severe  work  this  diet  may  not  be  adequate  to  supply 
the  necessary  quantity  of  energy.  Thus,  for  soldiers,  Voit's  ration  during 
manoeuvres  consists  of  : 


Protein 

Fat 

Carbohydrate 


135  gim. 

80     „ 
500     „ 


THE  NORMAL  DIET  OF  MAN 
with  a  total  calorie  value  of  3348.     His  ration  for  war-time  consists  of 


651 


Protein 

Fat 

Carbohydrate 


145  grm. 
100      „ 
500      „ 


corresponding  to  3575  calories.  Even  this  may  be  insufficient  to  supply  the 
energy  needs  during  a  period  of  intense  muscular  activity.  In  one  experi- 
ment by  Atwater,  in  which  the  individual  performed  muscular  work  for  a 
period  of  sixteen  hours  out  of  the  twenty-four  in  a  calorimeter,  the  total 
energy  given  out  amounted  to  over  9000  calories  in  the  course  of  the  twenty- 
four  hours.  It  is  probable,  however,  that  in  all  cases  where  such  excessive 
calls  on  the  energies  of  an  individual  are  made,  one  or  even  two  rest  days 
would  follow  the  day  of  exertion,  so  that  the  deficiency  of  the  food  on  the 
day  of  exertion  would  be  made  good  by  an  increased  intake  of  food  on  the 
following  days.  Thus  three  days'  intake  of  5000  calories  would  yield  suffi- 
cient energy  for  the  output  of  9000  calories  on  one  day  of  exertion  and  of  3000 
calories,  the  normal  amount,  on  each  of  the  two  succeeding  rest  days.  The 
relative  part  played  by  the  different  constituents  of  a  diet  in  yielding  energy 
to  the  body  has  been  determined  by  many  observers  and  especially  in  a  long 
series  of  researches  by  Atwater.  In  the  following  Table  are  given  details 
of  the  daily  food  in  one  such  experiment  on  a  man  weighing  76  kilos  : 


Food 

Weight 

per  day 

grm. 

Water 

Protein 

Fat 

Carbo- 
hydrate 
grm. 

N. 

c. 

H. 

Heat 
of  com- 

material 

grm. 

grm. 

grm. 

grm. 

gmi. 

grm. 

bustion 
calories 

Beef 

35 

22-0 

11-5 

1-0 

_ 

1-84 

6-73 

0-99 

76 

Butter       . 

245 

27-2 

2-9 

208-3 

— 

0-47 

1-54 

25-28 

1929 

Bread 

350 

148-7 

28-3 

3-9 

165-5 

4-97 

90-69 

13-55 

913 

Gingersnaps 

60 

2-4 

3-6 

3-4 

49-2 

0-63 

25-74 

3-98 

259 

Shredded 

wheat    . 

40 

2-5 

41 

0-6 

32-2 

0-72 

16-70 

2-54 

164 

Sugar 

60 

— 

— 

— 

60-0 

— 

25-26 

3-89 

238 

Cereal  coffee 

1200 

1191-6 

0-7 

— 

7-2 

0-12 

3-96 

0-60 

41 

Whole  milk 

1355 

1149-0 

52-9 

74-6 

69-2 

8-40 

108-00 

16-93 

1247 

Total  ration 
per  day 

J3345 

2543-4 

104-0 

291-8 

383-3 

17-15 

431-08 

67-76 

4867 

Very  few  accurate  experiments  have  been  made  on  the  daily  requirements 
of  women.  Since  the  average  weight  of  a  woman  is  less  than  that  of  a  man 
and  the  work  performed  less  severe,  she  will  require  a  smaller  amount 
of  food  both  to  meet  the  energy  expenditure  of  the  body  and  to  provide 
for  the  repair  of  her  tissues.  Voit,  under  the  assumption  that  the  body 
weight  of  woman  is  four-fifths  that  of  man,  and  that  her  energy  require- 
ments are  diminished  in  the  same  proportion,  has  given  the  following  as  the 
daily  requirements  of  a  woman  engaged  in  manual  labour  : 


652  PHYSIOLOGY 

Protein  .         .         .         .         .94  grm. 

Fat      f 45      „ 

Carbohydrate  ....     400      „ 

equivalent  to  a  gross  calorie  value  of  2444. 

«  VITAMINES  ' 

The  statement  that  a  diet  composed  of  the  five  classes  of  food-stuffs,  proteins, 
fats,  carbohydrates,  salts  and  water,  is  all  that  is  necessary  for  the  maintenance  of 
life  is  not  strictly  true.  It  is  found  that  if  rats,  for  instance,  be  fed  on  milk  or  bread 
and  milk,  they  can  live  and  grow  in  a  normal  manner.  If,  however,  the  proteins, 
fats  and  carbohydrates  be  extracted  from  the  milk,  purified,  and  then  mixed  in  the 
same  proportion  as  they  were  in  the  original  milk,  the  animals,  if  young,  cease  to  grow, 
and  after  some  days  or  weeks  die.  The  ordinary  nourishing  effect  may  be  restored 
by  adding  to  the  artificial  mixture  an  alcoholic  extract  of  milk,  or  of  yeast  cells,  or  of 
many  other  living  tissues.  It  was  thought  by  Stepp,  who  first  called  attention  to 
this  fact,  that  certain  lipoids  must  be  an  essential  ingredient  of  the  food.  Further 
light  has  been  thrown  on  the  question  by  the  researches  of  Hopkins  and  of  Funk. 
The  latter  has  investigated  especially  the  condition  known  as  beri-beri,  which  is 
a  state  of  mal-nutrition  brought  on  by  an  exclusive  diet  of  polished  rice,  i.e.  a  rice 
which  has  been  deprived  of  its  outer  coating.  This  condition  does  not  occur  if  to  the 
diet  be  added  the  dust  rubbed  off  the  rice  in  the  process  of  polishing.  A  similar  con- 
dition can  be  produced  in  fowls  and  is  rapidly  cured  by  addition  to  the  diet  of  rice 
polishings  or  of  an  alcoholic  extract  of  these  polishings,  of  yeast  cells,  or  of  lime  juice. 
It  seems  that  in  addition  to  the  five  classes  of  food-stuffs,  minimal  quantities  of  certain 
other  substances  are  necessary  in  order  that  the  processes  of  life  may  proceed  normally. 
How  these  substances  act  we  do  not  know,  but  we  must  imagine  that  they  have  a  drug- 
like effect  on  some  organs  of  the  body  and  take  the  place  of  or  give  rise  to  some  of 
the  hormones  which  are  essential  for  the  orderly  working  of  the  different  organs  of  the 
body.     Funk  has  given  to  these  substances  the  name  of  '  vitamines.' 


RELATIVE  PROPORTIONS  OF  THE  DIFFERENT  FOOD- 
STUFFS IN  THE  DIET  OF  MAN 
Since  we  have  exact  determinations  at  our  disposal  of  the  total  energy 
output  of  a  man  under  various  conditions,  it  is  easy  to  assign  a  total  diet 
to  each  class  which  shall  satisfy  these  energy  requirements.  In  such  a  diet 
fat  and  carbohydrate  are  mutually  replaceable  in  proportion  to  their  calorie 
value,  though  it  seems  that  in  most  individuals  for  the  conservation  of  perfect 
health  a  certain  minimum  amount  both  of  fats  and  carbohydrates  is  necessary. 
Some  observers,  however,  have  described  an  increased  output  of  carbon 
dioxide  as  the  result  of  the  ingestion  both  of  carbohydrates  and  of  fats, 
pointing  to  a  stimulating  effect  on  metabolism  of  these  food-stuffs  them- 
selves. If  these  results  are  generally  applicable,  we  cannot  regard  the  total 
energy  output  of  a  man  on  a  given  diet  as  affording  a  criterion  of  the  amount 
of  food  necessary  for  him  per  day,  since  it  is  possible  that  with  a  smaller 
amount  of  food  the  stimulating  effect  on  metabolism  might  be  wanting  and 
tnat  the  functions  of  the  body  might  be  normally  performed  with  a  greater 
economy  of  material.  The  stimulating  effect  of  fats  and  carbohydrates 
on  metaboUsm  has  not,  however,  been  universally  observed,  whereas  in  the 
case  of  proteins  every  worker  has  noted  an  increased  metabolism  in  propor- 


THE  NORMAL  DIET  OF  MAX  or.S 

tion  to  the  amount  of  protein  in  the  diet.  Especially  is  this  marked  in  man, 
where  the  power  of  storing  protein  in  the  body  seems  to  be  minimal  or  absent 
in  the  normal  adult.  As  we  have  seen,  the  protein  taken  in  the  food  has  a 
twofold  destiny.  Part  of  it,  probably  the  smaller  portion,  is  needed  to  be 
built  up  into  the  tissues,  and  to  form  living  protoplasm  in  replacement  of 
wear  and  tear.  The  other,  the  larger  portion,  serves,  like  the  fats  and  carbo- 
hydrates, for  meeting  the  energy  requirements  of  the  body.  The  amino- 
acids  produced  by  the  disintegration  of  the  proteins  in  the  alimentary  canal 
are  rapidly  absorbed  and  apparently  undergo  deamination  in  the  body. 
The  nitrogen  so  split  off  is  at  once  excreted  in  the  urine,  while  the  non- 
nitrogenous  moiety  is  rapidly  oxidised  to  carbon  dioxide  and  water.  How- 
ever much  protein  is  ingested,  so  long  as  the  digestive  powers  of  the  animal 
are  not  overtaxed,  all  that  is  not  required  for  replacing  tissue  waste  undergoes 
this  fate,  and  we  can  therefore  attain  nitrogenous  equilibrium  on  a  diet 
containing  50  grm.  or  150  grni.  of  protein  daily.  The  amount  of  protein 
taken  in  the  food,  and  digested  and  oxidised  in  the  body  by  any  given 
individual,  affords  no  clue  to  the  amount  \^'hich  is  absolutely  necessary  for 
the  maintenance  of  life  and  for  the  normal  discharge  of  the  bodily  functions. 
It  is  therefore  not  surprising  to  find  the  greatest  possible  divergences  between 
various  classes  of  men  i2i  the  quantity  of  protein  taken  in  their  daily  food. 
An  average  individual  in  affluent  circumstances,  eating  three  meat  meals  a 
day,  probably  takes  in  from  100  to  160  grm.  of  protein  daily,  corresponding 
to  a  nitrogen  content  of  16  to  25  grm.  On  the  other  hand,  there  is  no  doubt 
that  an  individual  can  lead  a  perfectly  normal  existence  with  a  nitrogen 
intake  as  low  as  5  or  6  grm.  a  day.  It  is  not  possible  to  explain  these  differ- 
ences as  determined  by  individual  idiosyncrasies,  nor  is  the  appetite  of  the 
individual  to  be  taken  as  a  safe  guide  to  the  relative  composition  of  the  foods. 
The  average  diet  of  any  race  has  been  determined  up  to  the  present  not  so 
much  by  the  physiological  requirements  of  the  body  as  by  the  nature  of  the 
food  available.  Hence,  whereas  the  races  living  in  tropical  climates  are 
mainly  herbivorous  or  frugivorous,  the  northerners,  who  have  developed  their 
intellectual  and  bodily  superiority  in  their  harder  struggle  for  food  amidst 
more  inclement  surroundings,  have  been  perforce  obliged  to  satisfv  their 
energy  requirements  at  the  expense  of  animal  food.  In  these  days  when  the 
products  of  all  climes  are  at  the  disposal  of  civilised  man,  his  food-supply 
is  no  longer  dependent  on  the  country  in  which  he  lives,  and  it  is  possible  to 
regulate  the  composition  of  his  food  according  to  the  results  of  physiological 
experience.  Since  the  proteins  represent  the  most  costly  constituents  of  the 
food,  it  becomes  impoitant  to  inquire  how  much  of  this  class  of  food-stuffs  is 
essential  to  the  maintenance  of  health  and  whether  any  advantage  is  given 
by  taking  proteins  in  excess  of  the  physiological  mininnim.  The  fact  that 
those  nations  which  hold  the  highest  place  in  the  world  are  mainly  flesh- 
eaters  cannot  be  regarded  as  any  proof  of  the  advantage  of  a  flesh  diet  over 
a  diet  poorer  in  piotein.  It  is  the  hard  struggle  for  existence  which  in  the 
northern  races  has  eliminated  the  weakling  and  resulted  in  the  production  of  a 
superior  race.     The  fact  that  he  is  a  flesh-eater  can  also  be  ascribed  to  the 


654  PHYSIOLOGY 

exigencies  of  plimate  and  does  not  necessarily  prove  that  a  large  flesh  diet 
is  responsible  for  his  greater  efficiency. 

Of  late  years  a  number  of  careful  experiments  have  been  made  to  deter- 
mine the  minimum  amount  of  protein  which  must  be  present  in  the  daily 
ration  of  man.  I  have  mentioned  above  two  experiments  in  which  nitrogen- 
ous equihbrium  was  obtained  with  much  smaller  amounts  of  protein  than 
those  given  in  the  normal  diets.  In  these  experiments,  in  one  of  which  the 
man  received  43-5  grm.  of  protein  daily,  and  in  the  other  only  33  grm.  of  pro- 
tein, it  was  found  necessary  to  give  at  the  same  time  amounts  of  carbo- 
hydrates and  fats  far  exceeding  those  in  the  normal  diet,  so  that  whereas, 
e.g.  the  normal  individual  takes  in  between  32  and  35  calories  per  kilo, 
the  man  on  43-5  grm.  of  protein  needed  47-5  calories  per  kilo,  and  the  one  on 
33  grm.  of  protein  needed  the  huge  amount  of  78-5  calories  per  kilo. 

Other  experimenters  have,  however,  succeeded  in  maintaining  perfect 
health  and  nitrogenous  equihbrium  for  a  considerable  time  on  a  diet  con- 
taining a  much  smaller  amount  of  protein  than  has  been  generally  considered 
necessary  without  adding  to  the  ration  abnormal  quantities  of  fats  or  carbo- 
hydrates. Thus  Siven,  in  an  experiment  on  himself,  found  that  he  could 
maintain  nitrogenous  equilibrium  for  thirty-two  days  on  a  diet  containing 
only  6-26  grm.  of  nitrogen.  The  total  heat- value  of  the  food  per  day  was 
only  2444  calories.  Folin,  in  individuals  with  an  insufficient  amount  of 
protein  containing  only  2-1  to  2-4  grm.  of  nitrogen,  found  that  the  nitrogen 
output  per  diem  was  only  3  to  4  grm.  It  would  seem  therefore  that  a 
healthy  adult  man,  having  a  sufficient  intake  of  non-nitrogenous  food,  need 
not  metabohse  more  protein  than  suffices  to  yield  3  to  4  grm.  of  nitrogen 
per  day,  i.e.  between  25  to  35  grm.  of  protein.  Other  observations  have  been 
made  on  vegetarians,  showing  that  individuals  can  maintain  perfect  health 
on  a  diet  containing  only  about  34  grm.  of  protein  a  day,  and  with  a  total 
calorie  value  of  1400  to  2000.  A  series  of  experiments  were  conducted  by 
Chittenden  with  a  view  to  determining  how  far  such  a  diet  is  suitable  to 
the  average  individual,  and  especially  whether  it  can  be  continued  for  long 
periods  of  time  without  interfering  with  the  well-being  of  the  subject  of  the 
experiment.  The  general  results  of  these  experiments  show  that  the 
physiological  needs  of  the  body  can  be  met  by  greatly  reduced  protein  intake 
with  the  estabhshment  of  continued  nitrogenous  equilibrium  on  a  far  smaller 
amount  of  protein  food  than  is  contained  in  the  ordinary  dietary  tables,  and 
that  on  this  diet  the  individual  in  some  cases,  far  from  suffering  in  health, 
has  his  physical  and  mental  efficiency  increased.  The  experiments  were  made 
on  various  classes  of  men  :  instructors  and  students  in  the  university, 
soldiers,  and  athletes.  In  the  case  of  Chittenden  himself  the  average  daily 
diet  contained  about  6  gi-m.  of  nitrogen  and  had  a  heat- value  of  about  1600 
calories.  In  the  case  of  another  individual  the  intake  of  nitrogen  per  day  was 
9-5  grm.  and  the  heat- value  of  the  food  2500  calories.  It  is  thus  possible 
to  reduce  the  total  energy  of  the  food  from  about  3300  calories  to  about  2500 
calories.  Of  the  protein  taken  in  by  a  normal  individual  therefore  a  certain 
amount  which  is  not  needed  by  the  organism  is  at  once  broken  up  and  serves 


THE  NORMAL  DIET  OF  MAN  655 

simply  to  increase  the  total  metabolism  of  the  body  without  serving  any 
useful  physiological  purpose  other  than  heat  production*  Many  ailments, 
especially  of  middle  age,  have  been  ascribed  to  an  excess  of  protein  in  the 
food.  It  has  been  thought  that  the  kidneys  and  other  organs  may  suffer 
from  the  strain  of  eliminating  excess  of  nitrogenous  waste  products.  But  the 
energy  metabolism  of  proteins  results  almost  entirely  in  the  formation  of  urea 
— an  innocuous  substance  which  can  have  little  harmful  effect  on  the  kidneys, 
even  if  we  assume  (an  assumption  hardly  justifiable)  that  these  organs  (unlike 
other  organs  of  the  body)  suffer  as  a  result  of  their  normal  functional  activity. 
There  is  no  doubt  that  many  disorders  of  middle  life  may  be  put  down  to 
over-feeding  and  lack  of  muscular  exercise,  but  there  is  just  as  much  reason 
to  ascribe  these  evils  to  the  carbohydrates  as  to  the  proteins  of  the  diet.  It 
is  indeed  possible  that  an  ahnost  exclusive  protein  diet  might  be  more 
suitable  than  carbohydrates  for  a  sedentary  life,  where  the  normal  stimulus 
to  oxidation  of  the  food-stuffs,  viz.  muscular  exercise,  is  absent,  and  that  the 
'  stimulant '  effect  of  proteins  on  metabolism  might  have  a  real  value  to  the 
organism. 

The  hmitation  of  protein  diet  to  a  minimum  is  only  justifiable  in  adult 
healthy  men.  Where  from  any  cause  there  has  been  a  loss  or  destruction 
of  nitrogenous  tissue,  as  after  infective  diseases,  the  body  possesses  the  power 
of  storing  up  nitrogen  in  the  form  of  flesh  or  muscular  tissue,  and  it  is 
important  under  such  circumstances  to  give  in  the  food  an  excess  of  protein 
which  can  be  used  for  this  purpose.  Moreover,  when  a  rapid  growth  of 
muscle  is  going  on,  as  during  training,  an  excess  of  protein  in  the  food  is 
also  desirable,  though  nothing  is  gained  in  pushing  this  administration  of 
protein  to  an  inordinate  extent. 

The  fact  that  in  many  cases  greater  economy  and  efficiency  of  nutrition 
are  attained  by  diminishing  the  protein  of  the  diet  affords  no  argument  for 
accepting  or  rejecting  any  given  class  of  foods.  Thus  the  normal  requirements 
of  the  individual  can  be  obtained  by  the  administration  of  a  diet  containing 
meat,  eggs,  vegetables,  and  cereals,  or  by  a  diet  derived  entirely  from  the 
vegetable  kingdom.  A  purely  vegetable  diet  is  rendered  possible  in  civilised 
countries  by  the  ease  with  which  the  products  fi'om  warmer  chmates  can  be 
obtained.  A  diet  composed  only  of  the  products  of  temperate  chmates 
would  tend  to  be  deficient  in  fats  and  oils.  In  such  climates  it  is  therefore 
necessary  to  import  the  oily  fruits  grown  in  warmer  lands,  or  to  supplement 
the  diet  with  such  animal  food  as  milk  or  butter  or  eggs.  In  drawing  up  a 
purely  vegetarian  diet  it  is  important  to  remember  that  its  constituents, 
especially  its  protein,  are  digested  with  greater  difficulty  than  the  corre- 
sponding ingredients  in  animal  food.  A  larger  quantity  therefore  has  to  be 
given  in  a  vegetable  diet  in  order  to  allow  for  the  greater  loss  by  the  fa}ces. 
Any  general  reform  of  diet  which  may  be  indicated  by  recent  physiological 
experiments  would  seem  to  lie  rather  in  the  direction  of  hmitation  of  the 

*  But  heat  production  is  a  very  important  function  of  the  food,  and  on  the 
Chittenden  diet  tends  to  be  deficient  ;  so  that  individuals  on  tliis  regime  'feel  the 
cold  '  more  than  they  did  when  on  an  ordinary  diet. 


656 


PHYSIOLOGY 


quantity  of  difEerent  articles  of  food,  perhaps  especially  of  those  rich  in 
protein,  than  in  a  limitation  to  foods  obtained  from  the  animal  or  vegetable 
kingdom.  In  certain  individuals  the  increased  bulk  of  indigestible  residue 
which  is  afforded  on  a  vegetarian  diet  presents  a  distinct  advantage,  since 
it  serves  to  promote  peristalsis  and  the  normal  evacuation  of  the  large 
bowel.  There  is  no  scientific  evidence  that  for  the  ordinary  person  any 
advantage  is  to  be  gained  by  adherence  to  a  strictly  vegetarian  diet. 

THE   DIET  OF  THE  GROWING   ANIMAL 

Since  the  young  animal  is  smaller  than  the  adult,  it  presents  a  greater 
surface  in  proportion  to  its  bulk,  and  therefore  will  need  more  energy  per 
kilo  body  weight  than  is  the  case  with  the  adult.  The  processes  of  growth 
are  attended  moreover  with  an  active  metabolism,  so  that  the  metabolism 
is  more  energetic  in  the  young  animal  than  in  the  adult,  even  if  we  take  into 
account  the  relative  surface  in  the  two  cases.  In  the  following  Table  is 
given  a  number  of  observations  showing  the  output  of  carbon  dioxide  per 
square  metre  body  surface  at  different  ages  in  boys  and  men  : 


Effeci 

OF  Age  on  Met 

\BOLisM  (Man) 

Ag 

e 

13t  d/  weight 
kUos 

CO.,  per  kilo  body 
weight  per  hour 

CO  J  per  square  metre 
per  hour 

lO.V      . 

30 

Ml 

28-2 

14 

45 

1  -DO 

27-6 

17 

56 

0-81 

24-2 

23 

05 

0-58 

18-6 

45 

77 

0-48 

16-3 

58 

85 

0-41 

14-2 

Between  the  ages  of  fourteen  and  nineteen  years  in  boys  the  carbon 
dioxide  output  is  absolutely  greater  than  at  any  other  age.  It  is  during  these 
years  that  the  growth  of  the  boy  is  most  marked.  A  boy  between  nine  and 
thirteen  years  old  requires  just  as  much  food  as  a  full-grown  man,  and 
between  the  ages  of  fourteen  and  nineteen  he  will  require  more.  This  great 
increase  between  the  fourteenth  and  nineteenth  years  is  not  noticed  in 
females.  There  is  a  gradual  absolute  increase  in  girls  up  to  the  eleventh 
year.  At  this  age  and  henceforward  the  total  carbon  dioxide  output  and 
therefore  the  total  food  requirements  remain  constant,  being  about  equal  to 
that  of  a  woman  of  thirty.  The  total  energy  requirements  of  the  growing 
animal  are  not,  however,  the  only  factor  which  we  have  to  consider.  The 
protein  of  the  food  has  not  only  to  replace  the  wear  and  tear  of  tissue,  but  also 
to  provide  material  for  the  growth  of  new  tissues.  The  protein  needs  there- 
fore of  the  growing  animal  are  relatively  greater  than  those  of  the  adult,  and 
absolutely  greater  during  the  period  of  most  rapid  growth,  namely,  in  boys 
between  the  ages  of  fourteen  and  nineteen.  It  is  a  popular  belief  that  in 
a  working-class  family  the  worker  or  wage-earner  needs  a  greater  protein 
supply  than  the  rest  of  the  family.  This  is  a  mistake.  The  adult  worker 
can  obtain  his  energy  equally  well  from  carbohydrates  and  fats,  whereas 


THE  NORMAL  DIET  OF  MAX  657 

an  excess  of  protein  is  absolutely  necessary  in  the  case  of  the  children  to 
provide  the  material  for  their  proper  development  and  growth.  The 
relation  between  rate  of  growth  and  protein  content  of  food  is  well  illustrated 
by  a  comparison  of  the  composition  of  the  milk  in  different  animals.  In  the 
following  Table  (Proscher)  it  will  be  seen  that  the  more  rapidly  an  animal 
grows  the  greater  is  the  protein  content  of  the  milk  with  which  it  is  supplied  : 


Time  iii  which 

the  body  weight 

of  the  uew-boiii 

animal  was 

doubled. 

Days 

100  parts  of  Milk  contain 

Protein 

Ash 

Lime 

rilUSljIldlic 

acid 

Man     . 

180 

1-6 

0-2 

0-328 

0-473 

Horse  . 

60 

2-0 

0-4 

1-240 

1-310 

Cow      . 

47 

3-5 

0-7 

1-600 

1-970 

Goat    . 

19 

4-3 

0-8 

2-100 

3-220 

Pig       . 

18 

5-9 

— 

— 

— 

Sheep  . 

10 

6-5 

0-9 

2-720 

4-120 

Dog     . 

8 

71 

1-3 

4-530 

4-930 

Cat      . 

7 

9-5 

— 

— 

— 

We  should  expect  then  that  the  milk  which  is  the  sole  food  of  the  growing 
infant  should  contain  a  relatively  greater  proportion  of  protein  than  is  neces- 
sary in  the  case  of  the  adult.  In  an  experiment  by  E.  Feei-,  ([uoted  by 
Bunge,  a  child  weighing  8226  grm.  at  the  thirtieth  week  took  951  grm.  of 
milk.     Human  milk  contains  : 


Protein 

' . 

. 

1  •()  per  cent. 

Fat 

. 

. 

3-4      „ 

Sugar    . 

•          • 

(M      „ 

Ash       . 

• 

0-2      „ 

The  child  was  therefore 

receiving  daily  : 

Protein 

•          • 

15-2  grm. 

Fat 

32-3     „ 

Sugar    . 

58-0     „ 

Ash       . 

. 

1-9     „ 

According  to  the  same  p 

ro 

)ortions  a  man  of 

70  kilos 

would  take  in  : 

Protein 

129  grm. 

Fat 

275     ., 

Sugar    . 

. 

494     ,. 

A.«h        . 

. 

16     „ 

It  is  interesting  to  note  that  the  protein  of  this  diet  differs  but  little 
from  that  in  the  diets  ordinarily  accepted  as  standard,  but  there  is  a  large 
excess  in  the  fat,  and  in  the  total  calori  value,  as  would  be  expected  from 
the  more  rapid  metabolism  and  the  velntively  larger  body  surface  of  the 
young  child. 


CHAPTER   X 
THE  PHYSIOLOGY  OF  DIGESTION 

CHANGES   UNDERGONE  BY  THE  FOOD-STUFFS  IN  THE 
ALIMENTARY  CANAL 

The  use  of  the  process  of  digestion  is  to  alter  the  food-stuffs  so  as  to  fit 
them  for  absorption  into  the  blood,  by  means  of  which  they  may  be  carried 
to  all  parts  of  the  body.  In  most  cases  the  food-stuffs  cannot  be  utilised 
in  their  original  form  by  the  living  cells.  When  we  nourish  ourselves  at 
the  expense  of  an  animal  or  plant,  we  are  taking  in  not  only  the  current  coin 
of  the  organism  which  is  being  used  for  the  supply  of  energy  to  its  vital 
processes,  but  also,  and  to  a  much  larger  extent,  the  framework  forming 
■  the  machinery  of  the  organism  as  well  as  its  stores  of  carbohydrate  or  fat. 
The  food-stuffs  as  we  ingest  them  are  in  the  most  inactive  form  possible. 
Practically  all  are  colloidal,  neutral,  and  tasteless,  and  present  no  tendency 
to  unite  with  oxygen  or,  indeed,  to  undergo  any  change  whatsoever,  apart 
from  the  interference  of  living  organisms  such  as  bacteria.  In  a  starving 
animal  the  stores  of  carbohydrate  and  fat  and  the  protein  structure  of  the 
inactive  living  cells  have  to  be  converted  into  a  soluble  form — transformed, 
so  to  speak,  into  currency — ^before  they  can  be  utihsed  by  other  Hving  cells, 
such  as  those  of  the  heart,  for  the  discharge  of  their  normal  functions  and  the 
maintenance  of  the  hfe  of  the  animal.  In  the  same  way,  when  we  take  these 
colloidal  or  insoluble  substances  into  our  alimentary  canal,  they  have  to  be 
rendered  soluble  or  diffusible,  in  order  to  allow  of  their  easy  transference 
across  the  wall  of  the  gut  into  the  blood  and  their  transport  to  the  tissue-cells. 
The  cells  of  the  body  cannot  deal  with  all  kinds  of  carbohydrate.  Most 
animal  cells  will  starve  when  presented  with  starch,  dextrin,  or  any  of  the 
disaccharides,  such  as  maltose,  lactose,  or  cane  sugar.  It  is  necessary  there- 
fore that  all  the  carbohydrates  shall  be  reduced  in  the  aUmentary  canal  or  in 
its  walls  to  the  form  of  monosaccharides.  As  regards  proteins,  the  processes 
of  digestion  have  a  different  significance  according  as  we  are  deahng  with  their 
value  as  givers  of  energy  or  their  value  as  builders  up  of  the  living  protoplasm. 
If  the  proteins  of  the  food  are  to  be  oxidised  and  utilised  as  a  source  of 
energy,  they  must  be  rendered  soluble  so  as  to  enable  them  to  be  absorbed 
and  carried  to  those  parts  of  the  body  where  they  may  undergo  deamination 
and  complete  oxidation.  If  they  are  to  be  built  up  as  integral  parts  of 
living  cells,  to  take  the  place  of  molecules  which  have  been  destroyed  in  the 

668 


THE  PHYSIOLOGY  OF  DIGESTION  659 

wear  and  tear  of  functional  activity,  the  change  must  be  almost  equally 
profound.  The  proteins  of  the  cells  from  different  parts  of  the  body  have 
different  molecular  constitutions.  Not  only  do  they  differ  among  themselves, 
but  they  differ  very  largely  from  many  of  the  proteins  which  may  be  taken  in 
with  the  food.  A  child  is  able  to  obtain  material  for  the  growth  of  his  brain- 
cells,  his  muscle-cells,  or  his  hver-cells,  from  a  diet  containing  protein  in  the 
form  of  caseinogen,  or  of  vegetable  gluten,  or  of  meat  fibrin.  A  reference  to 
the  Table  on  p.  91  will  show  the  striking  difference  in  composition  between 
the  various  proteins  of  the  food  and  the  proteins  which  have  to  be  formed 
from  them  in  the  living  tissues.  It  is  evident  that  to  form  serum  albumin, 
for  instance,  out  of  wheat  ghadin,  an  entire  reconstruction  is  necessary.  This 
can  only  be  accomplished  by  taking  the  protein  molecule  to  bits,  and  by 
selecting  certain  of  its  constituent  parts  and  building  these  up  in  the  proper 
proportions  to  form  a  new  protein  molecule.  For  the  purposes  of  nutrition 
therefore  the  changes  in  the  protein  molecule  must  be  greater  the  more 
variation  there  is  in  the  composition  of  the  protein  of  the  food  from  the 
composition  of  the  proteins  of  the  tissues. 

In  primitive  ahmentary  canals  every  cell  lining  the  canal  may  be  en- 
dowed with  amoeboid  properties  and  capable  of  devouring  the  food  particles, 
the  subsequent  changes  in  the  latter  to  fit  them  for  their  journey  through  the 
rest  of  the  body  being  performed  in  the  body  of  the  cell  itself.  In  all  the 
higher  animals,  however,  including  ourselves,  the  greater  part  of  the  prepara- 
tion of  the  food  is  accomphshed  extracellularly  in  the  lumen  of  the  ahmentary 
canal,  and  the  changes  are  effected  by  means  of  special  digestive  juices, 
which  are  formed  by  the  activity  of  masses  of  cells  produced  as  outgrowths 
from  the  wall  of  the  canal.  The  digestive  juices  attack  the  food-stuffs  by 
means  of  ferments,  and  in  every  case  the  action  of  these  ferments  is  hydro- 
lytic,  the  food-stuffs  taking  up  one  or  more  molecules  of  water  and  under- 
going dissociation  into  simpler  molecules.  Since  each  class  of  food-stuff 
requires  a  different  ferment,  a  great  variety  of  ferments  is  concerned  in  the 
processes  of  digestion. 

As  the  end-result  of  digestion  the  many  kinds  of  food  taken  by  man 
are  reduced  to  a  fairly  small  number  of  simpler  bodies.  These  end-products 
are  : 

(1)  Carbohydrates. 

The  monosaccharides  :  glucose,  fructose  or  levulose,  and  galactose. 

(2)  Fats.     Fatty  acids,  or  (in  alkaline  medium)  soaps,  and  glycerin. 

(3)  Proteins.  Here  we  have  a  great  variety  of  mono-  and  diamino-acids, 
which  may  be  enumerated  as  follows  : 

MONO-AMINO-ACrDS 

Glycine  (aminoacetic  acid)     .... 

Alanine  (amino propionic  acid) 

Serine  or  oxyalanine  (oxyaminopropionic  acid)  .  .  I    Monobasic  acids 

Aminovalerianic  acid j  of  fatty  series 

Leucine  (aminoisobutylacetic  acid) 
Isoleucine  (aminocapi'oic  acid) 


660 


PHYSIOLOGY 

Mono  -amino  -acids — continued 


Aspartic  acid        .... 

Glutamic  acid       .... 

Phenylalanine 

Tyrosine  (oxy phenylalanine) 

Proline  (pyrrolidine  carboxylie  acid) 

Oxj'proline  (oxypyrrolidine  carboxylie  acid) 

Tryptophane  (indolaminopropionic  acid) 


DiAMINO-ACIDS  AND  THEIR  COMPOUNDS 


Lysine  (diaminoca])roic  acid) 
Arginine  (guanidinaminovalerianic  acid) 
Histidine  (iminazolalanine)    .... 
'  Diaminotrioxydodecoic  acid '        .  .  . 

Cystine  (derived  from  aminothiopropionic  acid) 


Diabasic  acids 

Benzsne  (aromatic) 
derivatives 

Heterocyclic 

compound^ 


I  The 

j  '  hexone  bases  ' 

derived  from  a  12-carbon  acid 
f  Sulphur-containing 
I  bodv 


Those  constituents  of  the  food  which  undergo  no  oxidation  in  the  body, 
such  as  the'  water  and  salts,  are  practically  unchanged  in  the  alimentary 
canal,  and  are  absorbed  in  their  original  form  into  the  blood. 


SECTION   I 


DIGESTION   IN  THE   MOUTH 

It  is  a  common  experience  that  when  food  is  taken  into  the  mouth  there  is 

a  flow  of  a  liquid, '  saliva,'  into  this  cavity.     Saliva  is  the  product  of  secretion 

of  three  pairs  of  large  salivary  glands  situated  in  the  neighbourhood  of  the 

mouth  and  pouring  their  secretions  into  this  cavity  hy  means  of  ducts. 

It   is   possible   to   collect   the   fluid   secreted 

by  each  of  these  glands    separately,  and  it 

is  found  that  the  saliva  varies  in  properties 

according    to    the    gland    from    which    it    is 

derived.     In  addition  to  these  large  glands 

the  whole  mucous  membrane  of  the  mouth  is 

beset  with  small  glands. 

The  saliva  is  in  most  cases  a  mixture  of 
the  secretions  of  all  three  pairs  of  salivary 
glands  as  well  as  of  the  small  glands  of  the 
mucous  membrane.  When  collected  it  forms 
a  colourless  cloudy  liquid,  slimy  in  character. 
The  cloudiness  is  due  to  the  presence  of  a 
number  of  formed  elements  consisting  of 
desquamated  epithelial  cells,  disintegrating 
leucocytes,  and  gland-cells,  as  well  as  coagu- 
lated clumps  of  mucin.  Its  reaction  is  in 
healthy  individuals  slightly  alkaline.  Its 
specific  gravity  varies  between  1002  to  1008 
coagulable  proteins,  nuicin,  and  in  some  cases  a  diastatic  ferment,  ptyalin, 
and  traces  of  jiotassium  sulphocyanate.  Its  average  composition  is  as 
follows  : 


Fig. 


a. 


.32 J.  Dissection  to  display 
the  salivary  glands, 
sub-lingual  gland  ;  h,  sub- 
maxillary gland  ;  c,  parotid 
gland;  d,  common  opening  of 
ducts  of  sub-maxillary  and  sub- 
lingual glands ;  i,  opening  of 
duct  of  parotid  gland. 

Its  chief  constituents  are 


100  parts  mixed  yaliva  contain  : 

Total  solids 0-5    to  1-0 

Inorganic  solids    ........  O-l    to  0-6 

Organic  solids  (mucin,  serum  albumin,  scrum  globulin)      .  0-1    to  0-4 

Potassium  sulphocj'^anate       ......  0-00  to  0-016 

Freezing-point  (A)  =    -  0-07  to  -  0-34 

Potassium  suli)hocvanate  is  an  almost  constant  constituent  of  human  saliva,  though 
it  is  often  absent  in  that  of  other  animals,  such  as  tlie  dog.  It  is  generally  present 
to  the  extent  of  -01  per  cent,  so  that  on  the  addition  of  a  drop  of  ferric  chloride  to 

661 


662  PHYSIOLOGY 

saliva  a  definite  red  colour  is  obtained.  So  far  as  we  know  it  is  formed  in  the  body  when- 
ever cyanides  or  organic  nitriles  in  small  quantities  make  their  appearance  in  the 
circulating  fluid,  either  as  the  result  of  administration  or  perhaps  as  by-products  in 
the  normal  processes  of  metabolism.  The  conversion  of  the  poisonous  cyanides  into 
the  almost  innocuous  sulphocyanates  seems  to  be  a  means  by  which  the  organism 
protects  itself  against  the  poisonous  effects  of  the  former.  The  channels  of  excretion 
of  the  sulphocyanate  are  by  the  salivary  glands,  the  kidneys,  and  possibly  by  the 
gastric  juice. 

THE  USES  OF  SALIVA 
The  main  function  of  saliva  is  to  moisten  the  food  and  so  facilitate  its 
mastication  and  deglutition.  The  presence  of  the  mucin  is  of  special  value 
for  the  latter  process  since  it  renders  the  mass  of  food  sHppery.  In  animals, 
such  as  dogs,  where  the  saliva  is  devoid  of  any  digestive  ferment,  this  must 
represent  its  sole  function.  In  man  and  some  of  the  herbivora  the  saliva 
exerts  a  well-marked  digestive  effect  on  one  of  the  food-stuffs,  namely,  starch. 
If  a  warm  solution  of  starch  be  taken  into  the  mouth,  kept  there  for  one 
minute,  and  then  expelled  into  a  test-tube,  the  starch  will  be  found  to  have 
entirely  disappeared,  its  place  being  taken  by  a  reducing  sugar.  The  stages 
of  the  action  of  saliva  on  boiled  starch  can  be  followed  more  easily  if  its  action 
is  retarded  by  keeping  the  mixture  cool,  or  at  a  temperature  not  above 
25°  C.  The  first  change  is  a  conversion  of  the  opalescent  gelatinising  starch 
solution  into  a  clear  solution  which  no  longer  sets  on  cooling,  but  still  gives 
a  blue  colour  with  iodine.  The  fluid  contains  what  is  known  as  soluble  starch. 
The  soluble  starch  then  undergoes  hydrolytic  dissociation  into  a  dextrin, 
which  gives  a  red  colour  with  the  iodine  and  is  therefore  known  as  erythro- 
dextrin,  together  with  maltose.  The  erythrodextrin  is  then  hydrolysed  into 
an  achroodextrin  (giving  no  colour  with  iodine)  and  maltose,  and  the  achroo- 
dextrin  is  still  further  broken  up  into  dextrin  and  maltose.  The  conversion 
of  starch  into  maltose  is  never  complete,  though  if  the  maltose  be  removed 
by  dialysis  as  it  is  formed,  it  was  found  by  Lee  to  be  possible  to  convert  as 
much  as  95  per  cent,  of  the  starch  into  reducing  sugar.  The  stages  in  the 
conversion  are  represented  in  the  following  Table  : 

Starch 

I 

soluble  starch 


erythro-)  dextrines  Maltose 


(achroo-  )  dextrines  maltose 

The  process  by  which  the  huge  starch  molecule  is  converted  into  dextrins 
and  maltose  is  a  very  compHcated  one,  and  a  number  of  intermediate  com- 
pounds of  dextrins  and  maltose  can  exist  between  those  whose  presence  is 
revealed  by  their  varying  reaction  to  iodine. 

Ptyalin  is  most  active  in  a  neutral  medium,  so  that  the  addition  of 
minute  traces  of  acid  to  the  saliva  increases  its  diastatic  power.  In  the 
presence  of  free  mineral  acid  ptyaUn  is  rapidly  destroyed,  -003  per  cent. 


DIGESTION  IN  THE  MOUTH  663 

hydrochloric  being  sufficient  for  this  purpose.  It  acts  most  rapidly  at  the 
body  temperature.  At  0°  C.  its  action  is  stiU  just  perceptible./  If  heated  to 
60°  G.  it  is  destroyed. 

We  have  seen  that  boiled  starch  solution  is  changed  by  saliva  when  kept 
only  a  few  seconds  in  the  cavity  of  the  mouth.  When  the  starch  is  in  the 
solid  condition,  as  in  biscuits  and  most  farinaceous  foods,  its  stay  in  the 
mouth  during  the  normal  process  of  mastication  is  not  long  enough  to  allow 
of  any  considerable  hydrolysis  occurring.  When  a  meal  is  taken  the  food 
which  is  swallowed  forms  a  mass  lying  in  the  fundus  of  the  stomach.  This 
mass  is  penetrated  only  with  difficulty  by  the  acid  gastric  juice  secreted 
by  the  mucous  membrane  of  the  stomach  within  five  minutes  of  the  taking 
of  food.  Even  half  an  hour  after  a  meal  the  interior  of  the  mass  of  food  in  the 
stomach  may  be  still  found  to  be  neutral  or  slightly  alkahne.  The  food 
therefore,  thoroughly  moistened  by  and  mixed  with  saliva,  remains  in  the 
stomach  for  thirty  to  forty  minutes  before  the  salivary  ferment  is  destroyed 
by  the  penetration  of  the  acid  gastric  juice.  During  this  time  the  ptyahn 
continues  to  exert  its  efEect,  so  that  we  may  say  that  the  chief  part  of  the 
sahvary  digestion  occurs  actually  in  the  stomach,  and  results  in  an  almost 
complete  alteration  of  the  starch  into  dextrins  and  maltose.  Unboiled 
starch  is  attacked  with  extreme  slowness  by  the  diastatic  ferments  either  of 
the  saliva  or  the  pancreatic  juice,  so  that,  if  taken  by  man,  large  quantities 
are  unutilised  and  reappear  in  the  fseces.  Thirty  to  forty  minutes  after  a  meal 
the  food  becomes  thoroughly  soaked  with  the  acid  gastric  juice,  and  saUvary 
digestion  gives  place  to  gastric  digestion. 

THE  SECRETION  OF  SALIVA 
The  mucous  membrane  of  the  mouth,  especially  on  the  under  surface  of 
the  tongue,  presents  a  number  of  small  glands  which  contribute  by  their 
secretions  to  the  moistening  of  the  mouth.  The  greater  part  of  the  saliva  is, 
however,  formed  in  man  by  three  pairs  of  glands,  viz.  the  sub-lingual  and  the 
sub-maxillary  glands,  situated  in  the  floor  of  the  mouth  below  the  jaw,  and 
the  parotid  gland,  lying  in  the  cheek  over  the  ramus  of  the  inferior  maxilla. 

The  ari'angement  of  these  gland^^,  especially  of  those  in  the  floor  of  the  mouth, 
varies  somewhat  in  different  animals.  In  the  dog  and  cat  the  sub-lingual  gland  is 
wanting,  its  place  being  taken  by  a  gland  situated  somewhat  further  back  and  known  as 
the  retro-lingual  gland.  In  the  pig  both  retro-lingual  and  sub-lingual  glands  are  present 
in  addition  to  the  sub-maxillary,  and  one  may  sometimes  find  traces  of  the  retro- 
lingual  gland  in  man.  Many  animals,  e.g.  the  dog.  also  possess  a  gland  situated  in  the 
orbit,  which  pours  its  secretion  into  the  mouth — the  orbital  gland.  These  glands  can 
be  divided,  according  to  their  structure  and  the  nature  of  the  secretion  which  they  form, 
into  several  classes.  Among  the  salivary  glands  of  the  mucous  membrane  we  may 
distinguish  two  types,  the  mucous  gland  and  the  serous  gland.  In  specimens  hardened 
and  stained  by  the  orchnary  methods  the  mucous  gland  is  distingiiishcd  by  the  fact 
that  its  short  duct  opens  into  wide  alveoli,  the  lining  cells  of  which  are  distended 
with  mucin  and  therefore  present  a  clear  imstaincd  space  in  the  section.  In  the 
other  type,  the  serous  gland,  the  duct  lined  with  colunmar  cells  branches  into  a 
series  of  acini  which  present  a  well-marked  lumen  and  are  lined  \nt\\  small  granular 
cells  with  a  very  distinct  and  well -staining  nucleus.  The  same  general  distinction 
can  be  made  out  in  the  large  salivary  glands.      The  parotid  gland  in  man  and  in 


664 


PHYSIOLOGY 


all  the  higher  mammalia  is  a  typical  serous  gland,  though  here  and  there  A, 
mucous  cell  may  be  occasionally  seen.  The  orbital  gland  of  the  dog  represents 
practically  one  of  the  mucous  glands  of  the  general  mouth  cavity  on  a  large  scale. 
The  sub-lingual  and  sub-maxillary  glands  in  man  represent  a  third  type.  Most  of  the 
alveoli  are  mucous  in  character.  At  the  ends  of  the  alveoli  are  seen  crescent-shaped 
cells  between  the  mucin-distended  cells  and  the  basement  membrane.  These  are 
known  as  the  demilune  cells,  or  the  Crescent  cells  of  Gianuzzi.  In  some  cases  these 
mucous  alveoli  with  demilunes  may  be  found  along.^ide  of  typical  serous  alveoli. 


B         V 

Fig.  322.     a,  serous  gland  ;   b,  pure  mucous  gland  from  mouth. 
a,  ducts  ;   /,  fat-cells. 


(KoLLIKER. 


Thus  in  man  the  sub-maxillary  gland  is  usually  a  mixed  gland,  the  serous  alveoli 
predominating.  The  sub-lingual  gland  is  also  mixed,  but  with  a  predominance  of  the 
mucous  alveoli.  In  the  monkey  the  sub-maxillary  gland  is  almost  entirely  serous. 
In  the  dog  the  sub-maxillary  gland  is  a  pure  mucous  gland  with  demilunes,  while  the 
retro-lingual  and  sub-lingual  gland  when  present  are  of  the  mixed  type.  In  the  rabbit 
the  sub-maxillary  gland  is  serous,  while  the  sub-lingual  gland  is  mucous.  In  the  cat 
the  sub-maxillary  is  mucous,  the  retro-lingual  is  mixed,  and  the  sub-lingual,  when 
present,  is  mixed,  with  predominance  of  the  mucous  type. 

The  normal  behavioar  of  the  sahvary  glands  during  digestion  is  best 
studied  by  aid  of  a  method  used  long  ago  by  de  Graaf  and  reintroduced  with 
considerable  elaboration  of  late  years  by  Pawlow.  It  is  possible  without  any 
disturbance  of  the  animal's  nutrition  to  transplant  the  papilla  on  which  the 
duct  opens  to  the  outside  so  that  the  saliva  from  any  particular  gland  shall 
flow  externally  instead  of  into  the  cavity  of  the  mouth.  By  attaching  a  small 
funnel  to  the  fistulous  opening,  it  is  possible  to  collect  the  pure  saliva  unmixed 
with  the  secretion  of  any  other  of  the  glands. 

By  this  method  it  has  been  found  that  as  soon  as  food  is  introduced  into 
the  mouth  there  is  a  secretion  of  saliva,  the  relative  extent  to  which  different 
glands  are  involved  varying  according  to  the  nature  of  the  stimulation. 
Thiis  with  meat  there  is  only  a  small  amount  of  secretion,  which  is  derived 
chiefly  from  the  sub-maxillary  and  sub-lingual  glands,  and  is  rich  in  organic 
constituents.  When  dry  material,  such  as  dry  powdered  meat,  is  introduced 
the  flow  of  juice  is  more  copious  and  more  watery.  The  same  effect  may 
be  produced  in  the  dog  by  psychic  excitation.  Thus  salivation  may  be 
induced  by  showing  food  to  the  dog,  or  even  by  the  suggestion  that  dry 
powder  is  to  be  introduced  into  the  mouth.  A  comparison  of  the  juices  ob- 
tained from  different  glands  shows  that  the  serous  and  mucous  glands  differ, 
as  might  be  expected,  in  the  nature  of  their  secretion.  A  serous  gland,  such 
as  the  parotid,  gives  a  thin  watery  secretion  almost  free  from  mucin,  but 
containing  small  traces  of  coagulable  protein.     The  mucous  gland  delivers 


DIGESTION  IN  THE  MOUTH 


665 


a  secretion  which  is  viscid  from  the  presence  of  mucin,  and  contains  also  a 
small  trace  of  coagulable  protein.  Both  in  parotid  and  mucous  saliva  the 
percentage  of  salts  is  very  low,  so  that  the  freezing-point  of  these  fluids 
is  considerably  higher  than  that  of  the  blood-plasma.  In  the  dog  the  saliva 
is  free  from  any  ferments.  In  man  ptyalin — the  starch-sphtting  ferment — 
is  found  in  the  saliva  from  both  kinds  of  gland,  though  it  predominates  in  that 
obtained  from  the  parotid  gland.  The  total  amount  of  saliva  which  may  be 
obtained  varies,  of  course,  in  different  animals.  Each  gland  may,  however, 
in  the  course  of  the  day  give  an  amount  of  juice  far  exceeding,  e.g.  ten  or 
twelve  times,  its  own  weight.     In  man  it  is  reckoned  that  over  one  litre  of 


Fig.  323.     Diagram  of  nerve-supply  to  sub-maxillary  gland, 
Sm.G,   sub-maxillary    gland ;     N.L,   lingual    nerve ;     Ch.T,   chorda   tympani ; 
Sm.Gl,    sub-maxillary   ganglion ;     Sm.D,    \\'hartou"s    duct ;     V.J.    jugular   vein ; 
C.A,  carotid  artery ;    G.C.S,  superior  cervical  ganglion ;    N.S,  sympathetic  fibres 
ramifying  on  facial  artery.     (After  Foster.) 

saliva  may  be  formed  every  twenty- four  hours,  and  in  the  herbivora,  such  as 
the  horse,  the  total  diurnal  production  must  amount  to  many  htres  ;  500 
grammes  of  hay  alone  may  evoke  the  secretion  of  a  litre  of  sahva. 

The  intimate  dependence  of  the  secretion  of  sahva  on  the  events  occurring 
in  the  mouth  shows  that  the  activity  of  the  salivary  glands  must  be  excited 
by  reflex  means.  The  afferent  nerves  in  this  reflex  are  those  that  supply  the 
mucous  membrane  of  the  mouth,  i.e.  the  fifth  nerve  and  the  glossopharyngeal. 
The  efferent  channels  of  the  reflex  were  discovered  by  Ludw^g.  Each  one  of 
the  large  salivary  glands  receives  nerve  fibres  from  two  sources,  viz.  from  the 
cerebro-spinal  and  from  the  sympathetic  system.  It  is  probable  that 
the  cerebrospinal  supply  is  derived  always  from  one  part  of  the  cerebral 
axis,  namely,  from  the  filaments  which  make  up  the  nervus  intermedins. 
From  this  point  they  diverge  in  their  course  to  the  glands.  The  fibres  to  the 
sub-maxillary,  the  sub-lingual,  and  the  retro-lingual  glands  pass  into  the 
facial  nerve,  and  then  from  this  nerve  along  the  chorda  tympani  to  the  lingual 
division  of  the  fifth  nerve.  The  lingual  nerve  passes  below  the  duct,  and 
just  before  it  crosses  the  two  ducts  of  the  sub-maxillary  and  retro-  or  sub- 
lingual glands  it  gives  off  a  small  branch  backwards,  namely,  the  chorda 
tympani,  which  runs  along  the  sub-maxillary  duct  to  be  distributed  to  the 
glands,  and  in  its  course  gives  olf  fibres  also  to  the  retro-lingual  (Fig.  323). 


666 


PHYSIOLOGY 


The  fibres  are  apparently  finally  distributed  to  the  secreting  alveoh, 
where  they  end  freely  on  the  secreting  cells  just  below  the  basement  mem- 
brane. They  do  not,  however,  take  an  uninterrupted  course.  By  means 
of  the  nicotine  method  Langley  has  shown  that  all  the  fibres  to  the  sub-Hngual 
and  the  sub-maxillary  glands  end  somewhere  near  the  glands  in  connection 
with  ganghon-cells.  From  the  ganghon-cells  fresh  relays  of  fibres  are  given 
off  which  pass  to  the  gland-cells  themselves.  The  fibres  going  to  the 
sub-maxillary  gland  are  connected  with  scattered  cells  lying  in  the  substance 
of  the  gland  itself  ;  in  the  cat  those  passing  to  the  retro-lingual  gland  are 
connected  for  the  most  part  with  the  ganglion- cells  which  make  up  the 


Mylohyoid 


ngual .  N 


Hyog"lossus 


Geniohyoid 


Fig.  324,     Diagram  of  the  arrangement  of  the  nerve-supply  to  the  sub-maxillary 
gland,  as  exposed  in  an  actual  experiment. 
Duct,Wh,  Wharton's  duct  (of  sub-maxiUary) ;    Duct.R.L,  retro-lingual 
duct ;  Ch.Ty,  chorda  tympani  nerves.     (Alcock  and  Ellison.) 

so-called  '  sub-maxillary  ganghon.'  The  fibres  to  the  sub-hngual  gland  in 
man  probably  take  a  similar  course. 

The  fibres  to  the  parotid  gland  pass  along  the  glossopharyngeal  nerve 
and  its  tympanic  branch  (nerve  of  Jacobson)  to  the  tympanic  plexus.  Hence 
the  fibres  are  carried  by  the  small  superficial  petrosal  nerve  to  the  otic 
ganglion,  and  thence  by  the  auriculo-temporal,  which  is  a  branch  of  the 
third  division  of  the  fifth  nerve. 

The  sympathetic  supply  to  all  these  glands  is  contained  in  fine  filaments 
on  the  walls  of  the  arteries  with  which  they  are  supphed.  The  fibres  are 
derived  ultimately  from  the  spinal  cord,  whence  they  issue  by  the  upper  three 
anterior  dorsal  nerve-roots.  They  pass  into  the  stellate  ganglion,  round  the 
ansa  Vieussenii  to  the  inferior,  and  so  to  the  superior  cervical  ganglion 
of  the  sympathetic.  Here  the  fibres  end  around  the  cells  of  the  ganghon, 
and  a  fresh  relay  of  fibres,  chiefly  non-medullated,  arise  from  the  cells  and 
travel  on  the  walls  of  the  branches  of  the  external  carotid  artery  to  their 
destination. 

The  efliect  of  stimulating  the  peripheral  ends  of  the  cerebrospinal  nerves 
going  to  the  glands  presents  a  general  resemblance,  whichever  be  the  gland 
involved.  Within  a  period  of  half  to  two  seconds  after  the  stimulation  has 
been  applied,  a  secretion  of  saliva  is  produced,  presenting  similar  characters 


DIGESTION  IN  THE  MOUTH 


667 


to  that  which  would  be  obtained  from  the  gland  under  normal  conditions  if 
it  were  provided  with  a  permanent  fistula.  The  concentration  of  the  sahva 
as  well  as  its  rate  of  secretion  depends  on  the  strength  of  the  stimulus.  The 
following  Table  (Heidenhain)  shows  the  effect  on  the  amount  and  composition 
of  sub- maxillary  sahva  obtained  by  weak  and  strong  stimulation  of  the 
chorda  tympani  nerve  : 


strength  of  stimulus 

Quantity  in  one 
minute 

Per  cent,  of 
organic  solids 

Per  cent,  of 
salts 

Weak     . 
Strong    . 
Weak     . 

0-17 
0-72 
0-17 

0-84 
2-OG 
1-67 

0-20 

046 

0-26 

With  the  strong  stimulus  the  amount  of  saliva  was  increased  over  four- 
fold, while  the  percentage  of  organic  substances  in  the  sahva  was  raised  from 
0-84  to  2-06  per  cent.  There  was  at  the  same  time  an  increase  in  the  per- 
centage of  salts.  If  the  excitation  be  continued  for  a  considerable  time, 
there  is  a  gradual  rise  in  the  percentage  of  inorganic  salts  and  a  fall  in  the 
percentage  of  organic  matter. 

The  cranial  nerves  going  to  these  glands  have  another  important  effect, 
namely,  vaso-dilatation.  It  was  shown  by  Claude  Bernard  that  if  the 
outflow  from  the  vein  of  the  sub-maxillary  gland  were  measured,  on  exciting 
the  chorda  tympani  the  flow  might  increase  four  to  eight  times,  and  indeed 
to  such  an  extent  that  the  blood  passing  through  the  gland  did  not  stay  there 
long  enough  to  lose  its  oxygen.  Moreover  the  dilatation  of  the  arterioles 
removes  the  normal  resistance  which  serves  to  damp  and  obliterate  the  pulse 
between  the  arteries  and  the  veins.  As  the  result  of  exciting  the  chorda 
therefore  the  blood  coming  from  the  vein  may  show  distinct  pulsation,  and 
may  have  a  brilhant  scarlet  hue  just  as  if  it  were  derived  from  an  artery.  \ 
The  same  dilatation  has  been  observed  to  attend  excitation  of  the  cranial  ' 
supply  to  the  parotid  gland. 

The  effects  of  exciting  the  sympathetic  nerve-supply  differ  according  to 
the  gland  and  the  animal  which  is  the  subject  of  experiment.  In  the  dog 
excitation  of  the  cervical  sympathetic  causes  the  secretion  of  a  few  drops 
of  thick  viscid  saliva  from  the  sub-maxillary  gland.  In  this  animal  no 
secretion  is  obtained  at  all  from  the  parotid  gland  on  exciting  the  sympathetic, 
but  the  influence  of  the  excitation  is  sho^^■n  by  the  occurrence  of  histological 
changes  in  the  gland-cells.  In  the  cat  the  sub-maxillary  sahva  obtained  on 
sympathetic  excitation  may  be  as  copious  as  and  even  more  watery  than 
the  saliva  obtained  from  the  sub-maxillary  on  stimulation  of  the  chorda 
tympani.  We  shall  have  later  on  to  discuss  how  far  these  results  are  to  be 
ascribed  to  a  fundamental  difference  in  the  point  of  attack  of  impulses 
carried  to  the  secreting  cells  by  the  two  sets  of  nerve  fibres,  and  how  far  to 
the  varying  effects  of  the  cranial  and  sympathetic  nerves  respectively  on 
the  blood-vessels.     It  must  be  remembered  that  the  sympathetic  nerve 


Duct. 


668  PHYSIOLOGY 

carries  the  vaso-constrictor  fibres  to  most  or  all  of  the  vessels  of  the  head  and 
neck,  and  therefore  in  most  cases  we  should  expect,  and  we  find,  that  stimu- 
lation of  this  nerve  causes  vascular  constriction  in  the  gland  affected.  Before 
attempting  to  decide  this  point  we  must  study  in  somewhat  greater  detail  the 
changes  which  occur  in  the  gland  concomitantly  with  the  secretion. 

CHANGES  IN  THE  GLAND  ACCOMPANYING  SECRETION 
The  fact  that  a  sub-maxillary  gland  of  the  dog  under  favourable  condi- 
tions will  secrete  its  own  weight  of  sahva  in  five  minutes,  and  will  continue 
to  secrete  for  many  hours  afterwards,  shows  that  there  must  be  a  continual 

renewal  of  the  fluid  which  is  turned  out 
in  the  secretion.  The  source  of  this 
fluid  must  be  the  blood  which  is  circu- 
lating through  the  gland.  If  we  refer  to 
the  diagrammatic  representation  of  the 
elements  which  make  up  a  secreting  lobule  ' 
and  which  may  be  involved  in  the  act  of 
secretion  (Fig.  325),  we  see  that  between 
the  lumen  of  the  duct  and  the  blood, 
which  must  be  regarded  as  the  source  of 
the  fluid,  the  following  layers  of  cells 
intervene  :  (1)  the  endothelium  of  the 
blood  capillaries  ;  (2)  the  basement  mem- 
brane ;  (3)  the  epithehal  cells  of  the  gland 
proper.  We  have,  in  the  first  place,  to  decide  to  which  of  these  elements 
can  be  ascribed  the  chief  part  in  the  act  of  secretion. 

The  secretory  activity  of  the  sub- maxillary  gland,  whether  evoked 
reflexly  by  the  introduction  of  acids  into  the  mouth  or  directly  by  the 
injection  of  pilocarpine  or  by  stimulation  of  the  peripheral  end  of  the  chorda 
tympani  nerve,  is  always  associated  with  a  considerable  dilatation  of  the 
vessels  of  the  gland,  and  a  consequent  large  increase  in  the  blood  flow  through 
the  gland,  which  may  amount  to  between  three  and  eight  times  the  quantity 
passing  during  rest.  Such  an  increase  in  the  supply  of  blood  is  necessary 
in  order  to  afford  a  source  for  the  large  quantity  of  fluid  which  is  turned  out 
in  the  sahva.  Another  effect  of  the  dilatation  will  be  to  raise  the  pressure 
in  the  capillaries  of  the  gland.  We  cannot,  however,  regard  this  rise  of 
pressure  in  the  capillaries  as  an  essential  factor  in  the  act  of  secretion.  If  [ 
atropine  be  administered  excitation  of  the  chorda  causes  the  same  vaso- 
dilatation as  before,  though  no  secretion  is  produced.  Moreover  Ludwig 
showed  that  the  force  with  which  the  secretion  is  turned  out  into  the  ducts 
of  the  gland  is  greater  than  that  represented  by  the  blood  pressure.  The 
blood  pressure  in  the  capillaries  must  be  considerably  lower  even  with  full 
vascular  dilatation  than  the  pressure  in  the  carotid  artery.  If  two  mano- 
meters be  connected,  one  with  the  carotid  artery  and  the  other  with  the 
duct,  it  will  be  found  that  on  stimulating  the  chorda  tympani  nerve  the 
secretion  will  be  excited,  and  the  mercury  will  be  driven  up  by  the  pressure 


Lymph  spaces 


,  -Secreting 
cells. 

-  Blood 
capillary. 


Basement 
membrane 

Fig.  325.  Diagram  to  show  relation  of 
the  secreting  cells  of  a  gland  to  the 
blood  and  lymph  supply. 


DIGESTION  IN  THE  MOUTH 


669 


''Uk.UO^^^^^^J^- 


T,^»n«JU*-Z9Mi.     . 


[lofxtX  , 


Fig.  326.  Tracing  of  volume  of  sub-maxillary 
gland,  showing  effect  of  stimulation  of  the 
chorda  after  administration  of  10  mg.  atro- 
pine. The  blood-pressure  (lowest  line)  was 
unaltered  by  the  stiumlation.     (Bttnch.) 


of  the  secretion  in  the  corresponding  manometer  until  it  attains  a  height 
which  may  be  double  that  of  the  mercury  in  the  manometer  connected  with 
the  carotid  artery,  and  therefore  must  be  still  greater  than  the  pressure  in  the 
capillaries  of  the  gland.  This  ex- 
periment, which  is  easy  to  repeat, 
showed  the  impossibihty  of  the 
act  of  secretion  being  in  any  way 
determined  by  a  process  of  filtra- 
tion. We  have  now  further  evi- 
dence that  work  is  done  in  the 
production  of  the  salivary  secre- 
tion, evidence  which  was  not 
available  when  Ludwig  first  car- 
ried out  the  experiment  just  de- 
scribed. When  a  fluid  containing 
salts  in  solution  is  filtered  through 
a  porous  membrane  the  filtrate  has 
the  same  content  in  salts  as  the 
original  fluid.  We  can  effect  a 
separation  of  dissolved  salts  from 
a  fluid  by  filtration  under  pressure 
through  some  membrane  which  is 
impermeable  to  the  salts,  e.g.  a 
membrane  of  copper  ferrocyanide 
— a  so-called  semipermeable  mem- 
brane. Under  these  circumstances 
a  very  large  pressure  is  necessary 
in  order  to  cause  the  filtration  of 
any  fluid  at  all,  a  pressure  which 
is  equal  to  the  osmotic  pressure 
exerted  by  the  substances  in  solu- 
tion. Thus  if  we  were  filtering 
a  1  per  cent,  solution  of  NaCl 
through  a  semipermeable  mem- 
brane, we  should  have  to  exert  a 
pressure  of  about  seven  atmo- 
spheres in  order  to  obtain  a  filtrate 
free  from  sodium  chloride.  To 
obtain  a  filtrate  containing  half  the  amount  of  sodium  chloride,  if  such 
were  possible,  would  therefore  need  a  pressure  of  about  three  and  a  half 
atmospheres.  On  comparing  the  osmotic  pressures  of  sahva  and  blood 
respectively — and  for  this  pmpose  we  can  employ  the  depression  of  freez- 
ing-point as  our  index — we  find  that  the  molecular  concentration  of 
saliva,  and  therefore  its  osmotic  pressure,  is  always  very  much  less  than  that 
of  the  blood  plasma,  and  may  vary  between  half  and  three-quarters  of  the 
latter.     Supposing  the  membrane  separating  the  lumen  of  the  duct  from  the 


Fio.  327.  Tracing  of  volume  of  sub-maxillary 
gland  showing  decrease  on  excitation  of 
chorda.     (BuNcn.) 


670  PHYSIOLOGY 

blood-vessels  could  be  regarded  as  endowed  with  the  properties  of  a  semi- 
permeable membrane,  we  should  need,  in  order  to  effect  the  separation,  a 
pressure  ten  to  twenty  times  as  large  as  the  arterial  blood  pressure.  We 
must  conclude  then  that  work,  both  osmotic  and  mechanical,  is  performed 
in  the  separation  of  the  fluid  from  the  blood  and  its  transference  in  the 
form  of  saliva  to  the  duct.  A  very  simple  experiment  will  suffice  to  show 
that  this  work  must  be  effected,  not  by  the  endothehal  cells  of  the  blood- 
vessels, but  by  the  gland- cells  themselves.  The  fluid  passes  from  the 
blood-vessels  first  into  the  lymphatic  spaces,  whence  it  is  taken  up  by 
the  secretory  cells.  If  the  first  act  in  secretion  consisted  in  an  increased 
exudation  of  fluid  from  the  blood  into  the  lymph  spaces  the  first  effect  of 
exciting  the  chorda  tympani  nerve  should  be  to  cause  an  accumulation  of 
fluid  in  the  lymph  spaces,  some  increase  in  the  lymph  flow  from  the  gland, 
and  the  swelling  of  the  whole  gland.  By  placing  the  gland  in  a  plethysmo- 
graph  we  can  record  the  actual  changes  in  its  volume  which  ensue  on  ex- 
citation of  the  chorda  tympani.  If  all  secretion  be  prevented  by  the 
previous  administration  of  atropine,  stimulation  of  this  nerve  produces,  as 
might  be  anticipated,  an  increased  volume  of  the  gland  in  consequence  of  the 
dilatation  of  its  vessels  (Fig*  326).  If,  however,  the  gland  be  allowed  to 
secrete  we  obtain,  in  spite  of  the  simultaneous  increase  in  size  of  the  vessels, 
an  actual  diminution  in  the  size  of  the  gland  itself,  showing  that  the  first 
effect  of  the  stimulation  is  on  the  cells  of  the  alveoh  (Fig.  327).  Under  the 
stimulus  these  empty  themselves  of  the  fluid  they  contain,  replenishing  their 
loss  at  the  expense  of  the  fluid  in  the  lymph  spaces.  The  increased  passage 
of  fluid  from  blood  to  lymph  space  is  therefore  a  secondary  and  not  a  primary 
effect  of  the  nerve  stimulation,  and  the  first  effect  on  the  gland  is  a 
diminution  of  volume  and  not  an  increase,  as  one  would  expect  if  the  vascular 
endothelium  were  primarily  responsible  for  the  act  of  secretion. 

HISTOLOGICAL  CHANGES   DURING  SECRETION 

The  process  of  secretion  is  associated  with  marked  changes  in  the  structure 
of  the  cells  composing  the  secretory  alveoli.  The  changes  are  of  the  same 
general  character  whatever  class  of  glands  we  investigate,  though  the  ease 
with  which  they  are  to  be  demonstrated  varies  with  the  reactions  of  the 
variou-s  glands  to  the  hardening  fluids  usually  employed.  If  a  small  frag- 
ment of  a  mucous  gland  be  teased  in  blood  serum  or  in  2  per  cent.  NaCl 
solution,  the  cells  are  found  to  be  packed  with  a  mass  of  coarse  highly  refrac- 
tive granules  (Fig.  328).  If  a  corresponding  specimen  be  made  from  a 
serous  gland  (Fig.  329)  the  cells  are  also  packed  with  granules,  which,  how- 
ever, are  much  finer  in  structure.  On  making  similar  specimens  from 
glands  which  have  been  forced  to  secrete  for  six  or  seven  hours,  the  individual 
cells  are  found  to  be  much  smaller  and  the  protoplasm  of  the  cell  is  absolutely 
or  relatively  increased  in  amount,  while  the  granules  are  much  fewer  and  are 
now  confined  almost  entirely  to  the  inner  margin  of  the  cell.  Activity  is 
thus  associated  certainly  with  a  discharge  of  granules,  and  probably  with 
some  increased  building  up  of  protoplasm.     We  may  regard  the  act  of 


DIGESTION  IN  THE  MOUTH 


671 


secretion  as  determined  by  the  alteration  of  the  granules  and  their  discharge, 
together  with  water  and  salts,  to  form  the  specific  secretion  of  the  gland. 
During  rest  the  granules  are  re-formed  by  precipitation  in  or  modification 
of  the  protoplasm  surrounding  the  nucleus.  We  have  evidence  that  although 
the  granules  form  the  secretion,  they  represent,  not  the  secretion  itself,  but 
a  precursor  of  some  at  any  rate  of  its  constituents.  Thus  if  acetic  acid  be 
added  to  the  sahva  obtained  from  the  sub-maxillary  gland,  the  mucin  is  pre- 
cipitated as  threads  and  films.  If  the  granules  in  the  secreting  cells  also 
consist  of  mucin  we  should  expect  acetic  acid  to  have  a  coagulating  effect 
upon  them.  We  find,  on  the  contrary,  that  on  allowing  acetic  acid  to  flow 
over  a  section  of  the  fresh  gland  the  granules  at  once  sw^ell  up  and  burst. 


Fig.  3i8.  Mucous  cells  from  a  fresh 
subma xillary  gland  of  a  dog.  (Lang- 
ley.) 

a,  mucous  cell  examined  fresh  from 
a  resting  gland  ;  a',  the  same  cell 
treated  with  weak  alcohol  ;  b  and  b\ 
cells  from  a  discharged  gland  before 
and  after  treatment  with  weak  alcohol. 


Fig.  329.     Acini  of   a   serous   salivary 

gland.     (Langley.) 

A,  resting  condition ;    b,   discharged 
condition. 


We  must  regard  these  granules  therefore,  not  as  mucin,  but  as  a  precursor 
of  mucin,  mucigen.  The  effect  of  ordinary  hardening  reagents,  such  as  dilute 
alcohol  up  to  70  per  cent,  or  Miiller's  fluid,  is  to  cause  these  granules  to  swell 
up  so  that  the  cells  become  filled  with  a  mass  of  mucin  giving  the  typical 
hyahne  appearance  of  ordinary  sections  of  these  glands.  In  the  case  of  the 
serous  gland  the  granules  (Fig.  330)  are  apparently  protein  in  nature.  Where 
ptyalin  is  a  constituent  of  the  saliva  we  are  probably  justified  in  assuming 
that  it  is  contained  either  pre-formed  or  more  probably  as  a  precursor  in 
the  granules.  In  the  glands  of  the  stomach  we  have  evidence  that  the 
granules  are  not  pepsin — the  characteristic  ferment  of  gastric  juice — but  a 
precursor  of  this  substance,  namely,  pepsinogen.  It  is  very  customary 
therefore  to  speak  of  the  granules  in  a  secreting  gland  as  zymogen  granules, 
i.e.  the  precursors  of  zymins  or  ferments.  It  is  probable  that  we  ought  to 
regard  these  granules  not  merely  as  material  precursors  of  the  constituents  of 
the  secretion,  but  as  little  machines  or  cell  laboratories  in  which  proceed  a 
whole  series  of  chemical  and  osmotic  changes  which  determine  the  production 
of  the  fully  formed  secretion  directly  from  the  protoplasm  and  indirectlv 
from  the  ordinary  constituents  of  the  surrounding  lymph. 


672 


PHYSIOLOGY 


a--'^'i 


From  an  examination  of  the  stained  specimens  of  glands  the  following 
stages  in  the  production  of  secretion  have  been  described  : 

(1)  In  the  neighbourhood  of  the  nucleus,  and  probably  with  its  active 
co-operation,  a  differentiation  of  the  protoplasm  occurs  with  the  production 

in  most  cases  of  a  basophile 
substance  which  in  hardened 
specimens  generally  takes  the 
appearance  of  filaments.  Since 
these  filaments  are  sometimes 
regarded  as  the  working  part 
of  the  protoplasm,  they  have 
been  given  the  name  of  ergas- 
toplasm  (Fig.  331,  c  and  d). 

(2)  By  a  modification  of 
the  ergastoplasm  granules  are 
formed.  After  their  first 
appearance  these  granules 
undergo  gradual  modification, 
as  is  shown  by  the  fact  that 
the  staining  reactions  of  the 
granules  near  the  base  of  the 
cell  differ  from  those  of  the  gran- 
ules at  the  free  margin. 

(3)  When  the  secretion  is  ex- 
cited, the  fully  formed  granules 
take  up  water  and  salts  in  vary- 
ing proportions,  swell  up,  and 
discharge  their  contents  into  the 
lumen  of  the  alveolus  as  the 
secretion  proper  to  the  gland. 


Fig.  330,     Sub-maxillary  gland  of  rabbit. 
(ScHAFER  after  E.  Mtjller.) 
The  cells,   all  serous,   are  in  different  functional 
states  :    a,  a  loaded  cell ;    b,  a  discharged  cell ;  c,  a 
secretory  canaliculus  penetrating  into  a  cell. 


i 


D 


Fig.  331.  Cells  of  pancreas,  showing  succes 
sive  stages  in  activity,  a,b,C',d.  a,  resting 
D,  discharged  gland.     (Mathbws.) 


ELECTRICAL  CHANGES 
Every  locahsed  chemical  change 
in  a  system  permeated  by  electro- 
lytes must  give  rise  to  electrical 
difiierences  of  potential.  It  is 
therefore  natural  that  electrical  changes  should  accompany  the  intense 
chemical  activity  which  is  associated  with  secretion.  The  interpretation  of 
these  changes  is  difficult,  owing  to  the  simultaneous  operation  of  another 
factor  which  may  determine  electrical  differences  of  potential,  namely, 
the  movement  of  fluids  through  porous  membranes.  If  the  hilum  of 
the  sub-maxillary  gland  and  its  outer  surface  be  connected  with  a 
galvanometer,  a  resting  difference  of  potential  is  nearly  always  found, 
generally  in  such  a  direction  that  the  outer  surface  is  positive  to  the 
hilum.  The  current  through  the  gland  is  therefore  from  within  out.  On 
exciting  the  chorda  tympani  nerve  a  diphasic  efiect  is  generally  obtained, 


DIGESTION  IN  THE  MOUTH  673 

the  resting  difference  being  first  increased  and  later  on  diminished.  On 
excitation  of  the  sympathetic  nerve  we  generally  obtain  a  purely  negative 
variation  of  the  resting  difference.  These  results  were  interpreted  by 
BayHss  and  Bradford  as  due  to  the  co-operation  of  the  two  factors, 
chemical  change  in  the  gland-cells  and  movement  of  fluid  through  the  cells. 
The  positive  variation,  i.e.  the  current  from  within  out,  was  ascribed  to  the 
movement  of  fluid,  whereas  the  negative  variation  of  the  resting  differencft 
was  thought  to  be  due  to  the  chemical  changes  in  the  gland-cells. 

THE  SIGNIFICANCE  OF  THE   DOUBLE  NERVE-SUPPLY 
TO  THE  GLANDS 
Iccording  to  Heidenhain,  although  the  parotid  gland  gives  Httle  or  no  | 
secretion  on  stimulation  of  the  sympathetic  nerve,  prolonged  stimulation  \ 
of  this  nerve  causes  histological  changes  in  the  gland  even  more  marked 
than  those  produced  by  the  cranial  nerve.     Similar  histological  changes 
were  found  by  him  in  the  sub-maxiUary  gland.     He  was  therefore  led  to  put 
forward  the  hypothesis  that  the  salivary  glands  are  supplied  by  two  funda- 
mentally different  classes  of  fibres,  namely  :   (1)  trophic  fibres,  which  deter- 
mine the  chemical  changes  in  the  gland  responsible  for  the  production  of  the 
specific  constituents  of  the  secretion,  and  (2)  secreto-motor  fibres,  excitation 
of  which  causes  the  cells  to  take  up  water  and  salts  from  the  lymph  and 
blood,  and  pass  them  in  large  quantities  into  the  duct.     According  to  this    ^ 
view  the  sympathetic  nerve-supply  to  the  gland  would  consist  almost 
entirely  of  trophic  fibres,  whereas  secreto-motor  fibres  would  predominate  in 
the  cranial  nerve- supply.     The  action  of  atropine  would  appear  at  first  sight 
to  favour  this  hypothesis.     In  minute  doses  it  entirely  annuls  the  action 
of  the  chorda  tympani  nerve  or  the  corresponding  nerve  to  the  parotid, 
while  it  is  without  efl'ect  on  the  sympathetic  nerve-supply  imless  given  in 
huge  doses.     The  preponderating  effect  of  the  sympathetic  on  the  histological 
structure  of  the  gland-cells  has  not  been  confirmed  by  later  observers,  and 
the  varying  effects  of  atropine  on  the  two  sets  of  nerve  fibres  may  be  con- 
ditioned by  morphological  rather  than  by  functional  differences  between 
their  nerve- endings.     According  to  Langley  and  Carlson,  the  difference  in  the 
action  of  the  chorda  tympani  and  of  the  sympathetic  on  the  submaxillary 
gland  is  due  to  the  synchronous  action  of  these  nerves  on  the  blood-supply 
to  the  gland,  the  sympathetic  causing  vaso-constriction,  while  the  chorda 
tympani  causes  vaso-dilatation.     In  confirmation  of  this  explanation  they 
have  shown  that  clamping  the  carotid  artery  during  chorda  stimulation 
diminishes  the  amount  of  saliva  secreted  but  increases  the  percentage  of 
solids  in  the  fluid.     This  theory  is  however  inadequate  to  explain  the 
differences  observed  in  the  secretion  of  saliva  reflexly  aroused  by  introduction 
of  substances  into  the  mouth.     In  a  dog  with  a  permanent  submaxillary 
fistula  a  copious  flow  of  saliva  may  be  caused  by  the  introduction  of  -25  per 
cent,  hydrochloric  acid  or  of  meat  powder.     The  amount  of  saliva  secreted 
under  the  two  circumstances  is  approximately  the  same,  but  that  evoked 
by  the  introduction  of  meat  powder  contains  about  t^^'^ce  as  much  solid 

22 


674  PHYSIOLOGY 

contents  as  that  which  follows  the  introduction  of  acid  into  the  mouth. 
Babkin  has  shown  that  the  same  differences  are  foimd  after  complete  section 
of  the  sympathetic  and  that  there  is  the  same  acceleration  of  the  circulation 
through  the  gland  whether  the  secretion  is  aroused  by  introduction  of  meat 
powder  or  of  acid.  It  is  impossible  therefore  to  explain  the  difference  in  the 
composition  of  the  saliva  obtained  under  these  two  circumstances  as  due  to 
differences  in  the  blood-supply  to  the  gland,  and  we  must  conclude  either  that 
the  chorda  tympani  contains  different  kinds  of  fibres  which  are  excited  to 
varying  extent  according  to  the  nature  of  the  reflex  stimulations,  or  that  one 
and  the  same  nerve  fibre  can  convey  specifically  different  impulses.  The  latter 
explanation  would  not  be  in  accord  with  the  generally  accepted  Miiller's  law 
of  specific  irritability  but  is  the  explanation  to  which  Babkin  himself  inchnes. 
At  any  rate  it  is  certain  that  according  to  the  nature  of  the  reflex  stimulus 
.  either  the  secretion  of  water  and  salts  or  the  secretion  of  organic  sohds  may 
preponderate,  altogether  apart  from  changes  in  the  circulation  simultaneously 
evoked. 

THE  ENERGY  INVOLVED  IN  THE  ACT  OF  SECRETION 

The  source  of  the  energy  must  be  sought  in  the  processes  of  oxidation 
occurring  in  the  cells  of  the  gland,  and  Barcroft  has  attempted  to  determine 
the  total  amount  of  energy  put  out  by  the  gland  in  the  act  of  secretion 
by  measuring  its  respiratory  exchanges  under  the  conditions  of  rest  and 
activity.  He  found  that  the  resting  submaxillary  gland  in  a  small  dog  took 
up  0-25  c.c.  of  oxygen  per  minute  and  put  out  0-17  c.c.  COg,  while  during 
active  secretion  it  absorbed  0-86  c.c.  Og  and  gave  off  0-39  c.c.  COg.  Assuming 
that  the  total  oxygen  taken  up  is  employed  in  the  oxidation  of  a  food 
substance,  such  as  glucose,  and  that  the  whole  of  the  energy  of  the  chemical 
changes  is  set  free  in  the  form  of  heat,  we  find  that  a  resting  gland  weighing 
about  six  grammes  produces  about  1-1  calories  per  minute.  We  know, 
however,  that  a  certain  amount  of  external  work  is  performed  in  the  secretion 
of  a  sahva  containing  less  salts  than  the  original  blood,  and  also,  when  there 
is  any  resistance  to  the  flow  of  saliva  through  the  duct,  in  raising  the  hydro- 
static pressure  of  the  saliva  in  the  duct  to  a  height  greater  than  that  in  the 
blood  capillaries. 

Can  we  from  all  these  data  form  a  conception  of  the  total  changes 
occurring  in  the  gland  and  involved  in  the  formation  of  the  secretion  ?  Even 
during  rest,  changes  are  going  on  in  the  gland-cells,  changes  which  involve 
the  taking  up  of  food  material  and  its  assimilation  under  the  influence  of 
the  nucleus,  perhaps  into  the  nucleus  itself,  and  certainly  into  the  undifferen- 
tiated cytoplasm.  In  this  cytoplasm  a  further  change  occurs,  leading  to  its 
transformation  into  granules.  When  activity  is  excited  by  the  stimulation  of 
secretory  nerves,  rhe  primary  change  appears  to  involve  simply  the  granules. 
These  structures  must  absorb  water,  apparently  against  osmotic  pressure. 
Those  nearest  the  lumen  swell  up,  become  converted  into  spheres  containing 
water  and  salts  in  smaller  proportion  than  exists  in  the  lymph  bathing 
the  cells  (and  presumably  in  the  protoplasm  surrounding  the  granules),  and 
in  this  swollen  form  are  discharged  or  ruptured  on  the  periphery  of  the  cell 


DIGESTION  IN  THE  MOUTH  675 

into  the  lumen,  so  giving  rise  to  secretion.  This  discharge  of  a  fluid  with 
a  smaller  molecular  concentration  than  the  cell  or  surrounding  blood  plasma 
must  lead  to  an  increased  concentration  in  the  remaining  parts  of  the  cell. 
The  increased  concentration  would  naturally  induce  a  flow  of  water  from 
lymph  into  cell,  and  the  consequent  concentration  of  the  lymph  would  in  the 
same  way  cause  a  flow  of  water  from  blood  to  lymph.  This  pull  of  water  by 
the  cell  from  the  blood  is  still  further  increased  in  another  way.  The  act 
of  secretion,  involving  as  it  does  the  expenditure  of  energy,  can  be  carried  out 
only  at  the  expense  of  chemical  changes  in  the  cell.  These  chemical  changes, 
as  in  all  other  metabolic  processes  of  the  body,  will  result  in  the  formation  of 
a  number  of  small  molecules  from  the  great  coUoid  molecules  of  the  proto- 
plasm. The  products  of  metabolism,  or  metabolites,  will  therefore  accumulate 
in  the  cell,  pass  into  the  lymph,  and  increase  the  concentration  of  the  latter. 
The  increased  concentration  will  call  forth  an  increased  transudation  of 
fluid,  e.g.  water,  from  the  blood-vessels,  and  the  transudation  thus  evoked 
will  be  greater  than  that  necessary  to  provide  the  water  of  the  saHva,  and 
will  therefore  produce  a  distension  of  the  lymphatic  spaces  of  the  gland  and 
an  increased  discharge  of  lymph  along  its  efferent  lymphatics.  As  a  second- 
ary result  of  the  activity,  perhaps  in  consequence  of  the  removal  of  the 
products  of  the  resting  metaboHsm  of  the  gland,  there  is  increased  growth  of 
protoplasm,  increased  activity  of  the  nucleus,  and  therefore  a  tendency  to 
increased  assimilatory  changes  and  a  preparation  of  the  cell  for  further 
secretory  changes  either  immediately  or  hereafter. 

In  the  gland,  however,  as  in  muscle,  when  we  attempt  to  form  a  concep- 
tion of  the  mechanism  of  the  chemical  machine  in  the  Uving  cell,  we  are 
brought  up  against  insuperable  difficulties.  One  might  perhaps  conceive  of 
the  secretory  granules  being  bounded  by  a  membrane  impermeable  to  inter- 
mediate metabohtes  and  salts,  but  permeable  to  carbon  dioxide.  If  the" 
first  effect  of  stimulation  of  the  secretory  nerves  were  to  produce  an  explosive 
disintegration  of  the  complex  molecules  making  up  the  granules,  we  should 
have  a  sudden  multiplication  of  molecules  within  the  granules.  This  woidd 
cause  a  large  rise  of  the  osmotic  pressure  in  these  granules  and  the  consequent 
absorption  of  water  from  the  surrounding  protoplasm.  This  process,  how- 
ever, could  only  result  in  the  production  of  a  fluid  in  the  granules  having 
the  same  osmotic  pressure  as  the  surrounding  medium,  whereas  we  know  that 
saUva  has  a  molecular  concentration  which  is  only  one  half  of  that  of  the 
blood  or  lymph.  We  should  therefore  have  to  make  a  second  assumption, 
namely,  that,  before  the  extrusion  of  the  solution  from  the  granules,  there  is 
a  further  breakdown  of  the  metabolites  by  a  process  of  oxidation,  with  the 
production  of  carbon  dioxide  which  diffuses  into  the  surrounding  protoplasm. 
We  have,  however,  no  evidence  of  either  of  these  processes  or  for  any  of 
these  assumptions,  and  I  have  only  adduced  them  in  order  to  show  how  far 
we  are  still  from  the  actual  comprehension  of  the  events  occurring  in  every 
living  cell,  and  underlying  its  conditions  of  rest  and  activity. 


SECTION   II 


THE  PASSAGE  OF  FOOD   FROM  THE   MOUTH 
TO  THE  STOMACH 

The  food   after   mastication  is   carried  to   the    stomacli   by  a   complex 
series  of  co-ordinated  movements  involving  the  muscles  of  the  pharynx  and 

the  oesophagus  (Fig.  332).  Various 
methods  have  been  used  to  study 
the  process  of  deglutition  in  man 
and  the  higher  animals.  Important 
information  can  be  obtained  by 
allowing  a  man  or  animal  to  swallow 
either  a  fluid  or  solid  with  which 
bismuth  is  mixed  and  observing  the 
passage  of  the  opaque  substance 
under  the  Rontgen  rays.  The  sub- 
nitrate  of  bismuth  may  be  mixed 
with  milk  for  a  fluid  or  with  bread 
and  milk  for  a  semi-solid  substance, 
or  may  be  enclosed  in  a  cachet  and 
swallowed  as  a  solid  bolus.  The 
time  of  entry  of  the  food  into  the 
stomach  may  be  determined  by  aus- 
cultating with  a  stethoscope  over  the 
region  of  the  cardiac  orifice.  Since 
a  certain  amount  of  air  is  always 
swallowed  at  the  same  time  as  the 
food,  the  escape  of  this  air  through 
the  small  cardiac  orifice  gives  rise 
to  a  bubbling  noise  which  can  be 
easily  heard.  In  the  horse  the  move- 
ment of  a  bolus  down  the  oesophagus 
can  be  seen  or  felt  from  the  outside 
of  the  neck.  The  relative  time- 
relations  of  the  events  at  different 
parts    of    the    oesophagus   may   be 


Fig.  332.     Dissection  to  show  muscles 
employed  in  deglutition. 

h,  styloid  process,  from  which  arise  1,  the 
styloglossus;  2,  the  stylohyoid;  3,  the  stylo- 
pharyngeus  muscles ;  c,  section  of  lower  jaw ; 
d,  hyoid  bone ;  e,  thyroid  cartilage ;  17,  isth- 
mus of  thyroid  gland ;  4,  cut  edge  of  mylo- 
hyoid muscle  ;  5,  6,  7,  8,  muscles  of  tongue  ; 
9,  10,  11,  superior,  middle,  and  inferior 
constrictors  of  pharynx ;  12,  oesophagus. 
(Allen  Thomson.) 


obtained  by  passing  sounds   provided  with  rubber  balloons  to  different 
levels  in  the  tube  and  connecting  these  sounds  with  recording  tambours 

676 


PASSAGE  OF  FOOD  FROM  MOUTH  TO  STOMACH  677 

or  piston  recorders.  This  method  has  been  employed  both  in  men  and 
in  animals. 

When  a  mouthful  of  water  is  taken  two  sounds  may  be  heard  on  ausculta- 
ting over  the  oesophagus.  The  first  sound  immediately  follows  the  beginning 
of  the  act  of  swallowing  and  is  probably  due  to  the  impact  of  the  fluid 
against  the  posterior  pharyngeal  wall  brought  about  by  the  sudden  con- 
traction of  the  mylohyoid  and  other  muscles  which  throw  the  fluid  from  the 
back  of  the  tongue  across  the  pharynx.  The  second  sound  is  heard  best  by 
listening  over  the  epigastrium.  It  begins  from  four  to  ten  seconds  after  the 
first  sound,  and  lasts  for  two  or  three  seconds.  The  interval  between  the 
two  sounds  is  not  constant,  and  may  vary  in  the  same  individual.  If  the 
observation  be  carried  out  on  a  man  lying  on  his  back,  the  trickling  second 
sound  is  changed  into  a  series  of  sounds  which  have  been  described  as  squirts, 
which  vary  from  two  to  five  in  number,  each  lasting  about  one  second.  The 
second  sound  may  be  absent  when  a  solid  bolus  is  swallowed.  On  observing 
the  process  by  Rontgen  rays  very  much  the  same  time-relations  are  obtained. 
If  a  mouthful  of  milk  mixed  with  bismuth  carbonate  be  swallowed,  it  will 
be  seen  passing  rapidly  down  the  oesophagus  to  the  cardiac  orifice  of  the 
stomach.  Here  the  passage  becomes  slow,  and  the  fluid  escapes  slowly  in  a 
narrow  stream  into  the  stomach.  The  average  time  which  elapses  between 
the  beginning  of  deglutition  and  the  disappearance  of  the  last  trace  of  fluid 
from  the  oesophagus  is  about  six  seconds.  The  same  course  of  events  is 
induced  when  the  food  swallowed  is  semi-solid.  If,  however,  the  bolus  be 
dry,  such  as  a  cachet  of  bismuth  carbonate,  it  may  pass  down  the  oesophagus 
with  extreme  slowness  and  may  take  as  much  as  fifteen  minutes  to  reach  the 
cardiac  orifice,  although  the  individual  who  has  swallowed  it  is  quite  unaware 
of  its  continued  presence  in  the  oesophagus.  If,  as  would  normally  be  the 
case,  the  cachet  be  well  moistened  with  sahva  or  water  before  swallowing, 
it  passes  much  more  rapidly,  the  total  time  taken  being  between  eight  and 
eighteen  seconds. 

It  has  been  customary  since  the  time  of  Magendie  to  divide  the  act  of 
swallowing  into  three  stages,  during  the  first  of  which  the  bolus  of  food  is 
carried  past  the  anterior  pillars  of  the  fauces  ;  during  the  second  through  the 
pharynx,  past  the  openings  of  the  nasal  cavities  and  of  the  larynx ;  and 
during  the  third  through  the  oesophagus  into  the  stomach.  There  is,  how- 
ever, no  pause  between  these  various  stages.  The  act  of  deglutition  is  one, 
and  the  initiation  of  the  first  stage  inevitably  involves  the  completion  of  the 
third.  The  food  is  masticated,  and  is  collected  as  a  bolus  on  the  dorsum 
of  the  tongue.  A  pause  then  takes  place  in  the  movements  of  mastication, 
a  slight  movement  of  the  diaphragm  usually  occurs  known  as  '  respiration  of 
swallowing,'  and  then  a  sudden  elevation  of  the  tongue  throws  the  bolus  back 
through  the  anterior  pillars  of  the  fauces.  In  this  movement  the  chief 
factor  is  the  contraction  of  the  mylohyoid  muscle,  which  presses  the  tongue 
against  the  palate  and  pushes  it  backwards.  The  backward  movement  of 
the  tongue  may  also  be  aided  by  the  contraction  of  the  styloglossus  and 
palatoglossus  muscles  which  pull  the  base  of  the  tongue  suddenly  backwards. 


678 


PHYSIOLOGY 


These  muscles,  especially  the  palatoglossi,  serve  to  close  the  isthmus  faucium, 
thus  preventing  any  return  of  the  food  towards  the  mouth. 

As  the  food  is  passing  through  the  upper  part  of  the  pharynx  it  traverses 
a  region  common  to  the  respiratory  as  well  as  the  digestive  passages.  Its 
passage  through  this  region  is  therefore  rapid,  and  is  associated  with  a 
closure  of  the  two  openings  of  the  air  passages  into  the  pharynx.  The  nasal 
cavity  is  shut  off  by  a  simultaneous  contraction  of  the  levator-palati  and 
palato-pharjmgeus  muscles  and  azygos  uvulae,  by  which  means  the  soft 
palate  is  raised  (Fig.  333)  and  the  posterior  pillars  are  proximated  to  the  uvula. 


^Ma 


ir 


r^x 


Fig.  333.     Diagram  (after  Tigekstedt)  to  show  the  jDosition  of  the  soft  palate. 
I,  during  rest ;  II,  during  the  act  of  swallowing. 

The  upper  and  back  wall  of  the  palate  is  thus  formed  into  a  tense  sloping 
roof  which  guides  the  bolus  down  the  pharynx. 

More  important  is  the  shutting  off  of  the  lower  air  passages.  The  con- 
traction of  the  mylohyoid  muscles  which  initiate  deglutition  is  followed 
almost  immediately  (at  an  interval  of  0-47  sec.)  by  an  elevation  of  the  larynx, 
and  this  elevation  is  accompanied  by  closure  of  the  glottis  as  well  as  of  the 
superior  opening  of  the  larynx.  The  laryngeal  opening  is  bounded  in  front 
by  the  epiglottis,  behind  by  the  tips  of  the  arytenoid  cartilages,  and  at  the 
sides  by  the  aryteno-epiglottidean  folds.  When  deglutition  takes  place  the 
arytenoid  cartilages,  which  normally  lie  against  the  posterior  wall  of  the 
pharynx,  are  rotated  and  move  inwards  and  forwards,  so  that  the  laryngeal 
opening  assumes  the  form  of  a  tri-radiate  fissure,  the  vertical  limb  being  short, 
while  the  transverse  limb  is  rounded  owing  to  the  pulhng  inwards  of  the 
margins  of  the  epiglottis.  At  the  same  time  both  the  true  and  false  vocal 
cords  are  approximated,  while  the  movement  of  the  dorsum  of  the  tongue 
backwards  enables  the  closed  laryngeal  orifice  to  he  directly  under  the  back 
part  of  the  tongue.     The  muscles  which  are  actively  involved  in  this  closure 


PASSAGE  OF  FOOD  FROM  MOUTH  TO  STOMACH 


679 


of  the  lower  air  passages  are  the  external  thyro-arytenoid,  arytenoid,  ary- 
epiglottidean,  and  the  lateral  crico-arytenoid  muscles.  Since  the  approxi- 
mation of  the  posterior  to  the  anterior  boundary  of  the  laryngeal  opening 
is  only  rendered  possible  by  the  elevation  of  the  whole  larynx  under  the  hyoid 
bone,  the  act  of  deglutition  cannot  be  carried  out  unless  the  larynx  is  free 
to  move. 

The  two  openings  from  the  back  of  the  pharynx  into  the  air  passages 
being  thus  closed,  the  bolus  is  shot  rapidly  past  them  into  the  region  of  the 
middle  and  inferior  constrictors  of  the  pharynx.  If  the  bolus  be  liquid  or 
semi-fluid,  the  movement  of  the  back  part  of  the  tongue  may  be  sufficient  to 
propel  the  substance  past  the  constrictors  through  the  lax  oesophagus  to  its 
lower  end.  It  is  on  this  account  that,  when  corrosive  fluids  are  swallowed 
by  accident,  we  very  often  find  the  damage  to  the  oesophagus  Hmited  to  the 
three  points  where  it  is  narrowed  and  where,  therefore,  there  is  a  slight 
hindrance  to  the  onward  flow  of  fluid.  If  the  bolus  be  large  and  solid  or 
semi-solid,  it  is  seized  in  the  grasp  of  the  middle  constrictors  on  passing 
through  the  upper  part  of  the  pharynx,  and  is  thrust  by  successive  con- 
tractions of  this  muscle  and  of  the  inferior  constrictor  gradually  down  the 
oesophagus.  The  walls  of  the  cervical  part  of  the  oesophagus  are  composed 
of  striated  muscle.  In  the  thorax  striated  and  unstriated  muscles  are  asso-. 
ciated  together,  while  the  lower  third,  in  the  neighbourhood  of  the  stomach, 
consists  almost  entirely  of  unstriated  muscle.  Corresponding  to  these 
differences  in  structure,  Kronecker  and  Meltzer  have  found  differences  in  the 
duration  and  rapidity  of  propulsion  of  the  contractional  waves  in  each  part. 
The  following  Table  shows  the  time-relations  of  the  chief  muscles  engaged 
in  deglutition  as  determined  by  Kronecker  and  Meltzer  and  by  Marckwald  : 


Time  from 
commencement 

Interval 

Muscle  movement 

Duratioii  of 
contraction 

— 

— 

Mylohyoid 

0-6  sec. 

— 

0-03  sec. 

Respiration  of  swallowing 

— 

— 

0-07  sec. 

Elevation  of  larjiix 

0-8  see. 

()•;}  8t'c-. 

0-2  sec. 

Constrictors  of  pharynx 

1-0  to  2-0  sec. 

— 

0-9  sec. 

First  section  of  oesophagus 

2-(>  to  2-5  sec. 

3-0  sec. 

1-8  sec. 

Second  section  of  oesophagus 

0-0  to  7-0  sec. 

6-0  sec. 

3  0  sec. 

Third  section  of  oesophagus 

about  10  sec. 

The  free  passage  of  food  down  the  oesophagus  under  the  influence  of  the 
propulsive  force  exercised  by  the  mylohyoid  muscles  shows  that  the  walls 
of  this  tube  must  be  lax,  and  in  fact  one  must  assume  that  the  first  act  of 
deglutition,  so  far  as  concerns  the  oesophagus,  is  an  inhibition  initiated 


680 


PHYSIOLOGY 


reflexly  with  the  beginning  of  the  act  of  deglutition.  When  a  second  act 
of  deglutition  succeeds  the  first  with  a  sufficiently  short  interval,  the  reflex 
inhibition  due  to  the  second  act  may  prevent  the  development  of  any  wave 
of  contraction  in  the  oesophagus.     This  tube  thus  remains  in  a  lax  condition 


Fig.  334.  Curves  obtained  during  swallowing  by  placing  two  rubber  balloons,  one 
(the  upper  curve)  in  the  pharynx,  the  other  (lower  curve)  in  the  oesophagus. 
In  A  the  second  balloon  was  4  cm.  ;  in  B  12  cm.  ;  and  in  c  16  cm.  from 
the  upper  end  of  the  oesophagus.  In  each  curve  it  will  be  noticed  that  the 
excursion  of  the  upper  lever  is  followed  immediately  by  an  excursion  of  the 
lower  lever  (due  to  passage  of  the  swallowed  fluid  and  transmitted  rise  of 
pressure),  and  then,  after  an  interval  of  time  varying  with  the  distance  between 
the  balloons,  by  another  rise  due  to  the  peristaltic  contraction  of  the  wall  of 
the  oesophagus. 

and  allows  the  free  rapid  passage  of  the  food  downwards  until  the  movements 
of  deglutition  have  come  to  an  end,  when  a  peristaltic  contraction  occurs  and 
sweeps  all  remaining  adherent  particles  of  food  into  the  stomach.  The 
circular  fibres  of  the  lower  end  of  the  oesophagus  which  form  the  cardiac 
sphincter  of  the  stomach  are  normally  in  a  state  of  tonic  contraction.  When 
one  mouthful  of  food  is  swallowed  it  may  be  either  squirted  directly  into  the 
stomach,  or  may  remain  at  the  lower  end  of  the  oesophagus  until  the  following 


PASSAGE  OF  FOOD  FROM  MOUTH  TO  STOMACH  681 

peristaltic  wave  forces  it  through  the  orifice.  When  several  acts  of  deglu- 
tition succeed  one  another,  the  cardiac  sphincter  shares  in  the  inhibition 
of  the  oesophageal  walls,  and  offers  no  resistance  to  the  direct  propulsion 
of  food  from  the  mouth  to  the  stomach. 

Cannon  has  shown  that  the  relaxation  of  the  cardiac  orifice  which 
accompanies  swallowing  extends  also  to  the  cardiac  end  of  the  stomach. 
This  relaxation  lowers  the  pressure  within  the  stomach,  and  makes  room  for 
the  incoming  food. 

If  the  stomach  be  filled  with  a  fluid  such  as  starch  solution,  the  cardiac 
sphincter  may  be  seen  to  relax  rhythmically,  allowing  of  the  regurgitation  of 


Fig.  335.     Tracings  of  ^respiratory  movements' to  show  the  effect  of  stimulating  the 

central  end  of  the  glossopharyngeal  nerve.     (Makckwald.) 

The  point  of  stimulation  is  marked  with  a  cross.     Note  that  the  stoppage 

may  occur  at  any  phase  of  the  respiratory  movement. 

the  stomach  contents  into  the  lower  part  of  the  oesophagus.  Their  entry 
into  this  tube  is  at  once  followed  by  a  peristaltic  contraction  of  this  part  of  the 
oesophagus  (apparently  entirely  unconscious),  which  drives  the  fluid  back 
into  the  stomach.  These  movements  of  regurgitation  become  more  and 
more  infrequent  as  the  gastric  contents  become  acid,  and  are  not  observed 
at  all  if  the  stomach  be  filled  with  a  fluid  already  acid.  This  phenomenon 
has  been  spoken  of  as  the  '  acid  control  of  the  cardia.' 

THE  NERVOUS  MECHANISM  OF  DEGLUTITION 
Deglutition  is  a  reflex  act.  When  we  swallow  voluntarily  we  supply  the 
necessary  initial  stimulus  either  by  touching  the  fauces  with  the  tongue  or 
by  forcing  a  certain  amount  of  saliva  into  the  fauces.  The  afferent  channels 
of  the  reflex  are  contained  in  the  second  division  of  the  fifth  nerve,  the  glosso- 
pharyngeal nerve,  and  the  pharyngeal  branches  of  the  superior  laryngeal 
nerve.  We  can  excite  a  single  act  or  a  whole  series  of  acts  of  deglutition  by 
electrical  stimulation  of  the  central  end  of  the  last-named  nerve.  The 
efferent  fibres  which  determine  the  contraction  of  muscles  engaged  in  the 
act  of  deglutition  travel  by  the  hypoglossal  nerve  to  the  muscles  of  the 

22* 


682  PHYSIOLOGY 

tongue,  by  the  fifth  to  the  mylohyoid,  by  the  glossopharyngeal,  the  vagus, 
and  the  spinal  accessory  nerves  to  the  muscles  of  the  fauces  and  pharynx. 
The  closure  of  the  larynx  is  effected  by  impulses  which  travel  through  the 
superior  and  inferior  laryngeal  branches  of  the  vagus.  The  centre  for  the 
act  is  situated  in  the  medulla  oblongata,  and  can  be  considered  as  consisting 
of  a  chain  of  centres  stimulation  of  one  of  which  involves  the  firing  off  of  all 
the  others  in  orderly  sequence.  Thus,  as  Meltzer  has  shown,  the  propulsion 
of  the  contraction  down  the  oesophagus  is  determined  by  the  intracentral 
nervous  connections,  and  does  not  require  the  integrity  of  the  muscular  tube 
itself.  If  the  oesophageal  nerves  be  divided,  the  act  of  deglutition  is 
abohshed,  the  upper  part  of  the  oesophagus  becoming  permanently  relaxed, 
while  the  lower  part,  including  the  cardiac  sphincter,  enters  into  a  state  of 
tonic  contraction.  On  the  other  hand,  the  oesophagus  may  be  ligatured  or 
cut  across  without  interfering  with  the  propulsion  of  the  wave  of  contraction. 
On  the  other  hand,  the  oesophagus  may  be  ligatured  or  cut  across  without 
interfering  with  the  propulsion  of  the  wave  of  contraction,  started  in  the 
pharynx,  from  one  end  of  the  tube  to  the  other.  Stimulation  apphed  to  the 
mucous  surface  of  the  oesophageal  tube  is  wdthout  effect. 

There  is  an  important  interdependence  between  the  functions  of  respira- 
tion and  deglutition.  If  an  inspiratory  or  expiratory  movement  were 
going  on  during  the  act  of  deglutition,  food  might  be  drawn  into  the  lungs 
or  driven  into  the  nasal  cavities.  Such  an  accident  is  prevented  by  the  fact 
that  every  act  of  swallowing  inhibits  a  respiratory  movement.  This  in- 
hibition is  effected  reflexly  through  the  glossopharyngeal  nerve.  Stimula- 
tion of  the  central  end  of  this  nerve  at  once  causes  cessation  of  respiration 
in  whatever  phase  it  may  happen  to  be  (Fig.  335).  This  cessation  lasts  for 
five  or  six  seconds,  i.e.  a  sufficient  length  of  time  for  a  whole  series  of  acts 
of  deglutition.  Respiration  then  recommences,  and  the  inhibition  cannot  be 
prolonged  by  continuing  the  stimulation  of  the  glossopharyngeal  nerve.  This 
inhibition  of  the  activity  of  the  respiratory  centre  can  be  shown  on  oneself. 
If  the  breath  be  held  until  the  feehng  of  dyspnoea,  i.e.  the  need  to  breathe, 
becomes  insistent,  relief  is  at  once  experienced  by  swallowing,  and  the  feehng 
of  relief  will  last  for  three  or  four  seconds. 


SECTION   III 
DIGESTION  IN  THE  STOMACH 

GASTRIC  JUICE 

Within  five  minutes  of  the  taking  of  food  into  the  mouth  a  secretion  of  gastric 
juice  begins  from  the  multitude  of  tubular  glands  which  make  up  the  greater 
part  of  the  mucous  membrane  of  the  stomach.  As  the  food,  masticated  and 
thoroughly  mixed  with  saliva,  is  swallowed  in  successive  portions,  it  accumu- 
lates in  a  mass  in  the  fundus  of  the  stomach,  and  the  mass  thus  formed  is 
penetrated  with  difficulty  by  the  juice  which  is  continually  being  poured  out 
by  the  walls  of  the  stomach,  so  that  salivary  digestion  can  be  continued  for  a 
considerable  time. 

The  gastric  juice,  which  is  so  poured  out,  can  be  obtained  in  various 
ways,  most  of  them  yielding  it  mixed  more  or  less  with  the  food-stuffs.  In 
cHnical  practice  it  is  the  custom  to  give  a  definite  meal,  and  then  at  a  given 
interval  after  the  meal  to  wash  out  the  stomach,  so  obtaining  a  mixtm'e  of 
gastric  juice  and  partially  digested  food. 

A  method  of  obtaining  the  juice  in  a  perfectly  pure  condition  has  been 
devised  by  Pawlow.  A  case  had  been  previously  described  by  Richet  in 
which,  as  the  result  of  the  accidental  taking  of  a  corrosive  alkali,  the 
oesophagus  had  become  occluded  by  the  cicatrisation  of  the  ulcer  pro- 
duced. In  order  to  preserve  the  individual  from  starvation,  it  was  neces- 
sary to  perform  gastrostomy,  i.e.  to  make  an  artificial  opening  into  the 
stomach  through  which  he  could  be  fed.  Although  in  this  patient  the  pas- 
sage of  the  saliva  from  mouth  to  stomach  was  completely  prevented,  it  was 
observed  that  merely  taking  food  into  the  mouth  was  followed  by  the  secre- 
tion of  gastric  juice.  Pawlow  produced  this  condition  artificially  in  dogs. 
The  oesophagus  was  divided  and  the  two  ends  brought  to  the  surface  of  the 
neck.  At  the  same  time  an  opening  was  made  into  the  stomach.  The 
animals  could  be  fed  either  through  the  opening  of  the  oesophagus  in  the 
neck,  or  with  solid  food  through  the  gastric  fistula.  They  could  eat  also 
and  swallow  food  as  usual,  but  the  food  thus  swallowed  simply  fell  out 
of  the  opening  in  the  neck  without  passing  into  the  stomach.  Under  these 
circumstances  it  is  found  that  the  taking  of  food  is  quickly  followed  by  a 
secretion  of  gastric  juice,  which  can  be  collected  in  vessels  connected  with 
the  fistulous  opening.  If  taken  from  a  fasting  animal,  such  a  juice  is  per- 
fectly free  from  admixture,  and  can  be  regarded  as  pure  gastric  juice.  It 
is  quite  clear,  strongly  acid,  wnthout  smell.      It  contains  about  0-3  to  0-6  per 

683 


684  PHYSIOLOGY 

cent,  total  solids ;    it  contains  no  peptone,  but  traces  of  protein.     The 
following  Table  represents  its  average  composition  : 

Hydrochloric  acid        .  .  .  0-46  to  0-58  per  cent. 

ChloriBe 0-49  to  0-62       „ 

Total  solids  ....  0-43  to  0-60       „ 

Ash 0-09  to  0-16       „ 

If  the  juice  be  allowed  to  stand  in  the  ice  chest  for  a  day  it  becomes  cloudy 
and  deposits  a  fine  granular  precipitate,  which  apparently  represents  the 
active  agent  of  the  juice,  and  may  perhaps  be  regarded  as  pepsin  in  a  pure 
form. 

The  actions  of  gastric  juice  are  due  partly  to  the  acid,  partly  to  the 
combined  action  of  the  acid  and  the  ferments.  The  acid  of  the  gastric  juice, 
when  obtained  free  from  admixture,  is  entirely  hydrochloric  acid.  Dog's 
juice  contains  on  the  average  about  0-6  per  cent.  HCl ;  human  gastric  juice 
probably  contains  less,  about  0-2  per  cent.  When,  however,  we  examine  the 
gastric  contents,  composed  of  a  mixture  of  gastric  juice  and  semi-digested 
food,  we  always  find,  besides  the  hydrochloric  acid,  other  acids  present, 
among  which  the  most  prominent  is  lactic  acid.  So  constantly  is  this  latter 
acid  present  that  it  was  formerly  thought  by  some  physiologists  to  be  the 
chief  acid  of  the  gastric  juice.  It  is  produced  by  processes  of  fermentation 
occurring  in  the  food.  Whenever  we  take  carbohydrates  we  swallow  at  the 
same  time  micro-organisms,  and  these  in  the  warm  moist  mass  quickly 
attack  the  carbohydrates,  converting  them  into  sugar  and  then  into  lactic 
acid.  As  the  gastric  juice  gradually  soaks  into  the  food  and  renders  it  acid, 
it  stops  this  lactic  acid  fermentation,  so  that  whereas  in  the  early  stages  of 
gastric  digestion  both  acids  are  present  in  considerable  quantity,  towards  the 
end  of  gastric  digestion  lactic  acid  is  almost  entirely  absent. 

In  some  pathological  conditions  free  hydrochloric  acid  may  be  entirely  wanting  from 
the  gastric  juice,  and  the  detection  of  this  acid  in  gastric  juice  becomes  therefore  a 
matter  of  considerable  clinical  importance.  For  this  purpose  we  can  employ  various 
indicators,  which  change  colour  in  the  presence  of  a  free  strong  acid  such  as  HCl,  but 
are  unaffected  by  weak  acids  such  as  lactic  acids,  or  the  fatty  acids.  Chief  among 
these  indicators  are  Congo  red,  which  turns  blue  with  mineral  acids,  and  a  slaty  colour 
with  lactic  acid  ;  and  tropaolin  00,  which  turns  a  brilliant  red  in  the  presence  of  a  free 
mineral  acid,  but  is  imaltered  by  lactic  acid.  The  reagent  which  is  most  employed  is 
Gunzberg's  reagent.  This  is  a  mixture  of  phloroglucin  and  vanillin  dissolved  in  absolute 
alcohol.  A  drop  of  this  is  evaporated  to  dryness  in  a  porcelain  capsvde.  A  drop  of 
the  fluid  suspected  to  contain  free  acid  is  then  added,  and  also  evaporated  to  dryness. 
If  free  HCl  be  present,  the  residue  on  drying  becomes  a  brilliant  red  colour,  an  effect 
which  is  not  produced  by  the  presence  of  free  lactic  or  free  fatty  acids. 

Great  stress  has  been  laid  on  the  determination  of  the  actual  amount  of 
free  H  ions  present,  and  for  this  purpose  the  acidity  of  gastric  juice  or  of 
digestive  mixtures  has  been  tested  by  determining  its  inverting  power  on 
cane  sugar,  or  its  power  to  hasten  the  saponification  of  ethyl  acetate.  The 
acidity  estimated  in  this  way  is  diminished  considerably  by  the  presence  of 
albumens,  and  still  more  by  the  presence  of  albumoses  or  peptones.  But 
it  does  not  seem  that  the  adjuvant  action  of  the  acid  on  the  proteolytic 


DIGESTION  IN  THE  STOMACH  685 

powers  of  the  gastric  ferment  is  in  any  way  affected  by  the  diminution  of  its 
acidity  caused  by  the  presence  of  peptone.  The  coloured  indicators  men- 
tioned above,  however,  serve  as  trustworthy  indications  of  the  amount  of 
free  acid  present,  considered  with  regard  to  its  digestive  functions. 

In  order  to  determine  quantitatively  the  amount  of  free  HCI,  the  following  pro- 
cedure is  employed  (Morner  and  Sjoqvist) :  Ten  cubic  centimetres  of  the  gastric  juice 
are  neutralised  with  barium  carbonate  (litmus  being  employed  as  an  indicator).  The 
mixture  is  dried  in  a  platinum  dish,  incinerated,  and  the  ash  extracted  with  warm  water 
and  filtered.  In  this  process  the  organic  acids  are  destroyed  and  converted  into  barium 
carbonate.  The  solution  therefore  contains  merely  the  barium  which  was  taken  up  to 
combine  with  the  free  HCI.  Estimation  of  the  barium  in  the  filtrate  gives  the  amount 
of  BaCl  present,  and  therefore  the  amount  of  hydrochloric  acid  in  the  gastric  juice. 
The  barium  is  determined  by  titrating  in  presence  of  sodium  acetate  and  acetic  acid 
with  potassium  bichromate  solution,  '  tetra  paper  '  being  used  as  an  indicator.  This 
turns  deep  blue  in  the  presence  of  free  bichromate  in  solution. 

THE  ACTIONS  OF  GASTRIC  JUICE  ON  FOOD-STUFFS 

By  the  action  of  the  hydrochloric  acid  certain  changes  are  induced  in  the 
food-stuffs.  Cane  sugar  is  inverted  to  glucose  and  fructose  ;  some  proteins, 
such  as  blood  fibrin,  are  swollen  up  to  form  a  jelly-like  mass.  The  caseinogen 
of  milk  is  precipitated,  the  collagen  of  the  connective  tissues  is  swoUen  up. 
It  is  possible  that  a  certain  small  amount  of  hydrolysis  also  takes  place  in 
the  dextrins  and  maltose  produced  by  the  action  of  ptyalin  on  starch. 

The  chief  digestive  function  of  the  gastric  juice  is  dependent  on  the 
action  of  the  ferment  pepsin.  This  substance,  which  is  inactive  in  neutral 
medium,  needs  the  co-operation  of  an  acid,  hydrochloric  acid  being  the  most 
effective,  though  its  place  may  be  taken  by  phosphoric,  sulphuric,  or  lactic 
acid.  Its  main  effect  is  on  the  proteins  of  the  food.  The  stages  in  its  action 
may  be  best  studied  by  taking  as  an  example  its  action  on  blood  fibrin.  If 
fibrin  be  immersed  in  0-4  per  cent,  hydrochloric  acid,  it  swells  up  to  a  gela- 
tinous mass.  On  then  stirring  in  an  extract  of  gastric  mucous  membrane, 
or  any  preparation  of  pepsin,  the  gelatinous  mass  rapidly  undergoes  solution. 
If  the  mixture  be  boiled  and  neutraHsed,  immediately  after  solution  has 
occurred,  nearly  the  whole  of  the  protein  is  thrown  down  in  a  coagulated 
form.  The  first  effect  therefore  is  the  production  of  coagulable  soluble 
proteins  from  the  insoluble  fibrin.  If  the  action  be  allowed  to  proceed  for 
some  hours,  a  whole  series  of  products  of  hydrolysis  are  found  in  the  mixtm'e. 
On  neutrahsing  the  fluid,  a  precipitate  may  be  thrown  down  consisting  chiefly 
of  acid  albumen.  The  greater  proportion  of  the  protein  remains  in  solution. 
This  remainder  may  be  purified  from  any  unaltered  coagulable  protein  by 
boihng  in  slightly  acid  solution  and  filtering.  The  filtrate  contains  a 
mixture  of  bodies  belonging  to  the  class  of  hydrated  proteins,  viz.  proteoses 
and  peptones. 

By  means  of  fractional  precipitation  with  ammoniimi  sulphate  or  zinc 
sulphate,  these  mixtures  can  be  subdivided  into  various  substances,  although 
in  no  case  can  we  be  certain  that  we  are  dealing  with  chemical  individuals. 
The  Table  on  p.  686  represents  the  chief  bodies  obtained  by  Pick  by  this 


686 


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PHYSIOLOGY 


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DIGESTION  IN  THE  STOMACH 


687 


method    from    '  Witte's    peptone,'   a  commercial  preparation  containing 
proteoses  and  peptones. 

The  following  careful  analysis  of  the  constituents  of  protoalbumose  and 
heteroalbumose  (or  protoproteose  and  heteroproteose)  respectively  shows 
that  the  different  proteoses  really  correspond  to  different  groupings  of  the 
amino-acids  making  up  the  original  protein  molecule  : 


Results  of  the  Complet 

^E  Hydrolysis  of 

Hetero-  and  Protoalbumose 

Heteroalbumose 

Protoalbumose 

Glutaminic  acid  ...... 

9-51 

0-63 

Leucine 

305 

5-79 

Isoleucine   . 

2-96 

1-62 

Valine 

3-54 

0-76 

Alanine 

3-39 

2-50 

Valine-alanine  mixture 

1-86 

0  00 

Proline 

4-27 

4-96 

Phenylalanine 

2-45 

4-35 

Aspartic  acid 

4-73 

2-98 

Glycocoll    . 

015 

1-44 

Tyrosine     . 

3-48 

4-58 

Arginine     . 

7-30 

7-72 

Histidine    . 

3-90 

2-77 

Lysine 

8-90 

8-40 

Cystine 

1-36 

0-68 

Ammonia  . 

1-28 

0-92 

The  results  obtained  by  Pick  by  hydrolysis  of  these  different  bodies  show 
that  in  the  breakdown  of  protein  produced  by  gastric  juice  there  is  really 
a  division  of  the  complex  molecule  into  smaller  molecules,  which  are  quahta- 
tively  different.  Thus  of  the  fractions  which  he  obtained,  some  contain  the 
greater  part  of  the  sulphur  originally  present  in  the  protein  molecule,  another 
contains  the  greater  part  of  the  carbohydrate  group,  while  others  are  free 
altogether  from  the  tryptophane  group  which  is  responsible  for  Hopkins' 
reaction  obtainable  in  the  original  protein. 

Proceeding  from  primary  through  secondary  albumoses  to  peptones,  there 
is  probably  a  continuous  diminution  in  the  size  of  the  molecule.  During 
the  time  which  gastric  juice  has  to  exert  its  influence,  a  maximum,  say,  of 
twelve  hours,  the  breakdown  of  proteins  never  passes  beyond  the  albumose 
and  peptone  stage,  and  it  is  in  this  form  that  the  proteins  of  the  food  pass  on 
through  the  pyloric  orifice  into  the  small  intestine. 


ACTION  ON  THE  CONNECTIVE  TISSUES   AND  OTHER 

FOOD-STUFFS   ALLIED  TO  PROTEINS 

Collagen.     The  connective  tissues  are  made  up  chiefly  of  white  fibres 

more  or  less  modified,  which  consist  of  collagen.     This  substance  forms  the 

main  basis  of  areolar  tissue,  of  white  fibrous  tissue,  and  of    bone.     On 

prolonged  boiling,  it  is  converted  into  gelatin.     The  gastric  juice  dissolves 


638  PHYSIOLOGY 

collagen,  converting  it,  probably  tbrough  the  stage  of  gelatin,  into  gelatoses 
and  gelatin  peptones,  bearing  the  same  relation  to  the  original  substance 
as  is  borne  by  the  proteoses  and  peptones  to  the  proteins.  On  account  of 
this  action,  adipose  tissue  (which  consists  of  protoplasmic  cells  distended  with 
fat,  and  bound  together  by  connective  tissue)  is  broken  up  into  its  constituent 
cells.  The  protoplasmic  pellicle  is  dissolved,  and  the  fat  floats  freely  in  the 
gastric  juice. 

Elastin,  which  also  occurs  in  varying  amounts  as  the  chief  constituent 
of  the  elastic  fibres  of  connective  tissues,  is  slowly  acted  upon  by  gastric 
juice.  Under  the  conditions  of  natural  digestion,  however,  it  may  be 
regarded  as  indigestible. 

Mucin,  which  forms  a  considerable  proportion  of  the  ground  substance 
of  connective  tissues,  is  converted  by  gastric  juice  into  peptone-like  sub- 
stances, and  into  reducing  bodies  probably  allied  to  glycosamine. 

The  NUCLEO-PROTEiNS,  the  chief  constituents  of  cells,  and  therefore  in- 
gested in  large  amounts  with  food-stuffs  such  as  sweetbreads,  are  first 
dissolved  by  the  acid  of  the  gastric  juice,  and  are  then  broken  up  into  two 
moieties.  The  protein  half  is  converted  into  proteoses  and  peptones,  while 
the  nuclein  moiety  is  precipitated  in  an  insoluble  form. 

On  PHOSPHO-PROTEiNS  gastric  juice  acts  in  a  somewhat  similar  manner. 
The  protein  of  milk,  caseinogen,  undergoes  special  changes  in  the  stomach. 
The  first  effect  of  gastric  juice,  even  in  neutral  medium,  is  to  convert  the 
caseinogen  into  an  insoluble  casein.  This  action  is  generally  ascribed  to  the 
presence  of  a  distinct  ferment  of  the  gastric  juice,  named  rennin,  or  rennet 
ferment.  But,  according  to  some  authorities,  it  is  due  directly  to  the  pepsin, 
i.e.  rennin  and  pepsin  are  identical.  For  the  conversion  of  caseinogen  into 
the  solid  clot  of  casein  the  presence  of  Ume  salts  is  necessary.  The  addition 
of  remiet  to  an  oxalated  milk  apparently  produces  no  effect,  but  clotting 
ensues  if  a  soluble  hme  salt,  such  as  calcium  chloride,  is  then  added  to  the 
mixture.  Under  the  action  of  the  acid  gastric  juice  the  solid  clot  of  casein 
is  dissolved,  but  a  precipitate  is  left  containing  a  small  proportion  of  the 
original  phosphorus  of  the  caseinogen.  This  precipitate  is  sometimes 
spoken  of  as  para-nuclein,  or  fseudo-nuclein.  It  does  not  yield  purine 
bases  on  hydrolysis  with  acids,  but  contains  phosphoric  acid  in  organic  com- 
bination. By  prolonged  digestion  with  strong  gastric  juice  it  is  possible  to 
dissolve  the  whole  of  this  precipitate.  It  is  therefore  thought  that  in  the 
clotting  of  milk  the  caseinogen  under  the  action  of  the  rennet  first  undergoes 
a  conversion  into  a  soluble  casein,  or  perhaps  a  splitting  into  a  soluble  casein 
and  some  other  protein.  The  soluble  casein  then,  under  the  influence  of 
the  lime  salts,  forms  an  insoluble  casein  which  is  precipitated,  and  causes  the 
sohdification  of  the  milk.  In  the  absence  of  lime  salts,  the  conversion  or 
splitting  of  caseinogen  takes  place,  but  the  second  stage  of  the  process  cannot 
occur  until  the  lime  salts  are  added. 


DIGESTION  IN  THE  STOMACH  689 

THE  EFFECT  OF  GASTRIC  JUICE  ON  CARBOHYDRATES 

On  account  of  the  fact  that  cane  sugar  undergoes  inversion  into  equal 
molecules  of  glucose  and  fructose  in  the  stomach,  it  has  been  sometimes 
thought  that  gastric  juice  contains  a  ferment  inveitase.  It  seems,  however, 
that  the  inversion  which  takes  place  in  the  stomach  can  be  completely 
accounted  for  by  the  action  of  hydrochloric  acid  present,  and  that  there  is  no 
need  to  assume  the  presence  of  a  special  ferment. 

In  the  same  way  inuhn,  the  variety  of  starch  which  gives  rise  to  the 
Isevorotatory  sugar  fructose  on  hydrolysis,  and  is  found  in  dahlia  tubers  and 
certain  other  reserve  structures  of  plants,  is  converted  by  the  acid  of  gastric 
juice  into  fructose.  The  inulin  is  therefore  completely  utilised  in  the  ali- 
mentary canal  of  animals,  although  there  is  no  definite  ferment  inulase 
provided  for  its  hydrolysis. 

THE  EFFECT  OF  GASTRIC  JUICE  ON  FATS 
The  chief  action  of  this  juice  on  fats  is  the  solution  of  their  connective- 
tissue  framework  and  protoplasmic  envelopes,  so  as  to  set  the  fat  free  in  the 
stomach  contents.  After  a  fatty  meal  it  is  found  moreover  that  a  consider- 
able proportion  of  the  fat  in  the  stomach  has  undergone  hydrolysis  and  con- 
version into  free  fatty  acid.  In  this  hydrolysis  two  factors  are  involved,  viz. 
(1)  the  action  of  the  warm  dilute  hydrochloric  acid  ;  (2)  the  action  of  a 
special  fat-splitting  ferment  or  lipase,  which  is  secreted  by  the  walls  of  the 
stomach,  and  acts  especially  at  the  beginning  of  gastric  digestion  before  the 
contents  have  attained  a  high  degree  of  acidity.  The  action  of  this  ferment 
is  only  marked  if  the  fat  be  present  in  a  finely  divided  form,  e.g.  as  yolk  of 
egg.  The  chief  digestion  of  fat  takes  place  in  the  next  segment  of  the 
ahmentary  canal,  namely,  in  the  duodenum. 

THE  SECRETION  OF  GASTRIC  JUICE 
Pawlow  has  shown  that  if  an  animal  provided  with  gastric  and  oesophageal 
fistulae  be  given  food,  when  hungry,  it  will  eat  with  avidity,  and  since  the 
food  cannot  reach  the  stomach  and  so  satisfy  its  hunger,  it  will  continue  to 
eat  for  two  or  three  hours.  Five  minutes  after  the  beginning  of  this  sham 
feeding,  gastric  juice  begins  to  drop  from  the  fistulous  opening  ;  and  in  this 
way  large  quantities  of  juice,  free  from  any  admixture  with  other  substances, 
can  be  easily  obtained.  By  this  means  we  obtain  a  secretion  of  gastric  juice, 
which  is  excited  by  the  presence  of  food  in  the  mouth.  This  method  does  not , 
however,  enable  us  to  determine  whether  the  character  of  the  juice  will  be 
altered  in  any  way  by  the  changes  which  the  food  undergoes  in  the  stomach 
itself.  In  order  to  form  an  idea  of  the  normal  course  of  secretion  of  gastric 
juice,  when  food  is  taken  into  the  stomach  in  the  ordinary  way,  Pawlow  has 
devised  another  procedure.  A  small  diverticulum  representing  about  one- 
tenth  of  the  whole  stomach  is  made  at  the  cardiac  or  pyloric  pjid,  in  direct 
muscular  and  nervous  continuity  with  the  rest  of  the  stomach,  but  shut  off 
from  the  main  part  of  the  viscus  by  a  diaphragm  of  mucous  membrane.  The 
method  in  which  this  operation  is  carried  out  will  be  evident  by  reference  to 


690 


PHYSIOLOGY 


the  diagram  (Fig.  336).  In  a  dog  treated  in  this  way  it  is  found  that  the 
amount  of  juice  secreted  by  the  small  stomach  always  bears  the  same  ratio 
to  the  amount  secreted  by  the  large  stomach,  while  the  digestive  power  of  the 
juice  obtained  from  the  small  stomach  is  equal  to  that  obtained  from  the 
large.     This  is  shown  in  the  following  Table  :  * 

Secretion  from  Gastric  Fistula  after  Sham  Meal 


Hours 

Small  stomach                         |                         Large  stomach 

Quantity 

1 
strength  t                      Quantity 

strength 

1 
2 
3 

7-6  c.c. 
4-7  c.c. 
1-1  c.c. 

5  -88  mm. 
5-75  mm. 
5-5    mm. 

68-25  c.c. 
41-5    c.c. 
14-0    c.c. 

5-5    mm. 
5-5    mm. 
5-38  mm. 

Total 

13-4  c.c. 

— 

123-75  c.c. 

— 

Fig.  336.  Diagram  to  show  Pawlow's  method  of  making  a  cul-de-sac  of  the 
cardiac  end  of  the  stomach,  with  vascular  and  nerve  supply  intact. 
In  A  the  line  of  the  incision  into  the  stomach  wall  is  shown.  B  represents 
the  operation  as  completed.  In  A  ;  0,  oesophagus  ;  R.v,  L.v,  right  and  left 
vagus  nerves ;  P,  pylorus ;  C,  cardiac  portion  of  stomach ;  A,  B,  line  of 
incision.  In  B  :  V,  main  portion  of  stomach ;  8,  cardiac  cul-de-sac  ;  A, 
abdominal  wall ;  e,  e,  mucous  membrane  reflected  to  form  diaphragm  between 
the  two  cavities. 


In  this  case  a  fistulous  opening  had  been  estabhshed  into  the  large 
stomach,  so  that  the  juice  could  be  obtained  simultaneously  from  both 
sections  of  this  organ.  Secretion  was  excited  by  a  sham  meal,  in  which  the 
food  taken  by  the  animal  dropped  out  of  an  opening  in  the  neck,  and  was  not 
allowed  to  reach  the  stomach.  It  will  be  seen  that  the  secretions  in  the  two 
sections  of  the  stomach  run  parallel  to  one  another,  while  there  is  an  almost 
exact  equivalence  between  the  strengths  of  the  juices  obtained  from  each 

*  Pawlow,  "  The  Work  of  the  Digestive  Glands  "  (translated  by  W.  H.  Thompson, 
M.D.),  p.  80. 

t  The  strength  of  the  juice  was  determined  by  measuring  the  number  of  millimetres 
of  coagulated  egg-white  (in  Mett's  tubes)  which  were  digested  in  eight  hours. 


DIGESTION  IN  THE  STOMACH 


69] 


section.  We  may  therefore  regard  the  secretion  obtained  from  the  small 
stomach  as  a  sample  of  that  produced  by  the  large,  and  from  the  changes  in 
this  small  stomach  judge  of  the  effects  occurring  in  the  whole  organ.  By  this 
method  it  is  possible  to  study  the  effects  of  a  normal  meal  in  which  the  food 
is  swallowed,  or  of  a  sham  meal  in  which  the  food  is  merely  masticated  in  the 
mouth,  or  of  a  meal  in  which  the  food  is  directly  introduced  into  an  opening 
into  the  large  stomach. 

The  method  which  we  must  adopt  for  the  collection  of  gastric  juice  shows 
that  we  have  to  do,  in  the  first  place,  with  a  reflex  nervous  mechanism, 
since  an  active  secretion  is  excited  by  the  presence  of  food  in  the  mouth  and 
by  its  mastication.  Moreover  a  secretion,  which  is  at  least  as  vigorous  as  that 
produced  by  a  sham  meal,  can  be  evoked  by  merely  arousing  in  the  dog  the 
idea  of  a  meal.  If  the  animal  be  hungry,  it  is  sufficient  to  show  it  the  food  to 
produce  a  secretion.  In  the  experiment  from  which  the  following  Table  is 
taken,  the  dog  was  co:i':inually  excited  by  showing  it  meat  during  a  period 
of  an  hour  and  a  half.  At  the  end  of  this  time  the  animal,  which  had  an 
oesophageal  fistula,  was  given  a  sham  meal.  It  will  be  observed  that  the 
psychical  secretion  obtained  during  the  first  period  of  the  experiment  was 
rather  greater  than  the  secretion  produced  by  the  introduction  of  food  into 
the  mouth. 

Psychical  Secretion  of  Gastric  Juice  (Pawlow) 


Time 

Quantity 

8  minutes 

lOc.c. 

4 

10    „ 

4 

10   „ 

10 
10 

10   „ 
10   „ 

8 

10   „ 

8 

10   „ 

19        „ 

10   „ 

9         „ 

• 

3   „ 

Sham  Feeding 

Time 

Quantity 

17  minutes 

10  c.c. 

9 

10    „ 

8 

10   „ 

The  afferent  channels  for  this  reflex  may  be  therefore  either  the  afferent 
nerves  from  the  mouth,  or,  when  the  idea  of  food  is  involved,  any  of  the  nerves 
of  special  sense,  such  as  sight,  smell,  or  hearing,  through  which  these  ideas 
are  called  forth.  The  efferent  channels  can  only  be  one  of  two  nerves,  viz. 
the  vagus  and  the  sympathetic,  since  these  are  the  only  two  which  are 
distributed  to  the  stomach.  That  it  is  the  former  of  these  nerves  which  is 
involved  is  shown  by  the  fact,  recorded  by  Pawlow,  that  psychical  secretion, 
as  well  as  the  results  of  a  sham  meal,  is  entirely  abolished  by  division  of  both 
vagi.  On  this  account  division  of  both  vagi  may  give  rise  to  entire  absence  of 
gastric  digestion,  and  death  of  the  animal  may  ensue  from  inanition,  or  from 
poisoning  by  the  products  of  decomposition  of  food  in  the  stomach,  even 


692  PHYSIOLOGY 

when  care  has  been  taken  to  avoid  injury  to  the  pulmonary  and  tracheal 
branches  of  these  nerves. 

The  converse  experiment  of  exciting  secretion  by  direct  stimulation  of 
the  vagus  presents  greater  diflS.culties.  Stimulation  of  the  vagus  in  the 
neck  causes  stoppage  of  the  heart,  and  consequent  anaemia  of  the  mucous 
membrane  of  the  stomach.  Moreover,  the  stomach  seems  to  be  much  more 
susceptible  than  the  sahvary  glands  to  the  action  of  poisons,  such  as  anaes- 
thetics. Its  activity  is  also  easily  affected  by  inhibitory  impulses  arising 
in  the  central  nervous  system  as  the  result  of  either  painful  impressions  or 
emotional  states  of  the  animal.  In  order  to  avoid  these  disturbing  factors 
Pawlow  proceeded  as  follows  :  An  animal  with  fistulse  of  oesophagus  and 
stomach  had  one  vagus  nerve  divided.  A  thread  was  attached  to  the  peri- 
pheral end  of  the  cut  vagus  and  allowed  to  hang  out  through  the  wound.  Four 
days  after  the  operation  the  vagus  was  drawn  out  of  the  wound  by  carefully 
pulling  on  the  thread,  so  as  not  to  hurt  or  frighten  the  animal  in  any  way, 
and  its  peripheral  end  stimulated  by  means  of  induction  shocks.  No  effect 
was  produced  on  the  heart,  owing  to  the  degeneration  of  the  cardio-inhibitory 
fibres,  which  is  well  known  to  occur  within  this  period  after  section.  Five 
minutes  after  the  commencement  of  the  stimulation  the  first  drop  of  gastric 
juice  appeared  from  the  gastric  cannula,  and  a  steady  secretion  of  juice  was 
obtained  with  continuation  of  the  stimulation.  This  experiment  furnishes 
the  decisive  and  final  evidence  that  the  secretory  nerves  to  the  stomach  run  in 
the  two  vagi.  There  is  one  marked  difference,  however,  between  the  action 
of  these  nerves  and  the  action  of  the  chorda  tympani  nerve  on  the  submaxil- 
lary gland,  namely,  the  great  length  of  the  latent  period  before  gastric 
secretion  occurs.  The  length  of  this  latent  period  has  not  yet  been  satisfac- 
torily explained.  It  cannot  be  due  to  delay  occurring  between  the  vagus 
fibres  and  the  local  nervous  mechanism  in  the  stomach.  It  may  be  that 
the  chemical  changes  finally  resulting  in  secretion  require  a  longer  period  for 
their  accomphshment  than  is  the  case  in  the  sahvary  gland.  Physiologically 
there  is,  indeed,  no  special  need  for  a  rapid  secretion  of  gastric  juice,  whereas 
in  the  mouth  it  is  essential  that  the  introduction  of  food  should  be  immedi- 
ately followed  by  the  production  of  sahva,  for  the  tasting  and  testing  of  the 
food  and  for  its  subsequent  mastication  or  rejection. 

These  experiments  show  conclusively  that  an  important — probably  the 
most  important — part  of  the  gastric  secretion  is  determined  by  a  nervous 
mechanism.  This  nervous  secretion  does  not,  however,  account  for  the  whole 
of  the  gastric  juice  obtained  as  the  result  of  a  meal.  If  an  animal  provided 
with  two  gastric  fistulse,  one  into  a  diverticulum  and  the  other  into  the 
main  stomach,  has  both  its  vagi  divided,  it  is  found  that  the  introduction  of 
meat  into  the  large  stomach  is  followed,  after  a  period  of  twenty  to  forty-five 
minutes,  by  the  appearance  of  a  secretion  of  gastric  juice  from  the  small 
stomach.  Moreover,  when  an  animal  is  given  a  normal  meal  and  is  allowed 
to  swallow  the  food  after  mastication,  the  total  amount  of  gastric  juice 
obtained  is  greater  than  that  produced  by  the  sham  feeding  alone  and  the 
flow  is  of  longer  duration.     In  fact,  we  may  say  that  the  gastric  juice  secreted 


DIGESTION  IN  THE  STOMACH 


693 


in  response  to  a  normal  meal  consists  of  two  parts,  viz.,  (1)  a  large  amount, 
the  secretion  of  which  begins  within  five  minutes  of  the  taking  of  the  food 
and  is  determined  by  the  reflex  nervous  mechanism  described  above  ;  and 
(2)  a  smaller  portion,  the  secretion  of  which  is  excited  by  the  presence  of  the 
food  in  the  stomach.  This  combined  character  of  the  gastric  juice  produced 
by  a  normal  meal  is  shown  in  the  following  Table  (Pawlow)  : 


Secretion  of  Gastric  Jxhce 


Hours 

Normal  meal. 

200  grm.  meat  into 

stomarh 

150  grm.  meat  direct 
into  stomach 

Sham 

meal 

Sum  of  two 
last  ex- 
periments 

Quantity 
c.c. 

Strength 
mm. 

Quantity 
c.c. 

Strength 
mm. 

Quantity 
c.c. 

Strength 
mm. 

Quantity 
c.c. 

1 

12-4 

5-43 

5-0 

2-5 

7-7 

6-4 

12-7 

2 

13-5 

3-63 

7-8 

2-75 

4-5 

5-3 

12-3 

3 

7-5 

3-5 

6-4 

3-75 

0-6 

5-75 

7-0 

4 

4-2 

3-12 

,5-0 

3-75 

0 

() 

5-0 

In  the  first  column  is  given  the  result  of  a  normal  meal  on  the  secretion 
from  the  gastric  diverticulum.  In  the  second  column  are  given  the  amount 
and  digestive  power  of  the  juice  which  is  excited  by  the  direct  introduction  of 
150  grm.  of  meat  into  the  large  stomach  of  the  animal,  care  being  taken  not  to 
excite  in  any  way  the  nervous  reflex  mechanism.  In  the  third  colmun  are 
given  the  amount  and  digestive  power  of  the  juice  which  is  evoked  by  a  sham 
meal  of  200  grm.  of  meat.  In  the  fourth  column  is  given  the  sum  of  the 
last  two  experiments.  It  will  be  seen  that  the  total  effect  of  the  sham  meal 
plus  the  direct  introduction  of  meat  into  the  stomach  is  almost  identical  with 
the  secretion  obtained  when  the  food  is  taken  in  a  normal  way  and  allowed 
to  pass  through  the  oesophagus  into  the  stomach. 

The  second  phase  of  the  gastric  secretion  cannot  be  ascribed  to  the  inter- 
vention of  the  reflex  vagal  mechanism.  Since  it  occurs  after  cutting  off  the 
stomach  from  its  connections  with  the  central  nervous  system,  it  must  have 
its  causation  in  the  gastric  walls  themselves.  That  it  cannot  be  due  to 
mechanical  stimulation  is  shown  by  the  fact,  previously  mentioned,  that 
it  is  impossible  by  local  stimulation  of  the  mucous  membrane,  by  rubbing, 
or  introduction  of  sand,  or  any  other  method,  to  evoke  a  secretion.  Moreover 
it  is  not  produced  by  all  sorts  of  food.  The  introduction  of  white  of  egg,  of 
starch,  or  of  bread  into  the  stomach  causes  no  secretion.  On  the  other  hand, 
if  bread  be  mixed  with  gastric  juice  and  allowed  to  digest  for  some  time,  the 
introduction  of  the  semi- digested  mixture  into  the  stomach  evokes  a  secre- 
tion. We  have  already  seen  that  meat  produces  a  secretion ;  still  more 
potent  than  meat,  however,  is  a  decoction  of  meat,  or  bouillon,  or  Liebig's 
extract  of  meat,  or  certain  preparations  of  peptone.  Pure  albumoses  and 
peptones  have  no  effect,  so  that  the  exciting  mechanism  must  be  some 


694  PHYSIOLOGY 

chemical  substances  present  in  meat,  and  produced  in  various  other  foods 
under  the  action  of  the  first  gastric  juice  secreted  in  response  to  nervous 
stimuh.  Popielski  has  shown  that  this  secretion  occurs  after  complete 
severance  of  the  stomach  from  the  central  nervous  system,  as  well  as  after 
destruction  of  the  sympathetic  nervous  plexuses  of  the  abdomen.  Since 
the  injection  of  bouillon  directly  into  the  circulation  has  no  effect,  this  author 
concludes  that  the  second  phase  of  secretion  is  determined  by  the  stimulation 
of  the  local  nerve  plexus,  and  that  we  have  here,  in  short,  a  peripheral  reflex 
action,  the  centres  of  which  are  situated  in  the  walls  of  the  stomach  itself. 
There  is,  however,  another  possible  explanation  for  this  second  phase  of 
secretion.  Although  the  peptogenic  substances,  those  substances  which 
evoke  gastric  secretion  on  introduction  into  the  stomach,  have  no  effect  on 
the  gastric  glands  when  injected  directly  into  the  blood  stream,  it  is  possible 
that  they  may  have  an  influence  on  the  cells  which  line  the  cavity  of  the 
stomach,  and  that  they  may  produce,  in  these  cells,  some  other  substance 
which  is  absorbed  into  the  blood,  and  acts  as  a  specific  excitant  of  the  gastric 
glands.  A  process  of  this  nature  is  known  to  occur  in  the  next  segment  of 
the  ahmentary  canal,  viz.  the  duodenum,  where  it  determines  the  secretion 
of  the  pancreatic  juice  and  the  bile. 

Edkins  has  carried  out  a  series  of  experiments  to  determine  whether  such 
a  chemical  mechanism  may  not  also  account  for  the  secretion  of  gastric  juice, 
which  is  excited  by  the  introduction  of  substances  into  the  stomach.  Edkins' 
experiments  were  carried  out  in  the  following  way  :  The  animal,  dog  or  cat, 
having  been  anaesthetised,  the  abdominal  cavity  was  opened,  and  a  ligature 
passed  round  the  lower  end  of  the  oesophagus  so  as  to  occlude  the  cardiac 
orifice  and  effectually  crush  the  two  vagus  nerves.  A  glass  tube  was  then 
introduced  through  an  opening  in  the  abdomen  into  the  pyloric  part  of  the 
stomach,  and  fixed  in  this  position  by  a  ligature  tied  tightly  round  the 
pylorus.  The  glass  tube  was  connected  by  means  of  a  rubber  tube  with  a 
reservoir  containing  normal  salt  solution  at  the  temperature  of  the  body. 
By  means  of  this  reservoir,  a  certain  amount  of  fluid  was  introduced  into  the 
stomach  and  kept  there  at  a  constant  pressure  ;  the  quantity  of  fluid  intro- 
duced varied  from  30  to  50  c.c.  It  has  been  shown  by  Edkins,  as  well  as  by 
von  Mering,  that  no  absorption  of  water  or  saUne  fluid  occurs  in  the  stomach. 
It  is  therefore  possible  to  recover  the  whole  of  the  fluid  an  hour  after  it  has 
been  introduced,  by  simply  lowering  the  reservoir  below  the  level  of  the 
animal's  body.  If  secretion  of  gastric  juice  has  occurred  into  the  cavity  of 
the  stomach,  the  fluid  will  be  increased  in  amount,  and  will  contain  hydro- 
chloric acid  as  well  as  pepsin.  In  a  series  of  control  observations  Edkins 
showed  that  the  mere  introduction  of  this  fluid  into  the  stomach  caused 
no  secretion  of  gastric  juice,  the  fluid  removed  at  the  end  of  an  hour  having 
the  same  bulk  and  the  same  neutral  reaction  as  the  fluid  which  had  been 
injected.  Edkins  then  tried  the  influence  of  injecting  substances  into  the 
blood  stream.  The  injection  of  peptone,  of  acid,  of  broth,  or  of  dextrin  into 
the  blood  stream  produced  no  secretion  of  gastric  juice.  If,  however,  in  the 
course  of  the  hour  during  which  the  fluid  was  allowed  to  remain  in  the 


DIGESTION  IN  THE  STOMACH  695 

stomach,  a  decoction  made  by  boiling  pyloric  mucous  membrane  wdth  acid, 
or  with,  water,  or  with  peptone  was  introduced  in  small  quantities  every  ten 
minutes  into  the  jugular  vein,  the  fluid  removed  at  the  end  of  the  hour  was 
found  to  be  distinctly  acid  in  its  reaction  and  to  possess  proteolytic  properties. 
The  injection  of  these  substances  had  therefore  caused  the  secretion  of  a 
certain  amount  of  gastric  juice  containing  both  hydrochloric  acid  and 
pepsin.  In  order  to  produce  this  positive  effect,  it  was  necessary  to  employ 
pyloric  mucous  membrane,  extracts  made  by  infusing  or  boiling  cardiac 
mucous  membrane  with  any  of  these  substances  being  without  effect. 
Edkins  concludes  therefore  that  the  secondary  secretion  of  gastric  juice  is 
determined,  not,  as  Pawlow  and  Popielski  imagined,  by  a  local  stimulation 
of  the  reflex  nervous  apparatus  in  the  gastric  wall,  but  by  a  chemical 
mechanism.  The  first  products  of  digestion  act  on  the  pyloric  mucous 
membrane,  and  produce  in  this  membrane  a  substance  which  is  absorbed  into 
the  blood  stream,  and  carried  to  all  the  glands  of  the  stomach,  where  it  acts 
as  a  specific  excitant  of  their  secretory  activity.  This  substance  may  be 
called  the  gastric  secretin  or  gastric  hormone.  It  is  noteworthy  that  it  is 
produced  in  that  portion  of  the  stomach  where  the  process  of  absorption  is 
most  pronounced. 

The  normal  gastric  secretion  is  therefore  due  to  the  co-operation  of  two 
factors.  The  first  and  most  important  is  the  nervous  secretion,  determined 
through  the  vagus  nerves  by  stimulation  of  the  mucous  membrane  of  the 
mouth,  or  by  the  arousing  of  appetite  in  the  higher  parts  of  the  brain.  The 
second  factor,  which  provides  for  the  continued  secretion  of  gastric  juice 
long  after  the  mental  effects  of  a  meal  have  disappeared,  is  chemical,  and 
depends  on  the  production  in  the  pyloric  mucous  membrane  of  a  specific 
substance  or  hormone,  which  acts  as  a  chemical  messenger  to  all  parts  of  the 
stomach,  being  absorbed  into  the  blood  and  thence  exciting  the  acti^^ty  of 
the  various  secreting  cells  in  the  gastric  glands.  It  is  still  a  moot  point 
whether  this  gastric  hormone  is  formed  only  in  the  pyloric  mucous  membrane, 
or  whether  it  may  not  be  also  produced  in  the  lower  sections  of  the  gut. 
Popielski  has  stated  that  the  introduction  of  bouillon  into  the  small  intestine 
excites  a  secretion  of  gastric  juice  in  animals,  even  after  extirpation  of  the 
abdominal  sympathetic  plexuses  and  division  of  both  vagi.  On  the  other 
hand,  introduction  of  the  same  substance  into  the  large  intestine  has  no 
influence  on  gastric  secretion.  Popielski  ascribes  this  secretion  again  to  a 
local  reflex  ;  but  it  is  more  probable  that  the  mechanism  in  this  case  is  the 
same  as  that  involved  in  the  secretion  which  is  excited  by  the  presence  of 
semi-digested  food  in  the  stomach  itself. 

Pawlow  has  sho\vn  that  the  second  phase  of  the  gastric  secretion  is  largely 
influenced  by  the  character  of  the  contents  of  the  stomach.  Thus  the  inges- 
tion of  large  quantities  of  oil  diminishes  considerably  the  amount  of  gastric 
juice  secreted,  and  Pawlow  has  suggested  the  administration  of  oil  or  oily 
foods  as  a  possible  remedy  in  cases  where  the  production  of  gastric  juice, 
and  especially  of  hydrochloric  acid,  is  in  excess.  It  has  long  been  imagined 
that  the  secretion  of  gastric  juice  was  stimulated  by  the  taking  of  alkahes. 


696  PHYSIOLOGY 

This  idea  has  been  shown  by  Pawlow  to  be  erroneous.  Whereas  the  forma- 
tion of  gastric  juice  is  increased  by  the  administration  of  acids,  especially 
after  a  meal,  it  is  largely  diminished  by  the  administration  of  alkahes  such 
as  sodium  bicarbonate.  In  fact,  sodium  bicarbonate  diminishes  the  activity 
of  the  digestive  glands  throughout  the  ahmentary  tract,  and  can  be  used  as 
a  means  of  diminishing  the  secretion  of  gastric  juice  as  well  as  of  pancreatic 
juice. 

A  further  important  question  has  been  propounded  by  Pawlow,  namely, 
whether  there  is  any  alteration  in  the  constitution  and  amount  of  gastric 
juice  with  variations  in  the  character  of  the  food.  So  far  as  concerns  the 
first  phase  of  secretion,  the  psychical  or  '  appetite  '  juice,  this  observer  has 
shown  that,  whatever  the  previous  diet  of  the  animal,  the  juice  always  has 
the  same  characters,  the  same  digestive  power,  and  the  same  percentage 
of  hydrochloric  acid.  He  finds,  however,  that  in  the  case  of  the  second,  or 
what  we  may  call '  chemical '  secretion,  i.e.  that  produced  by  local  changes  in 
the  stomach,  there  is  considerable  variation  in  the  nature  of  the  juice. 
Whereas  the  secretion  of  juice  is  greatest  in  amount  after  a  meal  of  meat, 
the  digestive  power  of  the  juice  is  greatest  after  one  of  bread,  and  Pawlow 
regards  these  difierences  in  the  juice  as  determined  by  the  variations  in  the 
stimulus  apphed  to  the  gastric  mucous  membrane.  It  is  doubtful,  however, 
whether  these  results  justify  us  in  ascribing  a  number  of  specific  sensibihties 
to  the  gastric  mucous  membrane.  We  have  seen  that  the  psychical  juice 
depends  merely  on  appetite,  and  therefore  will  be  greater  in  amount  the  more 
welcome  the  food  is  to  the  animal.  On  the  other  hand,  the  juice  secreted  in 
the  second  phase  must  vary  according  to  the  quantity  of  gastric  hormone 
produced  in  the  pyloric  mucous  membrane,  and  therefore  with  the  nature 
and  amount  of  the  substances  produced  in  the  prehminary  digestion  of  the 
gastric  contents  by  means  of  the  psychic  juice.  The  amount  of  juice  may 
vary  also  with  the  salts  contained  in  the  food,  according  to  their  alkahne  or 
acid  character,  and  the  percentage  of  pepsin  in  the  juice  may  vary  with  the 
intensity  of  stimulus  as  well  as  with  the  quantity  of  fluid  available  for  the 
formation  of  the  gastric  juice.  These  factors  will  co-operate  in  determining 
the  characters  of  the  whole  juice  secreted  after  any  given  meal,  and  it  seems 
possible  to  explain  the  variations,  observed  on  such  different  diets  as  meat 
and  bread,  without  having  recourse  to  the  difficult  assumption  of  a  specific 
sensibihty  of  the  gastric  mucous  membrane  to  such  inert  substances  as 
dextrin  or  egg  albumin. 


SECTION  IV 


THE   MOVEMENTS   OF  THE   STOMACH 

These  can  be  best  studied  by  Cannon's  method — that  is,  by  direct  observa- 
tion of  the  movements  in  a  living  unanaesthetised  animal  by  means  of  the 
Rontgen  rays.  In  order  to  make  the  shape  of  the 
stomach  %asible,  the  food — bread  and  milk — is 
mixed  with  a  quantity  of  bismuth  subnitrate  or 
bismuth  oxychloride  (Hertz).  The  presence  of 
this  salt  does  not  interfere  with  the  processes  of 
digestion,  but  renders  the  gastric  contents  opaque 
to  the  Rontgen  rays.  On  examining  by  this 
means  the  stomach  of  a  cat  which  has  just  taken 
a  meal,  the  whole  of  the  food  is  seen  to  be  hnng 
in  the  fundus.  It  is  marked  off  by  a  strong 
constriction,  the  '  transverse  band,'  from  the 
pyloric  portion.  In  about  twenty  to  thirty 
minutes  faint  waves  of  contraction  begin  a  little  to 
the  cardiac  side  of  the  transverse  band  and  travel 
slowly  towards  the  pylorus.  These  waves  succeed 
one  another  so  that  the  pyloric  part  of  the  stomach 
may  present  a  series  of  constrictions.  Their  effect 
is  to  force  towards  the  pylorus  the  food  which  has 
been  digested  by  gastric  juice  and  detached  from 
the  surface  of  the  mass  in  the  fundus.  The 
pylorus  remaining  closed,  the  food  cannot  escape, 
and  therefore  is  squeezed  back,  forming  an  axial 
reflux  stream  towards  the  cardiac  end.  These 
contractions  last  throughout  the  whole  period  of 
gastric  digestion,  and  become  more  marked  as 
digestion  proceeds.  Their  eff'ect  is  to  bring  the 
whole  of  the  food  in  close  contact  wdth  every 
particle  of  pyloric  mucous  membrane  and  to 
cause  a  thorough  mixture  of  food  and  gastric 
juice.  At  varying  periods  after  a  meal,  accord- 
ing to  the  nature  of  the  food  taken,  the  arrival 
of  one  of  these  waves  of  contraction  at  the 
pylorus  causes  a  relaxation  of  the  orifice,  and  a 
of   gastric    contents  are 

697 


Fig.  3.37.  Shadow  sketches 
of  the  outlines  of  the 
stomach  of  a  cat,  imme- 
diately after  a  meal  (11.0), 
at  various  intervals  after- 
wards(  12.0,2.0.3.30,4.30). 

c,  situation  of  o?sophageal 
opening  ;  yz,  '  transverse 
band  '  ;  icr,  junction  of 
cardiac  and  pyloric  por 
tions.     (W.  B.  Caxxox.) 

few  cubic  centimetres 
squirted  into  the  first  part  of  the  duodenum. 


698 


PHYSIOLOGY 


While  these  movements  of  the  pyloric  mill  are  going  on,  the  cardiac  portion 
of  the  stomach  is  exercising  a  steady  pressure  on  its  contents  in  consequence 
of  a  tonic  contraction  of  its  muscular  wall,  so  that  each  successive  portion  of 
the  food  mass  which  is  loosened  by  the  digestive  action  of  the  gastric  juice  is 
forced  on  into  the  pyloric  mill.  As  digestion  proceeds  the  opening  of  the 
pylorus  becomes  more  frequent.  The  stomach  empties  itself  more  and  more, 
until  finally  the  whole  of  the  viscus  has  the  shape  of  a  curved  tube  (Fig.  337). 


Fig.  338.     Sketch  of  human  stomach,  in  erect  position,  shortly  after  a 

bismuth  meal.     (Hertz.) 

F,  fundus  ;   F,  umbilicus  ;   lA,  incisura   angularis  ;   PC,  pyloric  canal ; 

o,  oesophagus. 

At  the  very  end  of  digestion  the  pylorus  may  open  to  allow  the  passage  even 
of  undigested  morsels  of  food. 

Very  similar  are  the  changes  in  the  human  stomach,  as  shown  by  Hertz. 
The  term  fundus  is  by  him  limited  to  that  part  of  the  stomach  situated 
above  the  cardiac  orifice  (in  the  erect  position).  The  hody  of  the  stomach 
is  marked  off,  more  or  less,  by  the  incisura  angularis  on  the  lesser  curvature 
corresponding  to  what  we  have  called  the  transverse  band.  The  pyloric 
portion  consists  of  the  pyloric  vestibule  and  the  pyloric  canal,  the  latter 
being  a  tubular  portion  about  3-0  cm.  in  length,  especially  well  marked  in 
infants.  When  a  small  quantity  of  food  has  been  swallowed  (in  the  erect 
position)  its  weight  is  sufficient  to  overcome  the  resistance  of  the  contracted 
gastric  wall,  and  it  rapidly  passes  to  the  pyloric  part.  Peristalsis  begins 
almost  at  once,  each  constriction  starting  near  the  middle  of  the  stomach, 
and  deepening  as  it  slowly  progresses  towards  the  pylorus  (Fig.  338).  About 
one  inch  from  the  pyloric  canal  it  is  so  marked  that  part  of  the  pyloric 
vestibule  becomes  almost  completely  separated  from  the  rest  of  the  stomach. 


THE  MOVEMENTS  OF  THE  STOMACH  699 

The  part  thus  cut  off  then  diminishes  in  size  in  every  direction,  part  of  its 
contents  being  forced  through  the  pyloric  canal,  while  th3  remainder  escapes 
back  as  an  axial  reflux  stream  into  the  stomach.  The  waves  recur  at  regular 
intervals  of  fifteen  to  twenty  seconds,  and  three  or  four  are  present  simul- 
taneously. They  continue  without  cessation  until  the  stomach  is  empty — 
from  one  to  four  hours  after  the  meal  according  to  its  bulk  and  composition. 

The  foregoing  descriptions  apply  especially  to  the  events  which  succeed 
the  taking  of  a  considerable  meal.  If  warm  fluid  alone,  e.g.  water,  be  swal- 
lowed, the  opening  of  the  pylorus  occurs  within  a  very  short  time  after 
the  fluid  has  reached  the  stomach.  Thus  if  a  large  draught  of  water  be  taken 
to  quench  thirst  it  may  arrive  in  the  duodenum  within  a  minute  or  two  after 
being  swallowed,  and  it  is  from  the  duodenum  and  small  intestine  that  any 
absorption  takes  place.  When  a  meal  is  undergoing  digestion,  there  is  a  dis- 
tinct relation  between  the  amount  of  acid  present  in  the  gastric  contents  and 
the  opening  of  the  pylorus.  One  may  indeed  say  that  acidity  of  the  gastric 
contents  exercises  a  direct  inhibitory  stimulus  on  the  pyloric  sphincter. 

These  movements  of  the  two  portions  of  the  stomach  may  be  observed 
also  on  anaesthetised  animals  and  even  on  a  stomach  which  has  been  excised 
and  placed  in  warm  salt  solution.  They  must  therefore  have  their  origin  in 
the  walls  of  the  stomach  itself.  Although  the  co-ordination  between  the  two 
parts  of  the  stomach,  between  the  tonic  contractions  of  the  fundus  and  the 
rhythmic  contractions  of  the  pyloric  part,  may  be  carried  out  by  the  local 
nervous  system — Auerbach's  plexus — situated  between  the  layers  of  the 
muscular  coat,  it  is  probable  that  the  advancing  waves  of  contraction 
observed  in  the  antrum  are  myogenic,  i.e.  directly  originated  in  and  deter- 
mined by  the  muscle  fibres  themselves.  Cannon  has  shown  that  these 
movements  persist  after  complete  division  of  Auerbach's  plexus  by  2  to  6 
circular  incisions  carried  through  the  entire  muscular  coat  of  the  stomach ; 
and  it  is  evident  that  they  do  not  partake  of  the  nature  of  a  true  peristalsis, 
since  they  are  not  preceded  by  a  wave  of  relaxation.  The  opening  of  the 
pylorus,  on  the  other  hand,  which  occurs  at  increasingly  frequent  intervals 
at  the  end  of  a  wave,  must  be  ascribed  to  a  nervous  mechanism.  Although 
the  local  mechanism  probably  plays  the  greater  part  in  this  act  of  relaxation, 
the  normal  emptying  of  the  stomach  is  also  largely  dependent  on  the  integrity 
of  the  connection  of  this  viscus  with  the  central  nervous  system.  If  both 
vagus  nerves  be  divided  in  a  dog  below  the  point  at  which  they  give  off  their 
branches  to  the  lungs  and  heart,  a  large  amount  of  food  may  remain  in 
the  stomach  in  an  undigested  condition.  The  secretion  of  gastric  juice  is 
deficient,  and  the  opening  of  the  pylorus  is  not  easily  carried  out.  Such  dogs 
therefore  tend  to  die  of  sapra?mia,  being  poisoned  by  the  absorption  of  pro- 
ducts of  putrefaction  from  the  gastric  contents.  Pawlow  has  shown  that 
animals  can  be  kept  alive  for  months  after  di^'ision  of  both  vagi  if  a  gastric 
fistula  be  made,  the  animals  be  carefully  fed,  and  care  be  taken  to  wash  out 
adherent  non-digested  portions  of  food  from  the  stomach. 

The  opening  of  the  pylorus  depends  not  only  on  intragastric  events  but 
also  on  the  condition  of  the  duodenum.     It  has  been  sho^^^l  by  Serdjukow 


700 


PHYSIOLOGY 


that  the  pylorus  remains  firmly  closed  so  long  as  the  contents  of  the  duo- 
denum, are  acid.  If  alkaline  fluid  be  introduced  into  the  stomach,  this  is 
rapidly  passed  into  the  duodenum.  If,  however,  some  acid  be  introduced  at 
the  same  time  into  the  duodenum  by  means  of  a  duodenal  fistula,  the  pylorus 
remains  firmly  closed,  and  no  fluid  passes  into  the  duodenum  until  the  acid 


LSyCh 


G.SpM 


L.Sp.N 


Fig.  339.  Distribution  of  the  vagus  in  the  abdomen  of  the  dog. 
_(M.  H.  Naylor.) 
RV,  LV,  right  and  left  vagi.  The  right  vagus  runs  behind  the  oesophagus 
(Oe)  and  stomach  (St),  and  in  those  places  is  represented  by  a  discontinuous 
line.  Cb,  connecting  branch  between  right  and  left  vagi ;  P,  pancreas  ;  Dd, 
duodenum  ;  FD J,  flexura  duodeno-jejunalis  ;  I,  I,  I,  intestine  ;  L,  liver ; 
K,  kidney  ;  A,  suprarenal  capsule  ;  RG,  LG,  right  and  left  cura  of  diaphragm  ; 
L.Sy.Ch,  left  sympathetic  chain  ;  12  D,  13  D,  twelfth  and  thirteenth  dorsal 
ganglia;  3  L,  third  lumbar  ganglion;  G.Sp.N,  L.Sp.N,  great  and  small 
splanchnic  nerves ;  S.G,  left  semilunar  and  superior  mesenteric  ganglia ; 
D.A,  dorsal  aorta. 

which  was  placed  there  has  been  neutralised  by  the  secretion  of  pancreatic 
juice  and  succus  entericus.  We  have  probably  in  the  walls  of  the  ahmentary 
canal  a  local  nervous  mechanism  for  the  movements  of  the  pyloric  sphincter. 
This  may  be  played  upon  by  impulses  starting  either  in  the  stomach  or  in 
the  duodenum,  probably  by  the  contact  of  acid  with  the  mucous  membrane. 
Increasing  acidity  on  the  side  of  the  stomach  causes  relaxation  of  the  orifice, 
whereas  acidity  on  the  duodenal  side  causes  contraction  of  the  pyloric 


THE  MOVEMENTS  OF  THE  STOMACH  701 

sphincter.  The  exact  parts,  however,  played  in  this  mechanism  by  the  local 
system  and  by  the  central  nervous  system  respectively  have  not  yet  been 
thoroughly  made  out,  though  there  is  no  doubt  that  these  movements  may 
proceed  independently  of  any  connection  with  the  central  nervous  system. 

Stimulation  of  the  peripheral  end  of  the  vagus  nerves  may  exercise  vary- 
ing effects  on  the  stomach  wall  as  well  as  on  its  sphincters.     In  the  normal 
animal  stimulation  of  the  peripheral  end  of  the  vagus  as  a  rule  causes  strong 
contractions  of  the  oesophagus  as  well  as  of  the  cardiac  sphincter.     After 
the  administration  of  atropine,  stimulation  of  the  same  nerve  will  occasion 
dilatation  of  the  cardiac  sphincter.     On  both  cardiac  and  pyloric  portions  of 
the  stomach  the  vagus  exercises  inhibitory  as  well  as  augmentor  effects.     So 
far  as  concerns  the  musculature  of  the  fundus  or  body  of  the  stomach,  the 
most  usual  effect  is  an  inhibition  during  stimulation  of  the  vagus  succeeded 
by  an  augmented  tonus  immediately  the  stimulus  is  removed.     If  the  vagus 
be  excited  a  number  of  times  the  tonus  of  the  muscular  wall  augments  with 
each  stimulus.     On  the  pyloric  portion  stimulation  of  the  vagus  also  causes 
inhibition,  followed  by  contraction.     The  inhibition  may,  however,  be  very 
short  and  in  rare  cases  altogether  absent,  so  that  during  the  excitation  this 
inhibition  is  followed  by  a  series  of  large  rhythmic  contractions.     The  pre- 
vaihng  motor  effect  of  the  vagus  therefore  is  in  the  fundus  increased  tonus, 
in  the  pyloric  portion  augmented  peristaltic  waves.     On  the  pylorus  itself  we 
may  obtain  from  vagal  stimulation  either  increased  or  diminished  contrac- 
tion.    The  conditions  under  which  each  of  these  may  be  evoked  have  not  yet 
been  definitely  ascertained.     Whether  the  splanchnic  nerve,  i.e.  the  sym- 
pathetic system,  has  a  direct  influence  on  the  movements  of  the  stomach  has 
been  disputed.     According  to  Page  May  any  effect  produced  by  stimulation 
of  this  nerve,  generally  consisting  in  diminished  motor  activity,  is  probably 
due  to  the  simultaneous  influence  on  the  vascular  supply  to  the  organ  ;  the 
blood-vessels  being  constricted,  an  artificial  anaemia  is  produced  which  in 
itself  is  sufficient  to  account  for  diminished  activity.     Other  observers  regard 
the  splanchnic  as  having  an  influence  on  the  stomach  similar  to  its  action  oa 
the  intestine,  and  regard  it  as  the  chief  inhibitory  nerve  to  this  organ.     It  is 
possible  that  the  extent  to  which  the  stomach  is  brought  under  the  control  of 
the  sympathetic  system  may  vary  in  different  species  of  animals. 

Carlson  has  shown  that  the  '  pangs  of  hunger  '  are  associated  with  and  probably 
due  to  rhythmic  contractions  of  the  stomach  wall,  which  come  on  about  meal  time 
especially  if  this  be  delayed. 


INTESTINAL  DIGESTION 

The  products  of  gastric  digestion,  after  being  worked  up  in  the  pyloric 
half  of  the  stomach,  are  passed  at  intervals  into  the  first  part  of  the  duo- 
denum. Here  they  meet  the  secretions  of  three  glands,  namely,  the  pancreas, 
the  liver,  and  the  tubular  glands  of  the  intestine.  In  addition  to  these  must 
be  mentioned  the  secretion  of  Brunner's  glands,  which  are  situated  at  the  very 
beginning  of  the  duodenum.  The  glands  of  Brunner  extend  only  over  about 
half  to  one  and  a  haK  inches  in  the  carnivora,  such  as  the  dog  or  cat,  but 
in  the  herbivora  they  may  be  found  occupying  the  upper  six  inches  of  the 
intestine.  The  secretion  of  these  various  juices  is  practically  simultaneous 
and  is  aroused  by  the  very  act  of  entry  of  the  acid  chyme  into  the  duodenum. 
Although  they  co-operate  in  their  action  on  the  food-stuffs,  it  will  be  con- 
venient to  deal  separately  with  each  both  as  regards  their  action  and  the 
mechanism  of  their  secretion. 


SECTION  V 

THE  PANCREATIC  JUICE 

Pure  pancreatic  juice  can  be  obtained  either  from  an  animal  with  a  per- 
manent fistula  or  from  one  with  a  temporary  fistula  by  the  injection  of  secre- 
tin into  the  animal's  veins.  A  flow  of  pancreatic  juice  may  also  be  produced 
by  the  administration  of  pilocarpine.  This  drug  acts,  however,  as  a  poison 
on  many  tissues  of  the  body,  not  confining  its  action  to  the  pancreas  or 
even  to  the  secreting  glands.  It  is  not  to  be  wondered  at  therefore  that  the 
pancreatic  juice  obtained  by  its  injection  differs  in  quahty  from  that  obtained 
by  the  more  natural  method  of  injection  of  secretin.  The  average  com- 
position of  pancreatic  juice  is  shown  in  the  Table  on  p.  703. 

It  is  a  clear  or  shghtly  opalescent  fluid,  strongly  alkahne  from  the  presence 

N        N 
of  sodium  carbonate,  its  alkalinity  varying  between —  and  —  NaaCOs.     It  is 

therefore  about  as  alkaline  as  gastric  juice  is  acid,  and  it  will  be  found  that 
equal  quantities  of  gastric  juice  and  pancreatic  juice  when  added  together 
practically  neutrahse  one  another.  The  proteins  of  the  juice  may  be  roughly 
divided  into  three  groups,  a  small  amount  of  nucleo-protein  precipitated 
on  acidification,  a  protein  coagulating  at  55°  C,  and  another  at  about  75°  C. 
The  juice  tends  to  become  poorer  in  proteins  and  richer  in  alkali  as  secre- 

702 


THE  PANCREATIC  JUICE 


703 


A 

B 

c 

Alkalinity  : 

(«) 

(^^) 

Number  of  c.c.    —   NaOH  equal 

1 
j 

12-7 

12-4 

9 

5-5 

to  10  c.c.  juice 
I.e.  in  terms  of  Na  in  100  c.c. 

Total  solids  in  100  c.c. 

J 

0-2921 
1-6       1 
1-56      ( 

0-2852 
2-25 

0-2587 

1.    { 

0-1166 

6-38 

6-40 

Total  proteins  in  100  c.c.     . 
Ash  in  100  c.c. 

( 
I 
( 
1 

0-5 

1-00     \ 
0-92     J 

1-00 

1-00 

4-8 
1-3 

Chlorides  in  100  c.c.    . 

0-28081 
0-2966  ( 

— 

— 

0-2695 

Total  nitrogen    .... 

— 

— 

0-735 

A.  Secretin  juice  from  three  dogs.     Sp.  gr.  1014. 

B.  Secretin  juice,  specimen  collected  at  beginning  (a),  and  at  end  (6). 

C.  Pilocarpine  juice. 

tion  proceeds.  The  concentrated  juice  obtained  by  injection  of  pilocarpiu, 
which  may  contain  as  much  as  6  per  cent,  total  sohds,  is  always  considerably 
less  alkahne  than  the  more  dilute  juice  got  by  injection  of  secretin.  The 
most  interesting  and  important  constituents  of  the  juice  are  its  ferments 
or  precursors  of  ferments.  The  juice  on  arrival  in  the  intestine  has,  or 
develops,  an  effect  on  all  three  classes  of  food-stuffs,  namely,  proteins,  fats, 
and  carbohydrates, 

ACTION  ON  PROTEINS 
Although  the  digestive  action  of  pancreatic  juice  on  proteins  was  pointed 
out  by  Corvisart,  little  attention  was  paid  to  this  action  either  by  Claude 
Bernard  or  subsequent  authorities  until  Kiihne  subjected  the  action  of 
extracts  of  the  gland  to  a  thorough  investigation.  The  neglect  of  this 
action  by  Claude  Bernard  must  be  ascribed  to  the  fact  that  he  worked  with 
pancreatic  juice.  It  has  been  shown  more  recently  that  pancreatic  juice  as 
secreted  is  free  from  proteolytic  effects,  and  that  for  the  development  of  this 
power  it  is  necessary  that  some  change  should  be  brought  about  in  the  juice 
itself,  namely,  a  conversion  of  trypsinogen  into  trypsin.  This  change  under 
normal  circumstances  is  brought  about  directly  the  juice  enters  the  gut,  by 
the  action  of  a  substance — enterokinase — contained  in  the  succus  entericus. 
The  pancreatic  juice  thereby  acquires  a  proteolytic  activity  superior  to  that 
of  any  other  digestive  juice,  so  that  the  proteins  of  the  food  undergo  a  very 
thorough  disintegration.  The  different  constituents  of  the  protein  molecule 
show  a  varying  resistance  to  the  action  of  tr}^sin.  The  greater  part  of  the 
molecule  is  rapidly  broken  down  into  its  proximate  constituents,  namely, 
amino-acids,  and  the  same  change  is  undergone  by  the  proteoses  and  peptones 
resulting  from  the  gastric  digestion  of  proteins.  Within  a  few  minutes 
therefore  after  the  chyme  has  reached  the  small  intestine  a  certain  amount  of 


704  PHYSIOLOGY 

amino-acids  will  have  been  formed.  Some  of  the  groups  present,  however, 
a  resistance  to  disintegration.  After  tryptic  digestion  for  a  few  hours  the 
mixture  will  be  found  still  to  contain  a  considerable  quantity  of  peptone, 
which  in  consequence  of  its  resistance  to  further  alteration  was  designated  by 
Kiihne  '  antipeptone.'  The  antipeptone  of  Kiihne  certainly  included  some 
of  the  diamino-acids,  which  at  that  time  had  not  been  isolated.  There  is 
always  a  part,  however,  which  gives  the  biuret  reaction  and  is  only  sKghtly 
broken  down  after  the  prolonged  action  of  trypsin  into  the  amino-acids. 
Even  when  the  trypsin  has  acted  for  weeks  and  the  biuret  reaction  has 
entirely  disappeared,  the  mixture  will  be  found  to  contain,  in  addition  to  the 
separate  amino-acids,  some  members  of  the  polypeptide  class,  composed  of 
two  or  more  molecules  of  amino-acid  united  together.  One  of  these  poly- 
peptides has  been  isolated  by  Fisher  and  Abderhalden  from  the  products  of 
tryptic  digestion  of  the  protein  of  silk,  and  has  been  found  to  contain  glycine, 
alanine,  and  proHne.  The  stages  therefore  in  tryptic  digestion,  e.g.  on  fibrin, 
may  be  set  out  as  follows  : 

(1)  After  one  hour's  digestion — soluble  coagulable  protein,  deutero- 
albumose,  peptone,  amino-acids,  with  a  small  amount  of  alkah  metaprotein 
produced  by  the  action  of  the  alkali  of  the  juice. 

(2)  After  digestion  for  one  day — deutero-albumose,  '  antipeptone,' 
amino-acids,  polypeptides. 

(3)  After  digestion  for  one  month — amino-acids,  polypeptides. 
Among  the  amino-acids  tyrosine  is  one  of  the  first  to  be  spht  off,  and  this 

substance,  with  leucine,  was  among  the  earhest  known  products  of  pancreatic 
digestion.  The  action  of  trypsin  is  thus  seen  to  resemble  very  closely  the 
action  of  boihng  concentrated  hydrochloric  acid.  Like  the  latter  it  attacks 
the  protein  molecule  at  the — CO — ^NH —  couphng,  introducing  water  at  this 
point  and  therefore  breaking  up  the  polypeptide  groupings  into  simple 
amino-acids.  Why  it  always  leaves  a  certain  remnant  of  the  polypeptides 
unattacked  is  not  at  present  explained.  The  investigation  of  its  action  on 
the  polypeptides  has  shown  that  very  minute  differences  in  the  grouping 
of  the  molecule  may  determine  whether  or  not  the  molecule  is  attacked  by 
trypsin.  Apparently  it  will  only  attack  such  molecules  as  are  present  in  the 
naturally  occurring  proteins.  Thus  under  the  action  of  trypsin  the  following 
polypeptides  undergo  hydrolytic  dissociation  :  alanyl  glycine,  alanyl  alanine, 
alanyl  leucine  A ;  while  the  closely  similar  polypeptides  glycyl  alanine, 
glycyl  glycine,  alanyl  leucine  B  are  left  untouched. 

CONDITIONS  OF  TRYPTIC  ACTIVITY 

Since  the  pancreatic  juice  is  strongly  alkahne  it  might  be  expected  that 
trypsin  would  be  most  effective  in  an  alkaline  medium.  It  must  be  remem- 
bered, however,  that  the  alkahne  juice  when  secreted  meets  the  correspond- 
ijigly  acid  contents  discharged  from  the  stomach,  and  that  the  resulting 
mixture  is  practically  neutral.  This  neutrality  exists  throughout  the  small 
intestine,  the  reaction  of  the  contents  of  the  gut  being  similar  to  that  of  a 
fluid  containing  alkali  which  has  been  saturated  by  the  passage  of  carbonic 


THE  PANCREATIC  JUICE  705 

acid,  viz.  alkaline  to  such  indicators  as  methyl  orange,  and  acid  to  such 
indicators  as  phenolphthalein.  On  investigating  the  action  of  trypsin  outside 
the  body,  it  is  found  that,  at  any  rate  as  concerns  its  earlier  stages,  this 
ferment  is  more  active  in  the  presence  of  sodium  carbonate.  It  is  usual  to 
make  up  an  artificial  digestive  mixture  by  dissolving  commercial  trypsin  in 
0-2  to  0-3  per  cent,  sodium  carbonate.  The  optimum  amount  of  sodium 
carbonate  depends  on  the  strength  of  the  solution  in  trypsin  :  the  more 
trypsin  present  the  higher  is  the  optimum  amount  of  sodium  carbonate.  It 
is  stated  that  although  an  alkahne  reaction  is  more  advantageous  for  the 
earlier  stages  of  tryptic  activity,  the  later  stages  take  place  best  in  a  neutral 
medium.  This  result  is  probably  due  to  the  fact  that  trypsin  in  alkaline 
medium  is  extremely  unstable,  so  that  when  prolonged  digestions  are  carried 
out  the  trypsin  would  be  rapidly  destroyed  if  the  medium  were  strongly 
alkaline.  The  destructibihty  of  trypsin,  as  well  as  its  action,  is  largely 
affected  by  the  presence  of  proteins  or  their  digestion  products  in  solution. 
Bayliss  has  adduced  evidence  to  show  that  when  trypsin  acts  upon  protein  it 
enters  into  some  form  of  combination  with  the  protein  molecule.  This 
combination  protects  the  trypsin  from  the  destructive  action  of  alkali.  The 
velocity  of  the  reaction,  which  takes  place  under  the  influence  of  trypsin, 
gradually  diminishes,  owing  probably  to  a  combination  of  the  trypsin'  with 
the  products  of  digestion,  e.g.  with  the  peptones  or  amino-acids,  and  its 
consequent  removal  from  the  sphere  of  action.  If  by  any  means  the  amino- 
acids  be  removed  the  action  of  the  trypsin  is  renewed.  This  destruction  of 
ferment  occurs  in  the  intestine  itself.  If  the  intestinal  contents  be  collected 
by  means  of  a  fistula  at  the  lower  end  of  the  ileum,  they  show  little  or  no 
proteolytic  activity.  The  trypsin  is  therefore  an  extremely  active  ferment 
which  carries  out  its  function  of  protein  hydrolysis  at  the  upper  part  of  the 
gut  and  is  destroyed  before  reaching  the  lower  end. 

THE  ACTIVATION  OF  PANCREATIC  JUICE 

It  was  observed  by  Kiihne  that  extracts  of  the  fresh  pancreas  did  not 
develop  their  full  activity  for  some  considerable  time,  the  development 
being  aided  by  prehminary  treatment  with  a  weak  acid.  When  a  pancreatic 
fistula  is  made  according  to  Pawlow's  method,  the  juice  obtained  always 
presents  some  proteolytic  activity.  It  was  shown  by  Pawlow  and  Chepo- 
walnikofE  that  the  development  of  the  activity  of  the  juice  was  due  to  the 
action  of  a  constituent  of  the  succus  entericus  which  they  named  enterohinase, 
and  it  has  since  been  found  that  if  care  be  taken  to  avoid  contact  of  the 
juice  with  the  mucous  membrane  surrounding  the  orifice  of  the  duct,  it  is, 
when  secreted,  entirely  inactive.  The  enterokinase  acts  like  a  ferment 
on  a  body,  trypsinogen,  present  in  the  juice  as  secreted,  converting  this  into 
trypsin.     Pawlow  therefore  called  this  body  the  '  ferment  of  ferments.' 

This  view  of  the  action  of  enterokinase  lias  been  challenged,  especially  by  Delezcnne, 
according  to  whom  there  is  an  actual  combination  between  the  enterokinase  and  the 
trypsinogen.  trypsin  itself  being  a  mixture  or  combination  of  the  two  bodies.  He 
compared  the  reaction  to  that  of  the  h.vmolvsins,  which,  as  is  well  knowii.  involve  in 

23 


706  PHYSIOLOGY 

their  action  the  co-operation  of  two  bodies,  the  amboceptor  and  the  complement. 
If  this  "were  correct  there  should  always  be  a  proportionality  between  the  quantities 
of  trypsinogen  and  enterokinase  respectively  which  are  necessary  to  form  trypsin. 
It  has  been  shown  by  Bayliss  and  Starling  that  this  proportionality  is  not  present.  The 
smallest  quantity  of  enterokinase  is  sufficient  to  activate  any  amount  of  trypsinogen 
if  sufficient  time  be  allowed.  The  effect  of  increasing  or  diminishing  the  amount  of 
enterokinase  is  not  to  alter  the  total  amount  of  trypsin  finally  produced,  but  merely 
the  time  taken  for  its  production.  This  behaviour  characterises  a  ferment,  and  we  may 
therefore  conclude  that  the  view  originally  put  forward  by  Pawlow  is  correct,  namely, 
that  trypsin  is  produced  from  trypsinogen  under  the  action  of  a  ferment  enterokinase. 
If  pancreatic  juice  be  allowed  to  stand,  even  with  the  addition  of  toluol  to  prevent 
bacterial  infection,  it  gradually  acquires  a  certain  degree  of  activity.  If,  however, 
sodium  fluoride  be  used  as  an  antiseptic  the  juice  remains  permanently  inactive. 
The  spontaneous  activation  of  the  juice  may  be  hastened  by  neutralisation.  The  most 
potent  means  next  to  enterokinase  is  the  addition  of  lime  salts.  If  a  few  drops  of 
10  per  cent,  calcium  chloride  solution  be  added  to  fresh  pancreatic  juice,  the  calcium 
being  in  such  a  quantity  as  to  suffice  to  combine  with  all  the  carbonate  present  in  the 
juice,  complete  activation  of  the  juice  occurs  within  a  couple  of  days,  no  further 
increase  in  its  digestive  powers  being  obtained  on  subsequent  addition  of  enterokinase. 
It  has  been  suggested  that  the  action  of  calcium  is  in  some  way  to  assist  in  the  pro- 
duction of  an  enterokinase  from  some  precursor  of  this  body  already  present  in  the 
juice.  According  to  Mellanby,  the  calcium  acts  simply  by  neutralising  the  juice  and 
thus  allowing  minute  traces  of  enterokinase  already  present  in  the  juice  to  exert  their 
effect.  It  is  not  likely  that  this  calcium  activation  plays  any  part  in  the  normal  pro- 
cesses of  digestion,  since  for  its  completion  it  needs  twelve  to  sixteen  hours,  whereas 
the  enterokinase  present  in  the  succus  entericus  will  effect  the  activation  of  the  juice 
within  a  few  minutes. 


THE  ACTION  OF  PANCREATIC  JUICE  ON  MILK 

On  tlie  addition  of  pancreatic  juice  to  milk  a  clot  is  produced  which 
speedily  redissolves.  If  re-solution  takes  place  too  rapidly  the  production 
of  a  formed  clot  may  be  missed.  In  every  case,  however,  on  heating  the  milk 
a  few  minutes  after  the  addition  of  the  trypsin  a  clot  is  obtained.  How  far 
this  action  is  to  be  ascribed  to  the  proteolytic  ferment  trypsin,  or  how  far 
it  is  due  to  the  presence  of  a  free  rennet-like  ferment  in  the  juice,  is  not  yet 
definitely  settled.  Since  the  rennet  action  is  parallel  to  the  proteolytic 
activity  of  the  juice,  it  is  probable  that  we  must  regard  the  clotting  of  milk 
as  the  first  stage  in  its  proteolysis. 

THE  ACTION  OF  PANCREATIC  JUICE  ON  CARBOHYDRATES 

The  pancreatic  juice,  as  well  as  fresh  extracts  of  the  pancreas  itself, 
contains  a  strong  amylolytic  ferment,  diastase,  amylase,  or  amylopsin. 
If  a  few  drops  of  pancreatic  juice  be  added  to  a  1  per  cent,  solution  of  boiled 
starch,  within  a  few  seconds  the  solution  clears,  and  in  half  a  minute,  on  the 
addition  of  iodine,  a  red  colour  is  obtained,  showing  the  presence  of  erythro- 
dextrin.  At  the  end  of  a  few  minutes  no  colour  is  obtained  with  iodine,  and 
the  solution  contains  maltose.  The  stages  in  the  hydrolysis  of  starch 
brought  about  with  pancreatic  juice  are  exactly  similar  to  those  effected 
by  ptyalin.  If  the  juice  be  neutralised,  the  process  of  hydrolysis  goes  on 
to  the  formation  of  dextrose  or  glucose.     This  further  conversion  is  due  to 


THE  PANC!REATIC  JUICE  707 

the  presence  in  the  juice  of  a  second  ferment — maltase — which  converts 
the  disaccharide  maltose  into  the  monosaccharide  glucose.  The  juice  in 
the  gut  is  therefore  able  to  effect  the  further  digestion  of  the  products 
of  salivary  digestion.  On  the  other  disaccharides  pancreatic  juice  is  without 
effect.  It  contains  no  invertase,  nor  does  it,  in  spite  of  certain  statements 
to  the  contrary,  ever  contain  lactase.  It  has  therefore  no  effect  on  either 
cane  sugar  or  milk  sugar. 

THE  ACTION  OF  PANCREATIC  JUICE  ON  FATS 
Fresh  pancreatic  juice  contains  a  strong  lipase  or  fat-sphtting  ferment,  by 
means  of  which,  in  the  presence  of  water,  neutral  fats,  e.g.  the  triglycerides  of 
palmitic,  stearic,  and  oleic  acids,  are  broken  up  into  glycerin  and  the  corre- 
sponding fatty  acids.  This  ferment  is  active  either  in  alkaline,  neutral, 
or  very  slightly  acid  reaction.  If  the  reaction  be  alkahne  the  fatty  acids 
produced  by  the  lipolysis  combine  with  the  alkali  present  with  the  formation 
of  soaps.  The  ferment  may  be  obtained  from  extracts  of  the  fresh  gland,  but 
is  rapidly  destroyed  if  active  trypsin  be  present.  It  is  also  contained  in  some 
of  the  dried  commercial  preparations  of  trypsin.  It  is  apparently  insoluble 
in  distilled  water,  and  is  therefore  found  in  the  residue  after  extracting  these 
commercial  preparations  with  water.  It  is  easily  soluble  in  glycerin.  The 
velocity  with  which  lipolysis  occurs  is  much  increased  (four  to  five  times)  by 
the  addition  of  bile.  This  adjuvant  action  of  bile  is  not  destroyed  by  boihng, 
and  is  due  entirely  to  the  bile  salts.  These  act  in  two  ways.  In  the  first 
place,  by  their  physical  qualities  they  diminish  the  surface  tension  between 
water  and  oil,  so  enabling  a  closer  contact  to  be  effected  between  the  watery 
solution  contained  in  the  juice  and  the  oil  which  is  presented  to  it.  Moreover 
they  may  aid  in  the  solution  of  the  ferment  itself.  In  the  second  place,  bile 
salts  have  a  solvent  action  on  soaps  as  well  as  on  fatty  acids  in  slightly  acid 
medium.  Bile  may  be  regarded  therefore  as  a  favourable  excipient  or 
medium  for  the  interaction  of  the  lipase  and  the  neutral  fats.  The  lipase  of 
pancreatic  juice  will  also  hydrolyse  the  esters  of  the  fatty  acids,  such  as 
ethyl  butyrate  or  monobutyi'in.  On  the  phosphorised  fats  or  phosphatides, 
such  as  lecithin,  its  action  is  still  a  subject  of  doubt.  According  to  certain 
authors  extracts  of  the  pancreas  have  the  power  of  splitting  off  chohne  from 
lecithin.  It  is  not  known  whether  the  same  property  is  present  in  pancreatic 
juice  itself,  or  whether  any  other  dissociations  are  brought  about  in  the 
complex  molecule  of  lecithin  under  the  action  of  this  digestive  fluid. 

THE  SECRETION  OF  PANCREATIC  JUICE 
In  order  to  study  the  relation  of  the  secretion  of  pancreatic  juice  to  the 
other  processes  of  digestion,  observations  must  be  carried  out  on  an  animal 
with  a  permanent  pancreatic  fistula. 

Such  a  fistula  was  established  bj"  Claude  Bernard  hj  bringing  the  duct  of  the  pancreas 
to  the  surface  and  inserting  into  it  a  lead  or  silver  tube.  The  arrangement  was,  Jiowever. 
imsatisfactory  since  after  a  few  days  the  tube  dropped  out  and  the  natm-al  course  of 
the  duct  from  pancreas  to  intestine  was  restored.     In  order  to  avoid  the  disadvantages 


708  PHYSIOLOGY 

of  this  proceeding  Heidenhain  and  Pawlow  independently  devised  another  method 
to  enable  us  to  determine  the  causes  of  pancreatic  secretion.  The  pancreas  in  most 
cases  possesses  two  ducts,  the  upper  one  opening  along  with  the  bile  duct,  the  lower  one 
a  short  way  down.  The  relative  sizes  of  these  two  ducts  vary  in  different  animals, 
the  lower  one  being  larger  in  the  dog,  while  in  man  and  the  cat  the  upper  one  is  larger. 
In  order  to  establish  a  pancreatic  fistula  in  a  dog,  a  small  quadrilateral  piece  of  the 
duodenal  wall  is  exsected,  having  the  papilla  of  the  lower  duct  opening  in  the  middle 
of  its  mucous  siu-face.  The  integrity  of  the  gut  is  restored  by  suturing  in  a  single  line 
of  stitches  the  margins  of  the  woimd  in  the  duodenum,  and  the  exsected  piece  is  brought 
to  the  surface  and  stitched  in  the  middle  of  the  abdominal  wound.  The  greater  part 
of  the  pancreatic  secretion  will  escape  by  the  fistula,  and  can  be  collected  either  by  the 
insertion  of  a  cannula  into  the  duct  or  by  attaching  a  glass  funnel  below  its  orifice. 
Great  care  has  to  be  taken  in  the  after  treatment  of  such  animals.  The  pancreatic 
juice,  which  flows  over  the  papilla,  acquires  in  so  doing  strong  proteolytic  powers, 
and  tends  therefore  to  dissolve  and  irritate  the  adjacent  abdominal  wall.  This  can  be 
prevented  by  taking  care  to  collect  all  the  juice,  and  to  allow  none  to  flow  away  over 
the  surface  of  the  body.  Another  drawback  is  that  the  continual  loss  of  pancreatic 
juice  in  many  cases  seriously  affects  the  animal's  health.  This  may  be  obviated  to  a 
certain  extent  by  keeping  the  animal  on  a  milk  diet  with  the  addition  of  sodium  bicar- 
bonate to  replace  the  loss  of  this  salt  by  the  juice.  With  great  care  Pawlow  has  succeeded 
in  keeping  such  animals  in  a  perfectly  healthy  condition. 

In  the  fasting  condition  there  is,  as  a  rule,  no  secretion  of  juice,  though  the 
escape  of  a  few  drops  may  be  observed  at  long  intervals.  If  a  meal  be 
administered  to  the  animal,  a  flow  of  juice  begins  in  one  to  one  and  a  half 
minutes.  From  this  time  there  is  a  steady,  slow  rise  of  the  rate  of  secretion, 
which  lasts  for  two  to  three  hours,  and  then  gradually  diminishes.  The 
greatest  increase  in  flow  is  observed  at  the  time  when  the  first  portions  of 
digested  food  escape  from  the  stomach  into  the  duodenum.  The  secretion 
must  therefore  be  determined  in  some  way  by  the  entry  of  this  food  into  the 
duodenum.  By  experiments  on  dogs  possessing  a  gastric  as  well  as  a 
pancreatic  fistula,  it  has  been  shown  that  the  introduction  of  acid,  e.g.  0-4  per 
cent.  HCl,  into  the  stomach  evokes,  as  soon  as  it  passes  into  the  duodenum. 
a  rapid  flow  of  pancreatic  juice.  A  similar,  but  smaller,  effect  is  produced  by 
the  passage  of  oil  from  the  stomach  into  the  duodenum.  The  introduction 
of  alkahes  is  without  effect.  Weak  acids  are  also  effective  exciters  of 
secretion  if  they  be  introduced  directly  into  the  duodenum  itself  or  into  a  loop 
of  small  intestine.  The  effect  gradually  diminishes  as  the  loop  which  is 
chosen  comes  nearer  to  the  caecum,  and  as  a  rule  the  injection  of  dilute  acid 
into  the  lower  foot  or  eighteen  inches  of  ileum  is  without  effect  on  the 
pancreas.  The  striking  resemblance  between  the  secretion  thus  evoked  and 
that  produced  in  the  salivary  glands  by  injection  of  acid  into  the  mouth 
suggests  that  we  have  here  to  do  with  a  reflex  of  the  same  kind  as  that  which 
affects  the  salivary  glands.  In  the  search  for  the  channels  of  this  reflex 
Heidenhain  showed  that  stimulation  of  the  medulla  oblongata  occasionally 
produced  a  flow  of  pancreatic  juice.  He  was  unable,  however,  to  obtain  any' 
secretion  on  stimulation  of  the  vagus  nerve.  The  pancreas  receives  fibres 
from  the  vagi  as  well  as  from  the  splanchnic  nerves  (sympathetic  system). 
According  to  Pawlow  the  ill  success  of  Heidenhain's  experiments  was  due  to 
the  fact  that  in  any  operation  a  gland  is  played  upon  by  reflex  impulses 


THE  PAXCREATIC  JUICE  709 

partly  of  au  inhibitoiy,  partly  of  a  secretory  nature,  iu  which  the  iuhibitory 
predominate,  and  by  the  further  fact  that  the  pancreas  is  extremely 
susceptible  to  alterations  in  its  blood-supply,  so  that  any  stimulation  of  the 
vagus  which  caused  inhibition  of  the  heart  would  ipsojacto  prevent  the  effect 
of  simultaneous  excitation  of  secretory  fibres  from  making  its  appearance. 
Pawlow  noticed  that  if  in  an  animal  Avith  a  permanent  fistula  the  vagus  on  one 
side  were  cut  and  left  for  four  days  in  order  to  allow  the  cardio-inhibitory 
fibres  to  degenerate,  repeated  stimulation  of  the  peripheral  end  of  the  nerve 
evoked  a  flow  of  pancreatic  juice.  He  obtained  the  same  results  by  stimu- 
lating this  nerve  below  the  point  at  which  it  had  given  ofE  its  cardio-inhibitory 
fibres,  in  animals  in  which  the  reflex  inhibitions  from  the  operation  itself  were 
prevented  by  total  section  of  the  medulla.  Under  certain  circumstances 
he  obtained  also  secretion  on  stimulation  of  the  splanchnic  nerves,  and  there- 
fore concluded  that  these  two  nerves — splanchnics  and  vagi — were  the 
efferent  channels  in  the  reflex  secretion  set  up  by  the  introduction  of  the 
acid  into  the  duodenum.  It  was  shown  later,  however,  independently, 
both  by  Popielski,  a  pupil  of  Pawlow,  and  by  Wertheimer,  that  the  injection 
of  acid  into  a  loop  of  small  intestine  was  followed  by  secretion  of  juice  even 
after  section  of  both  vagi  and  destruction  of  the  sympathetic  gangha  at  the 
back  of  the  abdominal  cavity.  On  repeating  these  experiments  Bayhss  and 
Starling  found  that  a  secretion  of  juice  was  produced  even  when  the  acid  was 
introduced  into  a  loop  of  the  small  intestine  entirely  freed  from  any  possible 
nervous  connections  with  the  rest  of  the  body.  It  was  evident  therefore 
that  the  stimulus  or  message  from  the  intestine  to  the  pancreas  which  causes 
the  secretion  of  the  latter  must  be  carried,  not  by  the  nervous  system,  but  by 
the  blood  stream.  Since  the  injection  of  acid  into  the  portal  vein  was  without 
effect  on  the  pancreas,  it  was  concluded  that  something  must  be  produced  in  the 
epithehal  cells  of  the  gut  under  the  influence  of  acid,  and  that  this  product 
of  the  epithehal  cells  was  absorbed  in  the  blood  stream  and  was  the  active 
agent  in  exciting  the  pancreas.  On  pounding  up  some  scrapings  of  the 
intestinal  mucous  membrane  vnth  dilute  hydrochloric  acid  and  filtering,  and 
injecting  the  filtrate,  a  copious  flow  of  pancreatic  juice  was  produced.  This 
chemical  messenger  or  hormone  from  the  intestine  to  the  pancreas  is  called 
'  secretin,'  or  '  pancreatic  secretin  '  to  distinguish  it  from  possible  other 
members  of  the  same  class.  It  is  produced  in  the  mucous  membrane  from 
a  precursor— pro-secretin.  The  latter  has  not  been  isolated,  but  that 
it  is  present  in  the  mucous  membrane  is  shown  by  the  fact  that  secretin  can  be 
extracted  by  the  action  of  acids  from  mucous  membrane  which  has  been 
killed  by  heat  or  by  the  prolonged  action  of  alcohol. 

Secretin  itself  is  not  a  ferment.  In  order  to  prepare  it  the  mucous 
membrane  is  ground  up  with  sand,  boiled  with  O-i  per  cent,  hydrochloric 
acid,  and  then  neutraHsed  while  boihng  by  the  cautious  addition  of  sodium 
hydrate.  The  coagulable  proteins  are  in  this  way  precipitated,  and  the 
filtered  solution  contains  the  secretin.  It  is  not  precipitated  by  the  ordinary 
alkaline  reagents,  and  diffuses  slowly  through  animal  membranes.  Though 
stable  in  acid  solutions,  it  is  very  rapidly  destroyed  iu  alkahne  or  neutral 


710  PHYSIOLOGY 

solutions,  especially  under  the  influence  of  bacteria.  It  is  apparently 
oxidised  with  extreme  ease.  A  similar,  or  more  probably  the  same,  body 
may  be  produced  from  intestinal  mucous  membrane  by  treating  this  with 
solutions  of  soap. 

In  this  secreting  mechanism  we  have  a  very  striking  example  of  a 
correlation  between  the  activities  of  two  different  portions  of  the  body 
efiected  by  chemical  means.  The  strongly  acid  chyme  enters  the  first  part 
of  the  duodenum.  Immediately  a  certain  amount  of  secretin  is  produced 
by  the  acid  in  the  cells  of  the  mucous  membrane.  The  secretin  is  carried 
by  the  blood  stream  to  the  cells  of  the  pancreas  and  excites  there  the  secretion 
of  strongly  alkahne  pancreatic  juice.  As  soon  as  sufficient  juice  has  been 
secreted  to  neutralise  the  acid  chyme  the  formation  of  secretin,  and  therefore 
the  further  secretion  of  pancreatic  juice,  comes  to  an  end.  If  the  stomach 
still  contains  food  the  process  is,  however,  renewed  in  virtue  of  the  local 
reflex  mechanism  which  we  have  just  studied  regulating  the  opening  and 
closure  of  the  pylorus.  So  long  as  the  contents  of  the  duodenum  are  acid 
the  pylorus  remains  firmly  closed.  As  soon  as  these  are  neutralised  the 
pylorus  relaxes  and  allows  the  entrance  of  a  further  portion  of  acid  chyme. 
Thus  the  formation  of  secretin  proceeds  afresh,  and  the  whole  chain  of 
processes  goes  on  until  the  stomach  is  empty  and  all  its  contents  have  passed 
into  the  intestine. 

In  view  of  the  efficacy  of  this  chemical  reflex  mechanism,  the  question 
arises  whether  the  results  first  obtained  by  Pawlow  were  really  due  in  some 
way  to  the  formation  of  secretin.  Stimulation  of  the  vagus  may  cause  con- 
traction of  the  stomach,  opening  or  closing  of  the  pylorus,  and  it  seems 
possible  that  under  its  action  there  might  have  been  an  escape  of  acid  gastric 
contents  into  the  intestine,  and  therefore  the  formation  of  secretin,  which 
would  suffice  to  arouse  the  pancreatic  secretion.  Later  experiments  by  this 
observer,  in  which  the  escape  of  any  gastric  contents  was  effectively  pre- 
vented by  ligature  of  the  pylorus  while  the  stomach  itself  contained  an 
alkahne  solution,  have  shown  that  even  with  these  precautions  a  flow  of  juice 
may  be  obtained  on  stimulation  of  the  vagus  nerve.  The  flow,  however, 
is  very  small  in  comparison  with  that  obtained  by  injection  of  secretin,  and 
one  must  conclude  that,  although  the  nervous  system  may  play  a  small 
part  in  the  excitation  of  the  activity  of  this  gland,  the  main  factor  involved 
is  the  chemical  mechanism  which  has  just  been  described. 

The  amount  of  pancreatic  juice  obtained  after  a  meal  varies  with  the 
nature  of  the  latter.  The  Table  on  p.  711  represents  the  results  obtained  on 
an  animal  fed  with  60O  c.c.  of  milk,  250  grm.  of  bread,  and  100  grm.  of  meat 
respectively. 

The  difierences  between  these  results  seem,  however,  largely  determined 
by  the  duration  of  gastric  digestion,  and  therefore  the  amount  of  acid  secreted 
in  the  stomach  and  passed  on  to  the  duodenum.  It  was  suggested  by 
Walther  that  apart  from  this  quantitative  adaptation  there  was  a  quahtative 
alteration  in  the  constitution  of  the  juice  according  to  the  nature  of  the 
food  ingested,  that,  e.cj.,  excess  of  protein  causes  an  increase  of  the  trypsin, 


THE  PANCREATIC  JUICE 


711 


while  excess  of  carbohydrate  would  cause  an  increase  in  the  amylase  of  the 
juice.  Later  researches  have  failed  to  confirm  this  view.  Apparently  when 
the  pancreas  is  excited  to  secrete,  it  turns  out  its  various  ferments  in  constant 
proportion,  depending  on  the  amounts  of  these  already  present  and  stored 
up  in  the  gland. 

Secretion  of  Pancreatic  Juice  (Walther) 


Hours  after  meal 

600  c.c.  milk 

250  grm.  bread 

100  grm.  meat 

1 

8-5  C.C. 

36-5  c.c. 

38-75  c.c. 

2 

7-6  C.c. 

50-2  c.c. 

44-6    c.c. 

3 

14-6  C.C. 

20-9  c.c. 

30-4    c.c. 

4 

11-2  c.c. 

14-1  c.c. 

16-9    c.c. 

5 

3-2  c.c. 

16-4  c.c. 

0-8    c.c. 

6 

1-0  c.c. 

12-7  c.c. 

— 

7 

— 

10-7  c.c.  ♦ 

— 

8 

— 

6-9  c.c. 

— 

THE  STRUCTURAL  CHANGES  IN   THE  PANCREAS  WHICH 

ACCOMPANY  SECRETION 

The  ease  vnih  which  secretin  may  be  prepared  and  used  to  arouse  the 

activity  of  the  pancreas  has  rendered  it  possible  to  study  more  closely  the 

changes  which  in  this  gland  accompany  activity.     Kiihne  and  Sheridan 

Lea  succeeded  in  observing  the  gland  of  the  rabbit  in  a  living  state  under  the 


A  B 

Fig.  340.     A  terminal  lobule  of  the  pancreas  of  the  rabbit.     (Kuhne  and 
iSheriban  Lea.] 
A,  in  resting  condition  ;  b,  after  active  secretion. 

microscope.  They  noted  that  activity,  excited  by  pilocarpine,  was  associated 
with  a  discharge  of  granules,  a  clearing  up  of  the  cells,  and  a  diminution  in 
size  and  the  appearance  of  a  lumen  to  the  gland  alveoli  (Fig.  340).  A  normal 
resting  gland  is  of  an  opaque,  yellowish- white  colour,  and  of  firm  consistence. 
On  section  it  is  seen  to  consist  of  numerous  secreting  alveoli  which  open  into 
narrow  intercalary  tubules,  and  these  in  their  turn  into  wide  collecting 
tubules.  The  lining  epithelium  of  the  intercalated  tubules  is  often  con- 
tinued into  the  secreting  part,  where  they  lie  internal  to  the  secreting  cells, 
as  the  so-called  centro-acinar  cells.     The  secreting  cells  themselves  present 


712 


PHYSIOLOGY 


two  well-marked  zones,  a  narrow  peripheral  zone  in  which  the  nucleus  is 
embedded,  which  is  strongly  basophile,  and  a  central  part  which  is  turned 
towards  the  lumen,  occupying  two- thirds  or  three-quarters  of  the  cell,  and 
is  closely  packed  with  highly  refractive  granules  strongly  acidophile  and 
presumably  containing  or  composed  of  the  precursors  of  the  various  con- 


FiG.  341.     Alveoli  of  dog's  pancreas.     (Babkest,  Rubaschkin  and  Saavitsch.) 
A,  resting  ;  b,  after  moderate  secretion  with  discharge  of  granules. 


stituents  of  the  pancreatic  juice  (Fig.  341).  If  the  activity  of  the  gland  be 
aroused  by  injection  of  secretin  and  the  injection  be  contimied  until  the  rate 
of  secretion  evoked  by  each  injection  diminishes  considerably,  i.e.  the  gland 
shows  signs  of  fatigue,  marked  changes  are  observed  both  macroscopically 
and  under  the  microscope.  The  gland  is  now  pink  and  transparent  in  appear- 
ance, moist  and  soft  in  consistence.  On  section  the  lumen  of  each  alveolus 
is  enlarged,  the  cells  are  shrunken,  and  the  granules  are  found  to  lie  only 
along  the  border  of  the  cell  turned  towards  the  lumen,  the  rest  of  the  cell, 
which  is  much  reduced  in  size,  being  made  up  of  the  basophile  protoplasm. 
Similar  effects  are  observed  after  long  continued  stimulation  of  the  vagus 
(Fig.  341  B). 


SECTION  VI 

THE  LIVER  AND  BILE 

The  liver,  the  largest  gland  in  the  body,  is,  Uke  the  other  glands  associated 
with  the  ahmentary  tract,  formed  in  the  embryo  by  an  outgrowth  of  the 
hypoblast  Uning  the  ahmentary  canal.  At  first  it  resembles  in  structuie 
other  secreting  glands,  such  as  the  pancreas,  being  composed  of  branch 
tubules  which  pour  their  secretion  into  a  common  duct.  In  the  adult, 
however,  the  relation  of  the  Uver  cells  to  the  ducts  is  entirely  subordinated 
to  their  relation  to  the  blood-vessels  of  the  liver,  and  it  requires  special 
histological  methods  to  make  out  the  relations  between  the  hver  cells  and 
the  bile-ducts.  The  liver,  on  section,  is  seen  to  be  divided  off  into  lobules 
composed  of  columns  of  polygonal  cells,  radiating  from  the  centre  hke  the 
spokes  of  a  cart-wheel.  The  portal  vein,  which  drains  the  blood  from  the 
ahmentary  canal,  breaks  up  into  branches  which  lie  at  the  periphery  of  the 
lobules,  forming  the  interlobular  veins,  and  send  off  numberless  capillaries 
which  pass  inwards  between  the  columns  of  cells  to  join  the  intralobular  vein 
lying  at  the  centre  of  the  lobule.  From  the  intralobular  the  blood  passes 
by  the  large  sublobular  vein  into  the  hepatic  veins  and  inferior  vena  cava. 
In  an  injected  specimen  it  is  easy  to  see  that  every  hver  cell  is  connected 
with  at  least  one  blood  capillary,  and  the  Hver  thus  forms  a  blood  gland, 
lying  as  it  does  at  the  gate  of  entrance  of  blood  from  the  alimentary  canal 
into  the  general  circulation.  The  portal  vein  conveys  only  venous  blood  to 
the  hver.  In  order  to  supply  oxygen  to  the  working  Uver  cells,  this  organ 
receives  a  second  supply  of  arterial  blood  by  the  hepatic  artery  derived  from 
the  coehac  branch  of  the  aorta.  The  branch  of  the  hepatic  artery  runs  with 
the  branches  of  the  portal  vein  in  the  connective  tissue  of  Glisson's  capsule 
surrounding  the  lobules,  and  breaks  up  into  capillaries  which  are  in  free 
communication  with  the  capillaries  derived  from  the  portal  system  and  pour 
their  blood  finally  into  the  hepatic  vein. 

As  might  be  expected  from  its  structure,  the  secretory  functions  of  the 
liver  represent  but  a  small  proportion  of  its  activities  in  the  body.  The  liver 
is,  in  fact,  the  greatest  chemical  factory  of  the  body,  receiving  by  the  portal 
vein  the  products  of  digestion  as  they  are  absorbed  from  the  alimentary 
canal.  It  converts  these  into  other  substances,  breaking  them  down  or 
building  them  up  according  to  the  needs  of  the  body  as  a  whole.  Thus,  when 
carbohydrates  are  being  absorbed  in  quantity  it  converts  the  glucose 
contained  in  the  portal  blood  into  glycogen  which  it  stores  up,  reconverting 

713  23* 


714 


PHYSIOLOGY 


the  latter  into  glucose  and  letting  it  loose  into  the  circulation  when  this  sub- 
stance is  required  by  the  body  tissues.  In  the  complete  absence  of  carbo- 
hydrate from  the  food  the  liver  may,  as  we  shall  see  later,  actually  convert  the 
products  of  protein  digestion  into  sugar.  In  the  same  way  the  liver  plays  an 
important  part  in  the  metabohsm  of  proteins  and  of  fats,  so  that  its  functions 
will  have  to  be  dealt 'odth  in  the  various  chapters  concerned  with  the  fate  of  the 
difierent  food-stuffs  and  difierent  constituents  of  the  animal  body.  In  this 
chapter  we  are  merely  concerned  wth  its  action  as  a  secreting  gland.  The 
fact  that  its  secretion  is  in  so  many  animals  poured  into  the  intestine  by  an 
orifice  common  to  it  and  the  pancreatic  juice  suggests  that  these  two  fluids  co- 
operate in  their  actions  on  the  ingested  food-stuffs,  and  points  to  a  direct 
use  of  the  bile  in  the  processes  of  digestion.  In  addition  to  this  function, 
the  bile  must  also  be  regarded  as  an  excretion,  representing  as  it  does  the 
channel  by  which  the  products  of  disintegration  of  haemoglobin — the  red 
colouring- matter  of  the  blood — are  got  rid  of  from  the  organism.  As  an  ex- 
cretion the  production  of  bile  must  be  continuous,  and  related,  not  to  the 
processes  of  digestion,  but  to  the  intensity  of  destruction  of  the  red  corpuscles. 
On  the  other  hand,  bile,  as  a  digestive  fluid,  is  needed  in  the  gut  only  during 
the  period  that  digestion  is  going  on.  The  exigencies  of  the  body  therefore 
require  a  continuous  excretion  of  bile  by  the  liver,  but  a  discontinuous  entry 
of  this  fluid  into  the  small  intestine.  This  discontinuity  in  the  entry  of  a 
continuous  secretion  into  the  intestine  is  secured,  in  the  majority  of  animals, 
by  the  existence  of  the  gall-bladder,  a  diverticulum  from  the  bile-ducts,  in 
which  all  bile,  secreted  during  the  intervals  between  the  periods  of  digestive 
activity,  is  stored  up.  In  the  horse,  where  the  gall-bladder  is  absent,  its 
place  is  taken  to  some  extent  by  the  great  size  of  the  bile  ducts.  Moreover 
in  such  an  animal  the  process  of  digestion  is  much  more  continuous  in 
character  than  it  is  in  carnivora.  Since  the  bile  accumulates  in  the  gall- 
bladder during  the  whole  time  that  digestion  is  not  going  on,  and  is  only 
poured  into  the  gut  during  digestion,  in  a  fasting  animal  the  gall-bladder  is 
distended,  whereas  in  an  animal  some  hours  after  a  meal  the  gall-bladder  is 
practically  empty. 

During  the  period  that  the  bile  remains  in  the  gall-bladder  it  under- 
goes certain  changes,  as  is  shown  by  comparison  of  the  composition  of  bile 
obtained  from  the  gall-bladder  with  that  obtained  from  a  fistula  of  the 
bile-duct. 


Analyses  of  Bile  (Human) 


From  a  biliary  fistula  (Yec 

)  and  Herroun)  in 

Prom  the  gt 

ill-bladder  (Hoppe- 

.?eyler)  in 

100  parts 

100  parts 

Mucin  and  pigments 

0148 

Mucin 

.     1-29 

Sodium  taurocholate 

0055 

Sodium  taurochohxte 

.     0-87 

Sodium  glycocholate 

0  165 

Sodium  glycocholate   . 

.     303 

Cholesterin     . 

.0-038 

Soaps 

.     1-39 

Lecithin 

Cholesterin 

.     0-35 

Fats 

Lecithin     . 

.     0-53 

Inorganic  salts 

0-840 

Fats 

. 

.     0-73 

Water 

.       98-7 

THE  LIVER  AND  BILE  715 

During  its  star  in  the  bladder  the  bile  is  concentrated  by  the  loss  of  water 
and  by  the  addition  to  it  of  mucin  or  nucleo- albumen,  derived  from  the 
cells  lining  the  bladder.  Of  the  other  constituents  of  bile,  the  pigments 
must  be  regarded  simply  as  waste  products,  and  an  index  to  the  disintegration 
of  haemoglobin.  Their  mode  of  origin  will  be  discussed  in  deahng  with  the 
history  of  the  red  blood  corpuscles.  They  pass  into  the  intestine  and  are 
there  converted  by  the  processes  of  bacterial  reduction  into  stercobilin,  which 
is  excreted  for  the  most  part  with  the  fseces,  a  small  proportion  being  ab- 
sorbed into  the  blood-vessels  and  turned  out  in  a  more  or  less  altered  condi- 
tion as  the  pigments  of  the  urine.  From  the  point  of  view  of  digestion, 
the  important  constituents  of  bile  are  the  bile  salts,  with  the  lecithin  and 
cholesterin  held  in  solution  by  these  salts.  The  time-relations  of  the  secre- 
tion, as  well  as  of  the  flow  of  bile  into  the  intestine  in  connection  "u-itli  the 
processes  of  digestion,  can  be  learnt  from  animals  in  which  the  bile  is 
conducted  to  the  outside  of  the  body  by  means  of  a  permanent  fistula. 

For  this  purpose  Pawlow  has  devised  the  following  operation  :  In  the  dog  the 
abdomen  is  opened,  and  the  common  bile-duct  sought  as  it  passes  through  the  intestinal 
wall.  The  orifice  of  the  duct,  with  a  piece  of  the  surroimding  mucous  membrane 
is  cut  out  of  the  wall  of  the  intestine,  and  the  aperture  thus  made  sutured.  The  ex- 
cised portion  of  mucous  membrane,  with  the  opening  of  the  duct,  is  then  se'mi  on  to  the 
surface  of  the  duodenum,  and  the  loop  of  duodenum  at  this  point  is  stitched  into  the 
abdominal  woimd.  After  healing,  the  natural  orifice  of  the  bile-duct  is  thus  made  to 
ojien  on  the  surface  of  the  abdomen. 

In  an  animal  treated  in  this  way  the  flow  of  bile  from  the  fistula  is  found 
to  run  parallel  to  the  pancreatic  secretion.  Although  smaller  in  amount,  it 
rises  and  falls  \-vith.  the  latter.  Thus  a  meal  of  meat  produces  a  large  flow  of 
bile,  a  meal  of  carbohydrates  only  a  small  flow.  Moreover,  beginning  almost 
immediately  after  taking  food,  it  attains  its  maximum  ^^^th  the  pancreatic 
juice  in  the  third  hour  and  then  rapidly  declines. 

In  the  production  of  this  flow  of  bile  two  factors  may  be  involved  :  (1)  the 
emptying  of  the  gall-bladder ;  (2)  an  increased  secretion  of  the  bile.  In 
order  to  determine  the  relative  importance  to  be  ascribed  to  each  factor,  we 
must  compare  the  results  obtained  on  an  animal  possessing  a  Pawlow 
fistula  with,  those  obtained  on  an  animal  provided  with  a  fistulous  opening 
into  the  gall-bladder,  the  common  bile-duct  in  the  latter  having  been  ligated 
to  ensure  that  the  total  secretion  of  bile  passed  out  by  the  fistula.  In  such 
animals  we  find,  as  we  should  expect,  that  the  secretion  of  bile  is  a  continuous 
process,  but  that,  synchronously  with  the  great  outpouring  of  bile  into  the 
intestine  during  the  third  hour  after  a  meal,  there  is  an  increased  secretion 
of  this  fluid.  The  passage  therefore  of  the  semi-digested  food  from  the 
stomach  into  the  duodenum  causes  not  only  a  slow  contraction  and  emptying 
of  the  gall-bladder  but  also  an  increased  secretion  of  bile  by  the  liver. 
What  is  the  mechanism  involved  in  the  production  of  these  two  eft'ects  ?  The 
muscular  wall  of  the  gall-bladder,  as  has  been  shown  by  Dale,  is  imder  the 
control  of  nerves  derived  both  from  the  vagus  and  from  the  sympathetic,  the 
former  conveying  motor  and  the  latter  inhibitory  impulses.  It  is  usual  to 
suppose  that  the  entry  of  acid  chyme  into  the  duodenum  provokes  reflexly 


716  PHYSIOLOGY 

the  contraction  of  the  gall-bladder,  but  the  exact  paths  and  steps  in  this 
reflex  act  have  not  yet  been  fully  determined.  The  increased  secretion 
of  bile,  which  is  produced  by  the  passage  of  the  acid  chyme  through  the 
pylorus,  can  be  also  evoked  by  the  introduction  of  acid,  such  as  04  per  cent. 
HC],  into  the  duodenum,  and  occurs  even  after  division  of  all  connection 
between  the  liver  and  the  central  nervous  system.  Since  the  presence  of 
bile  is  necessary  for  the  full  development  of  the  activities  of  the  pancreatic 
juice,  and  its  secretion  is  initiated  by  the  same  sort  of  stimulus,  i.e.  acid 
apphed  to  the  mucous  membrane  of  the  gut,  the  question  naturally  arises 
whether  the  mechanism  for  the  secretion  of  bile  may  not  be  identical  with 
that  for  the  secretion  of  pancreatic  juice.  In  order  to  decide  this  point  we 
must  make  a  temporary  bihary  fistula  by  inserting  a  cannula  into  the  hepatic 
duct.  A  solution  of  secretin  is  then  prepared  from  an  animal's  intestine. 
In  making  this  solution  we  must  be  careful  to  avoid  any  contamina- 
tion by  bile  salts,  which  may  possibly  be  adherent  to  the  mucous  membrane 
of  the  gut  and  would  in  themselves,  on  injection,  evoke  an  increased  secretion 
of  bile.  It  is  therefore  better  to  extract  the  pounded  mucous  membrane  with 
boihng  absolute  alcohol,  until  this  fluid,  evaporated  into  a  small  bulk,  shows 
no  trace  of  bile  salts.  The  dried  and  powdered  gut  is  then  boiled  with  dilute 
acid.  On  injecting  the  solution  of  secretin  so  obtained  into  the  animal's 
veins,  an  increased  flow  of  bile  is  at  once  produced.  In  one  experiment,  for 
instance,  the  injection  into  the  veins  of  5  c.c.  of  a  solution  of  secretin,  pre- 
pared in  this  way,  increased  the  secretion  of  bile  by  the  liver  from  twenty- 
seven  drops  in  fifteen  minutes  to  fifty-four  drops  in  fifteen  minutes.  The 
rate  of  secretion  was  therefore  doubled.  We  may  conclude  that  the  mechan- 
ism, by  which  the  increased  secretion  of  bile  is  produced  at  the  time  when 
this  fluid  is  required  in  the  intestine,  is  identical  with  that  for  the  secretion  of 
pancreatic  juice,  and  that  in  each  case  one  and  the  same  substance — secretin 
— ^is  formed  by  the  action  of  the  acid  on  the  cells  of  the  mucous  membrane, 
and,  on  absorption  into  the  blood  stream  excites  both  the  fiver  and  pancreas 
to  increased  activity. 

THE  DIGESTIVE  FUNCTIONS  OF  THE  BILE 
Bile  contains  a  weak  amylolytic  ferment.  Its  uses  in  digestion  are 
dependent,  however,  not  on  the  presence  of  this  ferment,  but  on  the  peculiar 
action  of  the  bile  salts  on  the  fermentative  powers  of  the  pancreatic  juice. 
It  was  shown  long  ago  by  Williams  and  Martin  that  the  amylolytic  power 
of  pancreatic  extracts  is  doubled  by  the  addition  of  bile  or  of  bile  salts. 
Pawlow  has  stated  that  the  same  holds  good  oi  the  proteolytic  power  of  this 
juice.  Most  important,  however,  is  the  part  played  by  the  bile  in  the  diges- 
tion and  absorption  of  fats.  The  fat-splitting  action  of  pancreatic  juice  is 
trebled  by  the  addition  of  bile,  whether  boiled  or  unboiled.  This  quickening 
action  of  the  bile  probably  depends,  like  its  function  in  the  absorption  of 
fats,  on  the  pecuhar  physical  properties  of  the  bile  salts,  with  those  of  the 
lecithin  and  cholesterin  which  they  hold  in  solution.  Not  only  does  such 
a  solution  diminish  the  surface  tension  between  watery  and  oily  fluids,  so 


THE  LIVER  AND  BILE  717 

promoting  the  closer  approach  of  the  lipase  of  the  pancreatic  juice  to  the  fats 
on  which  it  is  to  act,  but  it  has  also  the  power  of  dissolving  fatty  acids  and 
soaps,  including  even  the  insoluble  calcium  and  magnesium  soaps.  It  is 
probable  that  it  aids  also  in  holding  in  solution,  and  bringing  in  contact 
with  the  fat,  the  Upase  of  the  pancreatic  juice.  It  has  been  shown  by 
Nicloux  that  the  lipase  contained  in  oily  seeds,  such  as  those  of  the  castor 
plant,  is  insoluble  in  water,  but  soluble  in  fatty  media.  The  dried  ferment 
obtained  from  the  pancreas  in  many  cases  yields  no  hpase  to  water,  but  gives 
a  strongly  lipolytic  solution  when  extracted  with  glycerin.  The  digestive 
function  of  bile  therefore  lies  in  its  power  of  serving  as  a  vehicle  for  the 
suspension  and  solution  of  the  interacting  fats,  fatty  acids,  and  fat- 
splitting  ferment.  This  vehicular  function  plays  an  important  part 
in  the  absorption  of  fats.  These  pass  through  the  striated  basilar 
membrane  bounding  the  intestinal  side  of  the  epithelium,  not,  as  was 
formerly  thought,  in  a  fine  state  of  suspension  (an  emulsion),  but  dissolved 
in  the  bile  in  the  form  of  fatty  acids  or  soaps  and  glycerin.  On  the  arrival 
of  these  products  of  digestion  in  the  epithelial  cells,  a  process  of  resynthesis 
is  set  up.  Droplets  of  neutral  fat  make  their  appearance  in  the  cells, 
whence  they  are  passed  gradually  into  the  central  lacteal  of  the  villus  and  so 
into  the  lymphatics  of  the  mesentery  and  into  the  thoracic  duct.  The 
bile  salts  thus  released  from  their  function  as  carriers  are  absorbed  by  the 
blood  circulating  through  the  capillaries  of  the  villi,  and  carried  by  the 
portal  vein  to  the  Hver.  On  arrival  they  are  once  more  taken  up  by  the 
liver-cells  and  turned  out  into  the  bile.  Owing  to  the  fact  of  their  ready 
excretion  by  the  liver-cells,  bile  salts  are  the  most  reliable  cholagogues  with 
which  we  are  acquainted.  By  this  circulation  of  bile  between  liver  and  intes- 
tine the  synthetic  work  of  the  liver  in  the  production  of  the  bile  salts  is 
reduced  to  a  minimum,  and  it  has  oidy  to  replace  such  of  the  bile  salts  as 
undergo  destruction  in  the  alimentary  canal,  under  the  influence  of  micro- 
organisms, and  are  lost  to  the  organism  by  passing  out  in  the  faeces  as  a 
gummy  amorphous  substance  known  as  dyslysin.  Further  investigation  is 
still  wanted  as  to  the  exact  method  in  which  secretin  acts  on  the  liver-cells, 
and  especially  as  to  whether  it  actually  excites  in  them  the  manufacture  of 
fresh  bile  salts,  or  whether  it  simply  hastens  the  excretion  of  such  bile  salts 
as  have  been  formed  by  the  spontaneous  activity  of  the  liver-cells  or  have 
arrived  at  them  after  absorption  from  the  alimentary  canal.  Such  questions 
can  only  be  decided  by  studying  the  action  of  secretin  on  animals  possessing 
a  permanent  biliary  fistula. 

The  effect  of  various  diets  on  the  secretion  of  bile  has  been  studied  by  Barbera. 
He  finds  that,  whereas  the  secretion  of  bile  is  greatest  on  a  meat  diet,  it  is  somewhat 
less  on  a  diet  of  fat,  and  is  insigniticant  on  a  purely  carbohydrate  diet.  That  is  to  say, 
the  secretion  of  bile  is  greatest  on  those  diets  the  digestion  of  which  is  attended  by  the 
passage  of  a  large  anioiuit  of  acid  chyme  or  of  oil  into  the  duodenum.  Oil  is  almost 
as  efficacious  as  acid  in  promoting  the  production  of  secretin  in  the  living  duodenum, 
the  production  in  this  case  being  probably  determined  by  the  formation  of  soap  from 
the  oil,  and  tlie  direct  action  of  the  soap  on  the  prosecretin  in  the  epithelial  cells  of 
the  gut. 


SECTION  VII 

THE  INTESTINAL  JUICE 

For  the  development  of  one  of  its  most  important  properties,  namely,  that 
of  proteolysis,  the  pancreatic  juice  is  dependent  on  the  co-operation  of  the 
intestinal  juice  or  succus  entericus.  Besides  this  activating  power  on  the 
pancreatic  juice,  the  intestinal  juice  has  numerous  other  functions  to 
discharge  in  the  digestion  of  the  food-stuffs.  In  spite  of  the  great  similarity 
which  obtains  between  the  microscopic  structure  of  the  wall  of  the  gut  at 
different  levels  from  duodenum  to  ileocohc  valve,  functionally  there  are  many 
differences  between  the  upper,  middle,  and  lower  portions  of  the  gut. 
Speaking  generally,  we  may  say  that,  whereas  the  processes  of  secretion  are 
better  marked  in  the  upper  portions  of  the  gut,  the  processes  of  absorption 
predominate  in  the  lower  sections,  i.e.  in  the  ileum.  Much  of  the  divergence 
in  the  statements  which  have  been  made  with  regard  to  the  factors  determin- 
ing secretion  and  absorption  in  the  small  intestine  is  due  to  the  failure  to 
appreciate  this  great  difference  between  the  activity  of  the  mucous  membrane 
at  various  levels. 

The  process  of  secretion  in  the  small  intestine  may  be  studied  by  isolating  loops  by 
means  of  ligatures,  and  determining  the  amount  of  secretion  formed  in  these  loops  in 
the  course  of  a  few  hours'  experiment  on  an  anaesthetised  animal.  Better  results, 
however,  may  be  obtained  by  establishing  permanent  fistulse.  These  fistulse  are  of 
two  kinds.  Thiry's  original  method  of  establishing  a  fistula  consisted  in  cutting  out 
a  loop  of  intestine,  and  restoring  the  continuity  of  the  gut  by  suturing  the  two  ends 
from  which  the  loop  had  been  severed.  The  upper  end  of  the  loop  itself  is  closed  and 
the  lower  end  is  sutured  into  the  abdominal  woimd.  For  some  purposes  it  is  better 
to  make  a  Tliiry-Vella  fistula.  In  this  case  the  continuity  of  the  gut  is  restored  as  in 
the  simple  Thiry  fistula,  but  both  ends  of  the  excised  loop  are  left  open  and  brought 
into  the  abdominal  wound.  In  such  a  fistula  it  is  easy  to  introduce  substances  into 
the  upper  end  and  determine  the  flow  of  juice  from  the  lower  end,  the  constant  empty- 
ing of  the  loop  being  provided  for  by  the  peristaltic  contractions  of  its  muscular  coat. 

In  animals  with  intestinal  fistulse  a  number  of  different  conditions  have 
been  found  to  give  rise  to  a  flow  of  succus  entericus,  and  so  far  no  qualitative 
difference  has  been  recorded  between  the  upper  and  lower  ends  of  the  gut, 
A  condition  which  will  cause  a  free  flow  of  juice  from  a  fistula  high  up  in  the 
intestine  mil  generally  cause  a  scanty  flow  from  a  fistula  made  from  the 
ileum.  In  all  cases  it  is  found  that  a  flow  of  juice  is  produced  in  consequence 
of  a  meal.  If  a  dog  with  a  fistula,  which  has  been  starved  for  twenty-four 
hours,  be  given  a  meal  of  meat,  a  flow  of  juice  may  begin  within  the  next 

718 


INTESTINAL  JUICE  719 

ten  minutes.  The  flow  remains  very  slight  for  about  two  hours  and  then 
suddenly  increases  in  amount  during  the  third  hour,  corresponding  thus 
very  nearly  to  the  flow  of  pancreatic  juice  excited  by  the  same  means.  In 
this  post-prandial  secretion  of  juice  it  is  not  probable  that  the  nervous  system 
takes  any  very  large  share,  though  its  intervention  in  the  secretion  has  not 
been  excluded  by  direct  experiment. 

There  are  certain  facts  which  .seem  indeed  to  speak  for  an  action  of  the  central 
nervous  system  on  the  process  of  intestinal  secretion,  not  in  the  direction  of  augmenta- 
tion, but  in  the  direction  of  inhibition  of  secretion.  Thus  it  has  been  observed,  on 
many  occasions,  that  extirpation  of  the  nerve  plexuses  of  the  abdomen  or  section  of 
the  splancluiic  nerves  causes  a  condition  of  diarrhoea  which  may  last  for  two  or  thrco 
days.  This  conchtion  might  be  determined  either  by  an  increased  motor  activity  of 
the  gut,  or  by  removal  of  inhibitory  impulses  normally  arriving  at  the  intestinal  glands, 
Such  a  view  receives  support  from  an  experiment  first  performed  by  Moreau.  The 
abdomen  of  a  dog  is  opened  under  an  anaesthetic,  and  three  contiguous  loops  of  small 
intestine  are  separated  by  means  of  ligatures  from  the  rest  of  the  gut.  The  middle 
loop  is  then  denervatcd  by  destruction  of  all  the  nerve  fibres  lying  on  its  blood-vessels, 
as  they  course  through  the  mesentery,  care  being  taken  not  to  injure  the  blood-vessels 
themselves.  The  loops  are  then  replaced  in  the  abdomen  and  the  animal  left  from 
four  to  sixteen  hours.  On  killing  the  animal  at  the  end  of  this  time,  it  is  often  found 
that  the  middle  loop,  i.e.  the  denervated  loop,  is  distended  vrith.  fluid  having  all  the 
properties  of  ordinary  intestinal  juice,  whereas  the  other  two  loops  are  empty.  A 
series  of  comparative  experiments  by  Mendel  and  by  Falloise  have  sIiotsti  that  the 
secretion  begins  about  four  hours  after  the  operation,  increases  for  about  twelve  hours, 
and  then  rapidly  declines,  so  that  at  the  end  of  two  daj'S  all  three  loops  will  be  fomid 
empty.  This  has  often  been  interpreted  as  due  to  the  removal  of  inhibitory  impulses 
passing  from  the  central  nervous  system  to  the  local  secretory  mechanism,  and  we  have 
no  direct  evidence  which  can  be  adduced  against  such  a  view.  It  is  possible,  however, 
that  the  hyperaemia  of  the  gut,  which  is  produced  by  the  process  of  denervation, 
may  be  sufficient  to  account  for  the  increased  formation  of  intestinal  juice,  since  the 
hyperfemia  will  tend  to  pass  off  as  the  vessels  recover  a  local  tone. 

It  is  not  possible  to  explain  the  flow  of  intestinal  juice  which  follows  a 
meal  by  any  assumption  of  nervous  impulses  transmitted  through  the  local 
nerve  plexuses  of  the  gut,  since  these  have  been  divided  in  the  making 
of  the  fistula.  It  we  exclude  a  nervous  reflex  action  by  the  long  paths, 
namely,  through  the  spinal  cord  and  the  sympathetic  or  vagus  nerves,  the 
flow  which  attends  the  passage  of  food  into  the  first  part  of  the  duodenum 
must  be  excited  by  the  formation  of  some  chemical  messenger.  As  to  the 
existence  of  such  a  chemical  messenger  or  hormone  for  the  intestinal  secretion 
there  can  be  no  doubt,  but  the  evidence  as  to  its  precise  nature  is  at  present 
conflicting.  It  is  stated  by  Pawlow  that  the  most  effective  stimulus  to  the 
flow  of  succus  entericus  is  the  presence  of  pancreatic  juice  in  the  loop  of 
gut.  No  evidence  has  yet  been  brought  forward  that  injection  of  pancreatic 
juice  into  the  blood  stream  will  cause  any  flow  of  intestinal  juice.  On  the 
other  hand,  Delezenne  and  Frouin  have  shown  that  in  animals  provided 
with  a  permanent  fistula  involving  the  duodenum  or  upper  part  of  the 
jejunum,  intravenous  injection  of  secretin  always  causes  a  secretion  of 
intestinal  juice.  In  the  upper  part  of  the  gut  therefore  the  sinuiltaneous 
presence  of  the  three  juices  necessary  for  complete  duodenal  digestion  is 


720  PHYSIOLOGY 

ensured  by  one  and  the  same  mechanism,  namely,  by  the  simultaneous 
activity  of  the  secretin,  produced  in  the  intestinal  cells  by  the  action  of 
the  acid  chyme,  on  pancreas,  liver,  and  intestinal  glands.  A  further 
chemical  mechanism  for  the  arousing  of  intestinal  secretion  has  been  de- 
scribed by  Frouin.  According  to  this  observer,  the  flow  of  juice  can  be  excited 
by  intravenous  injection  of  intestinal  juice  itself.  Since  this  juice  is  alkahne, 
and  does  not  produce  any  effect  on  the  pancreas,  it  must  be  free  from  pan- 
creatic secretin.  It  would  seem  therefore  that  the  flow  of  juice  in  the  upper 
part  of  the  gut,  excited  by  the  pancreatic  secretin,  causes  also  a  production  of 
a  different  secretin  or  hormone,  which  can  be  absorbed  from  the  lumen  of  the 
gut,  travel  by  the  blood  stream  to  other  segments  of  the  small  intestine,  and 
there  excite  a  secretion  in  preparation  for  the  on-coming  food.  Further 
experiments  are,  however,  necessary  on  this  point. 

The  glands  of  the  small  intestine  can  also  be  excited  by  direct  mechanical 
stimulation  of  the  mucous  membrane.  The  easiest  method  of  exciting  a 
flow  of  intestinal  juice  from  a  permanent  fistula  is  to  introduce  into  the 
intestine  a  rubber  tube.  The  presence  of  the  sohd  object  in  the  gut  causes 
a  secretion,  and  within  a  few  minutes  drops  of  juice  can  be  obtained  from 
the  free  end  of  the  tube.  The  object  of  such  a  sensibihty  to  mechanical 
stimuh  is  obvious  ;  it  is  of  the  highest  importance  that  the  onward  passage 
of  any  sohd  object,  especially  if  it  be  indigestible,  shall  be  aided  by  the 
further  secretion  of  juice  in  the  portions  of  gut  which  are  immediately 
stimulated.  This  mechanical  stimulation  probably  acts  on  the  tubular 
glands  of  the  intestine  through  the  intermediation  of  the  local  nervous 
system,  the  plexus  of  Meissner.  It  is  stated  by  Pawlow  that  a  juice  obtained 
by  mechanical  stimulation  differs  from  that  produced  by  the  introduction  of 
pancreatic  juice  into  the  loop  in  containing  httle  or  no  enterokinase,  so  that 
the  pancreatic  juice  excites  the  secretion  of  the  substance  which  is  necessary 
for  its  own  activation. 

CHARACTERS  OF  INTESTINAL  JUICE 
The  intestinal  juice  obtained  from  a  permanent  fistula  has  a  specific 
gravity  of  about  1010.  It  is  generally  turbid  from  the  presence  in  it  of 
migrated  leucocytes  and  disintegrated  epithehal  cells.  It  contains  about 
1-5  per  cent,  total  solids,  of  which  0-8  per  cent,  are  inorganic  and  consist 
chiefly  of  sodium  carbonate  and  sodium  chloride.  It  is  markedly  alkahne  in 
reaction,  but  less  so  than  the  pancreatic  juice.  The  organic  matter,  besides 
a  small  amount  of  serum  albumin  and  serum  globuhn,  includes  a  number  of 
ferments,  all  of  which  are  adapted  to  complete  the  processes  of  digestion 
of  the  food-stuffs  commenced  in  the  stomach  and  duodenum.  Of  these 
ferments  two  are  concerned  in  proteolysis.  Enterokinase  we  have  already 
studied  in  detail.  Possessing  no  action  itself  on  proteins,  it  is  a  necessary 
condition  for  the  development  of  the  full  proteolytic  powers  of  the  pancreatic 
juice.  In  addition  to  this  ferment  another  ferment  has  been  described  by 
Cohnheim  under  the  name  '  erepsin.'  Erepsin  or  some  similar  ferment  is 
present  in  the  fresh  pancreatic  juice  and  in  almost  all  tissues  of  the  body.     It 


INTESTINAL  JUICE  721 

is  distinguished  by  the  fact  that,  although  it  has  no  power  of  digesting  coagu- 
lated protein  or  gelatin,  and  only  slowly  dissolves  caseinogen  and  fibrin,  it 
has  a  rapid  hydrolytic  effect  on  the  first  products  of  proteolysis,  converting 
albumoses  and  peptones  into  amino-  and  diamino-acids — their  ultimate 
cleavage  products. 

The  other  ferments  of  the  intestinal  juice  are  connected  with  the  digestion 
of  carbohydrates.  In  all  mammals  the  intestinal  juice  is  found  to  contain 
invertase,  which  transforms  cane  sugar  into  glucose  and  levulose  or  fructose, 
and  maltase,  which  converts  maltose  into  glucose.  In  young  mammals,  as 
well  as  in  those  in  whom  the  milk  diet  is  continued  throughout  fife,  the 
intestinal  mucous  membrane  also  contains  lactase,  i.e.  a  ferment  converting 
milk  sugar  into  galactose  and  glucose.  Such  a  ferment  can  be  extracted 
from  the  mucous  membrane  of  all  young  animals,  but  may  be  very  slight  or 
even  absent  in  the  intestines  of  older  animals,  when  it  is  no  longer  needed  for 
the  ordinary  processes  of  nutrition.  By  means  of  these  three  ferments, 
coming  as  they  do  after  the  digestion  of  the  starches  by  the  amylase  of  the 
saHva  and  pancreatic  ju.ice,  it  is  provided  that  all  the  carbohydrate  food  of 
the  animal  is  transformed  into  a  hexose,  in  which  form  alone  carbohydrate 
can  be  taken  up  and  assimilated  by  the  cells  of  the  body.  The  seat  of  origin 
of  these  various  ferments  has  been  the  subject  of  special  investigations  by 
Falloise.  Whereas  secretin  can  be  obtained  from  the  whole  thickness  of  the 
mucous  membrane,  and  is  probably  therefore  contained  in  the  form  of 
prosecretin  in  the  epithelial  cells  covering  the  villi  as  well  as  in  those  lining 
the  follicles  of  Lieberkuhn,  a  superficial  scraping  of  the  mucous  membrane, 
which  removes  only  the  epithelial  cells  covering  the  villi  with  the  adherent 
mucus  and  intestinal  secretion,  gives  a  much  more  active  solution  of  entsro- 
kinaise  than  a  deeper  scraping.  The  most  active  solutions  of  enterokinase 
are,  however,  to  be  obtained  from  the  fluid  found  in  the  cavity  of  the  intestine 
after  the  injection  of  secretin.  It  seems  therefore  that  enterokinase  is  not 
present  as  such  in  the  epithelial  cells,  but  is  first  produced  in  the  proce?s  of 
secretion  and  formation  of  the  intestinal  juice.  The  other  ferments,  namely, 
erepsin,  maltase,  invertase,  and  lactase,  probably  pre-exist  as  such  in  the 
epithelial  cells,  especially  in  those  lining  the  tubular  gland'^  of  the  gut,  since 
pounded  mucous  membrane  in  water  yields  a  solution  of  these  ferments  which 
is  generally  more  powerful  in  its  action  than  the  succus  entericus  itself.  So 
great  is  the  difference,  in  fact,  that  many  physiologists  have  suggested  that 
the  chief  action  of  these  ferments  occurs,  not  in  the  lumen  of  the  gut,  but  in 
the  passage  of  the  food-stufis  through  the  epithelial  cells  of  the  small  intestine 
on  their  way  to  the  blood-vessels. 


SECTION  VIII 

FUNCTIONS  OF  THE  LARGE  INTESTINE 

Great  differences  are  found  in  the  structure  of  the  large  intestine  of  different 
animals,  differences  which  depend,  not  on  the  zoological  position  of  the 
animal,  but  entirely  on  the  nature  of  its  food.  In  the  carnivora  the  large 
intestine  is  short  and  narrow  and  possesses  little  or  no  caecum.  In  herbivora 
the  large  intestine  is  well  developed  with  sacculated  walls,  and  the  csecum, 
i.e.  that  part  of  the  large  gut  distal  to  the  opening  of  the  ileum  into  the 
colon,  is  very  large.  Man  occupies  a  somewhat  intermediate  position  be- 
tween these  two  classes.  The  differences  between  the  total  length  of  the 
ahmentary  canal  in  various  animals  are  largely  determined  by  the  varying 
development  of  the  large  intestine.  The  relation  of  these  differences  to  the 
diet  is  seen  if  we  compare  the  length  of  the  intestine  with  the  length  of  the 
animal.  Thus  in  the  cat  the  intestine  is  three  times  the  length  of  the  animal, 
in  the  dog  from  four  to  six  times,  in  man  from  seven  to  eight  times,  in  the 
pig  fourteen  times,  and  in  the  sheep  twenty-seven  times.  The  great  develop- 
ment of  the  large  intestine  in  vegetable  feeders  is  due  to  the  fact  that  in  this 
class  of  food  all  the  nutritious  material  is  enclosed  in  cells  surrounded  by 
cellulose  walls.  In  order  that  the  food-stuffs — e.g.  proteins,  starch,  &c. — 
may  be  dissolved  by  the  digestive  juices  and  absorbed  by  the  wall  of  the 
gut,  these  cellulose  walls  must  be  disintegrated.  In  none  of  the  higher  verte- 
brates do  we  find  any  cellulose  digesting  ferment,  cytase,  produced  in  the 
ahmentary  canal.  The  cellulose  has  therefore  to  be  dissolved  either  by  the 
agency  of  bacteria  or  by  means  of  cellulose- dissolving  ferments  which  may  be 
present  in  the  vegetable  cells  themselves.  Thus  in  ruminants  the  masses  of 
grass  and  hay  are  first  received  into  the  paunch,  where  they  are  kept  warm 
and  moist  with  saliva.  In  the  paunch  opportunity  is  thus  given  for  the 
development  of  huge  numbers  of  micro-organisms  which  can  dissolve  cellu- 
lose. From  time  to  time  portions  of  the  sodden  mass  are  returned  to 
the  mouth,  chewed  and  then  swallowed  again  to  be  subjected  to  the  action 
of  the  proper  digestive  juices.  In  the  horse  and  rabbit  the  chief  part  of  the 
digestion  of  the  cellulose  occurs  in  the  csecum.  Even  after  abstinence  from 
food  for  some  time  the  caecum  is  still  found  to  contain  food  material.  In  the 
caecum,  under  the  action  of  bacteria,  the  cellulose  is  dissolved  and  the  cells 
are  opened  up  so  as  to  allow  their  contents  to  escape.  The  products  of 
digestion  of  cellulose  include  a  number  of  organic  acids,  chiefly  of  the  lower 
fatty  acid  series,  as  well  as  methane,  carbon  dioxide,  and  hydrogen.  In  the 
paunch  the  acids  accumulate  so  that  fermentation  occurs  in  an  acid  medium, 

722 


FUNCTIONS  OF  THE  LARGE  INTESTINE  723 

whereas  in  the  caecum  the  acids  are  neutrahsed  by  the  secretion  of  alkalies 
and  the  reaction  remains  practically  neutral.  The  products  of  digestion 
of  cellulose,  as  well  as  the  contents  of  the  vegetable  cells  set  free  by  the 
solution  of  the  cell  walls,  are  gradually  absorbed  by  the  walls  of  the  large  gut. 
In  carnivora  the  large  intestine  has  very  unimportant  functions  to  discharge 
in  digestion  and  absorption.  The  proteins  of  meat  are  practically  entirely 
absorbed  by  the  time  that  the  food  has  arrived  at  the  ileocolic  valve,  and  the 
same  applies  to  fat.  In  man  the  importance  of  the  large  intestine  will  vary 
with  the  nature  of  his  food.  Under  the  conditions  of  civilised  life  the  food 
material  is  almost  entirely  absorbed  by  the  time  that  it  reaches  the  lower  end 
of  the  ileum.  If,  however,  a  large  quantity  of  vegetable  food  be  taken,  such 
as  fruit  or  green  vegetables,  or  cereals  roughly  prepared  and  coarsely  ground, 
a  considerable  amount  of  material  may  reach  the  large  intestine  unabsorbed. 
A  certain  proportion  of  this  may  undergo  absorption  in  the  large  intestine, 
while  the  rest  will  pass  out  with  the  faeces,  increasing  their  bulk. 

It  is  hardly  possible  to  speak  of  a  secretion  by  the  mucous  membrane 
of  the  large  intestine.  In  herbivora  alkahne  carbonates  are  secreted  to 
neutrahse  the  acids  produced  in  the  bacterial  fermentation  of  the  food,  but 
the  processes  of  absorption  and  secretion  keeping  pace,  there  is  no  accumu- 
lation of  the  products  of  secretion  in  the  intestine.  A  section  of  the  mucous 
membrane  shows  a  number  of  simple  tubular  glands.  The  greater  number  of 
the  cells  lining  these  glands  are  typical  '  goblet '  cells  and  contain  plugs  of 
mucin.  The  secretion  of  mucus  not  only  aids  the  passage  of  the  faeces 
along  the  gut,  but  probably  impedes  the  propagation  of  the  bacteria  which 
are  present  in  comitless  numbers  in  the  faeces.  This  may  accoimt  for  the 
fact  that  although  bacteria  are  so  numerous  in  the  faeces,  it  is  difficult  to 
cultivate  any  large  numbers  most  of  them  being  dead. 

As  an  absorbing  organ  the  large  intestine  of  man  is  of  little  importance. 
From  observations  on  fistulae  in  man  it  has  been  calculated  that  about  500 
c.c.  of  water  pass  the  ileocohc  valve  in  the  twenty- four  hours.  Of  these  about 
400  c.c.  undergo  absorption  in  the  large  intestine.  The  absorption  of  any 
of  the  food  substances  by  this  part  of  the  gut  is  much  slower  than  that  which 
takes  place  on  introduction  by  the  mouth.  Feeding  by  nutrient  enemata 
is  thus  always  very  inadequate.  In  some  cases  after  the  introduction  of 
large  enemata  into  the  large  intestine  a  certain  amount  may  escape  back- 
wards into  the  ileum  and  may  there  undergo  absorption.  The  isolated  large 
intestine  of  man  is  able  to  absorb  only  about  six  grammes  of  dextrose  per 
hour  and  about  80  c.c.  of  water.  If  egg  albumin  or  caseinogen  solutions 
be  introduced  by  the  rectum  no  absorption  can  be  detected  after  several 
hours.  In  observations  extending  over  a  considerable  time  some  disappear- 
ance has  been  observed  of  proteins  and  emulsified  fats,  as  well  as  of  boiled 
starch.  This  was  due,  however,  to  the  action  of  bacteria  on  these  substances, 
and  was  probably  of  very  little  value  for  the  nourishment  of  the  individual. 
Feeding  by  nutrient  enemata  is  thus  merely  a  method  of  slow  starvation. 
If  it  is  employed  it  should  be  limited  to  administration  of  water,  Salines, 
or  solutions  of  glucose. 


724  PHYSIOLOGY 

The  chief  value  of  the  large  intestine  in  carnivora  and  in  civilised  man 
would  seem  to  be  as  an  excretory  organ,  since  it  plays  an  important  part  in  the 
excretion  of  lime,  magnesium,  iron,  and  phosphates.  Lime  salts  are  ex- 
creted partly  with  the  faeces,  partly  in  the  urine.  The  path  taken  by  the 
hme  under  different  conditions  varies  with  the  character  of  the  other  con- 
stituents of  the  food.  If  phosphates  are  present  in  large  quantities  the 
greater  part  of  the  hme  will  be  excreted  by  the  large  intestine  and  escape 
with  the  faeces  as  insoluble  calcium  phosphate.  If  acids  be  administered, 
such  as  hydrochloric  acid,  the  amount  of  hme  in  the  urine  will  increase,  that 
in  the  faeces  will  diminish.  Thus  in  herbivora  normally  only  about  3  to  6 
per  cent,  of  the  lime  is  excreted  with  the  urine,  whereas  in  carnivora  with 
an  acid  urine  the  proportion  leaving  the  body  by  this  channel  rises  to  27 
per  cent.  The  excretion  of  magnesium  is  determined  by  very  similar  con- 
ditions. Its  phosphates  are  somewhat  more  soluble  than  those  of  hme. 
In  man  about  50  per  cent,  of  the  magnesium  leaving  the  body  is  contained  in 
the  urine,  whereas  the  amount  of  lime  in  the  faeces  is  ten  to  twenty  times 
as  much  as  that  contained  in  the  urine.  It  must  be  remembered  that  the 
whole  of  this  difference  is  not  due  to  excretion  of  hme  into  the  gut,  since  a 
certain  proportion  of  this  substance  may  be  precipitated  as  an  insoluble 
phosphate  or  carbonate  in  the  upper  part  of  the  small  intestine  and  pass 
through  the  gut  without  undergoing  absorption. 

The  absorption  of  iron  takes  place  in  the  duodenum  and  upper  part  of 
the  jejunum.  Only  1  or  2  milhgrammes  appear  in  the  urine,  all  the  rest 
being  excreted  in  the  large  gut  and  appearing  in  the  faeces,  chiefly  as  sulphide 
of  iron. 

Of  the  acid  radicals  phosphates  may  pass  out  either  with  the  urine  or  with 
the  faeces,  the  exact  path  taken  being  determined  by  the  relative  amount  of 
calcium  and  alkahne  metals  present  in  the  food.  If  there  is  an  excess  of 
calcium  most  of  the  phosphates  will  leave  with  the  faeces. 

The  large  intestine  is  the  main  channel  of  excretion  for  certain  substances 
which  cannot  be  regarded  as  normal  constituents  of  the  food,  e.g.  the  heavy 
metals,  such  as  bismuth  and  mercury.  If  bismuth  be  administered  sub- 
cutaneously  the  faeces  will  be  found  to  contain  this  substance,  and  the  wall 
of  the  large  intestine  will  be  stained  black  from  a  deposit  of  sulphide  of 
bismuth.  This  deposit  stops  short  at  the  ileocohc  valve.  The  excretion 
of  mercury  by  the  wall  of  the  large  intestine  may  account  for  the  frequent 
presence  of  ulceration  of  this  part  of  the  gut  in  cases  of  poisoning  by  mercury. 


SECTION  IX 

MOVEMENTS  OF  THE  INTESTINES 

The  movements  of  the  intestines  can  be  investigated  either  by  observation 
of  the  exposed  gut,  or  by  the  shadow  method  introduced  by  Cannon,  in  which 
the  nature  of  the  movements  is  judged  from  the  shadows  of  food  containing 
bismuth  which  are  thrown  on  a  sensitive  screen  by  means  of  the  Routgen 
rays.  These  movements  have  been  the  subject  of  experimental  investigation 
for  many  years,  but  with  varpng  results.  The  great  discrepancy  which 
obtained  between  the  statements  of  earher  observers  is  due  to  the  fact  that 
they  failed  to  exclude  the  many  disturbing  impulses  which  can  play  on  any 
segmsnt  of  the  gut,  either  reflexly  through  the  central  nervous  system,  or 
from  other  parts  of  the  ahmentary  canal  itself  through  the  local  nervous 
system.  In  order  to  observe  the  normal  movements  of  the  gut,  it  is  neces- 
sary to  exclude  the  distm'bing  influences  due  to  reflexes  through  the  central 
nervous  system  either  by  extirpation  of  the  whole  of  the  nerve  plexuses  in 
the  abdomen,  or  by  division  of  the  splanchnic  nerves,  or  by  destruction  of  the 
lower  part  of  the  spinal  cord  from  about  the  middle  dorsal  region.  If  the 
abdomen  of  an  animal  which  has  been  treated  in  this  way  be  opened  in  a 
bath  of  warm  normal  salt  solution,  so  as  to  exclude  the  disturbing  influence 
of  drying  and  cooling  of  the  gut,  the  small  intestine  wdll  be  seen  to  present 
two  kinds  of  movements.  In  the  first  place,  all  the  coils  of  gut  imdergo 
swaying  movements  from  side  to  side — the  so-called  pendular  movements. 
Careful  observation  of  any  coil  will  show  that  these  movements  are  attended 
with  slight  waves  of  contraction  passing  rapidly  over  the  sui'face.  If  a 
rubber  balloon,  filled  with  air  and  connected  with  a  tambour,  be  inserted 
into  any  part  of  the  gut,  it  wU  reveal  the  existence  of  rhythmic  contractions 
of  the  circular  muscle  repeated  from  twelve  to  thirteen  times  per  minute. 
By  means  of  a  special  piece  of  apparatus  (the  '  enterograph  ')  it  is  possible 
without  opening  the  gut  to  record  the  movements  of  either  circular  or 
longitudinal  muscular  coats ;  and  it  is  then  found  that  both  coats  present 
rhythmic  contractions  at  the  same  rate,  the  two  coats  at  any  point  con- 
tracting synchronously.  When  the  contractions  are  recorded  by  means  of  a 
balloon,  the  constriction  which  accompanies  each  contraction  is  seen  to 
be  most  marked  at  the  middle  of  the  balloon,  i.e.  at  the  point  of  greatest 
tension,  and  the  amphtude  of  the  contractions  is  augmented  by  increasing 
the  tension  on  the  walls  of  the  gut.  These  movements  are  unafl'ected  by 
the  direct  application  of  drugs  such  as  nicotine  or  cocaine,  which  we  might 

725 


726  PHYSIOLOGY 

expect  to  paralyse  any  local  nervous  structures  in  the  wall  of  the  gut. 
Bayhss  and  Starhng  concluded  that  these  rhythmic  contractions  were 
myogenic,*  that  they  were  propagated  from  muscle  fibre  to  muscle  fibre,  and 
that  they  coursed  down  the  gut  at  the  rate  of  about  5  cm.  per  second.  Since, 
however,  they  may  apparently  arise  at  any  portion  of  the  gut  which  is  subject 
to  any  special  tension,  it  is  not  easy  to  be  certain  that  a  contraction  recorded 
at  any  point  is  really  propagated  from  a  point  two  or  three  inches  higher  up. 
These  contractions  must  cause  a  thorough  mixing  of  the  contents  of  the  gut 
with  the  digestive  fluids.  Oii'  examining  under  the  Rontgen  rays  the 
intestines  of  a  cat  which  has  taken  a  large  meal  of  bread  and  milk  mixed  with 
bismuth  some  hours  previously,  a  length  of  gut  may  be  seen  in  which  the 
food  contents  form  a  continuous  column.     Suddenly  movements  occur  in  this 


^     (P  CD  O  CD  CD  a5  m 


Fii.  343.     Diagram  of  the  'segmentation'  (pendular)  movements  of  the  intestines  as 
observed  by  the  Rontgen  rays,  after  administration  of  bismuth.     (C'AiifNON.) 

I.  A  continuous  column,  intestinal  movements  being  absent.  2.  The  column 
broken  up  into  segments.  3.  Five  seconds  later,  each  segment  divided  into  two, 
the  halves  joining  the  corresponding  halves  of  adjacent  segments.  4.  Condition 
(2)  repeated  five  seconds  later. 

column,  which  is  split  into  a  number  of  equal  segments.  Within  a  few 
seconds  each  of  these  segments  is  halved,  the  corresponding  halves  of  ad- 
jacent segments  uniting.  Again  contractions  recur  in  the  original  positions, 
dividing  the  newly  formed  segments  of  contents  and  re-forming  the  segments 
in  the  same  position  as  they  had  at  first  (Fig.  343).  If  the  contraction  is  a 
continuous  propagated  wave,  it  is  evidently  reinforced  at  regular  intervals 
down  the  gut,  so  as  to  divide  the  column  of  food  into  a  number  of  spherical 
or  oval  segments.  The  points  of  greatest  tension  immediately  become  the 
points  which  are  midway  between  the  spots  where  the  first  contractions 
were  most  pronounced.  The  second  contractions  therefore  start  at  these 
points  of  greatest  tension,  and  divide  the  first  formed  segments  into  two  parts, 
which  join  with  the  corresponding  halves  of  the  neighbouring  segments.  In 
this  way  every  particle  of  food  is  brought  successively  into  intimate  contact 

*  Magnus  has  shown  that  strips  of  the  longitudinal  coat,  pulled  off  from  the  small 
intestine  of  the  cat,  may  continue  to  beat  regularly  in  oxj-genated  Ringer's  solution.  He 
stated  that  these  contractions  only  occurred  if  portions  of  Auerbach's  plexus  were  still 
adherent  to  the  muscle  fibres,  and  concluded  therefore  that  the  rhythmic,  like  the 
peristaltic,  contractions,  were  neurogenic.  Gunn  and  Underbill  however  have  obtained 
well-marked  rhythmic  contractions  from  strips  of  muscle  entirely  free  from  any  remains 
of  the  nerve  plexus,  thus  confu-ming  the  view  enunciated  above. 


MOVEMENTS  OF  THE  INTESTINES  727 

with  the  intestinal  wall.  These  movements  have  not  a  translatory  effect,  and  a 
column  of  food  may  remain  at  the  same  level  in  the  gut  for  a  considerable  time. 
The  onward  progress  of  the  food  is  caused  by  a  true  peristaltic  contrac- 
tion, i.e.  one  which  involves  contraction  of  the  gut  above  the  food  mass  and 
relaxation  of  the  gut  below.  If  a  balloon  be  inserted  in  the  lumen  of  the 
exposed  gut,  it  will  be  found  that  pinching  the  gut  above  the  balloon  causes 
an  immediate  relaxation  of  the  muscular  wall  in  the  neighbourhood  of  the 
balloon.  This  inhibitory  influence  of  the  local  stimulus  may  extend  as 
much  as  two  feet  down  the  intestine  towards  the  ileocaecal  valve.  On  the 
other  hand,  pinching  the  gut  half  an  inch  below  the  situation  of  the  balloon 
causes  a  strong  continued  contraction  to  occur  at  the  balloon  itself^^(Fig.  344). 


Fig.  344.  Intestiiical  contractions  (balloon  method).  In  this  dog  all  the  abdominal 
ganglia  had  been  excised,  and  both  vagi  cut.  Sho^ving  proimgated  effects  oi 
mechanical  stimulation,  above  and  below  the  balloon. 

(1)  pinch  above,  (2)  pinch  below,  (3)  pinch  below  balloon. 

Stimulation  at  any  portion  of  the  gut  causes  contraction  above  the  point  of 
stimulus  and  relaxation  below  the  point  of  stimulus  (the  '  law  of  the  intes- 
tines ').  The  same  efiect  is  produced  by  introduction  of  a  bolus  of  food, 
especially  if  it  be  large  or  have  a  direct  irritating  efiect  on  the  wall  of  the  gut 
(Fig.  345).  In  this  case  the  contraction  above  and  the  inhibition  below 
cause  an  onward  movement  of  the  bolus,  which  travels  slowly  down  the 
whole  length  of  the  gut  until  it  passes  through  the  ileocaecal  opening  into 
the  large  intestine.  The  peristaltic  contraction  involves  the  co-operation  of 
a  nervous  system.  Whereas  in  the  oesophagus  it  is  the  central  nervous 
system  which  is  involved,  the  peristaltic  contractions  in  the  small  intestine 
occur  after  severance  of  all  connection  with  the  brain  and  spinal  cord.  On 
the  other  hand,  they  are  absolutely  abolished  by  painting  the  intestine  with 
nicotine  or  with  cocaine.  They  must  therefore  be  ascribed  to  the  local 
nervous  system  contained  in  Auerbach's  plexus,  which  we  can  regard 
as  a  lowly  organised  nervous  system  ^vith  practically  one  reaction, 
namely,  that  formulated  above  as  the  '  law  of  the  intestines.'  An  anti- 
peristalsis  is  never  observed  in  the  small  intestine.  Mall  has  shown  that, 
if  a  short  length  of  gut  be  cut  out  and  reinserted  in  the  opposite  direction,  a 
species  of  partial  obstruction  results,  in  consequence  of  the  fact  that  the 
peristaltic  waves,  started  above  the  point  of  operation,  cannot  travel  down- 


728  PHYSIOLOGY 

wards  over  the  reversed  length  of  gut.  The  intestine  above  this  point  there- 
fore becomes  dilated.  If  however  the  reactions  of  the  local  nervous  system 
be  paralysed  or  inhibited,  a  reflux  of  intestinal  contents  is  quite  possible,  since 
the  contractions  excited  at  any  spot  by  local  stimulation  of  the  muscle  have 
the  effect  of  driving  the  food  either  upwards  or  downwards  ;  the  direction  of 
movement  of  the  food  will  be  that  of  least  resistance. 

:  The  .movements  of  the  small  intestine  are  also  subject  to  the  central 
nervous  system.  Stimulation  of  the  vagus  has  the  effect  of  producing  an 
initial  inhibition  of  the  whole  small  intestine,  followed  by  increased  irrita- 
bility and  increased  contractions  (Fig.  346).  On  the  other  hand,  stimulation 
of  the  splanchnic  nerves  causes  complete  relaxation  of  both  coats  of  the  small 
gut  (Fig.   347).     It  seems  that  the  splanchnics  normally  exercise  a  tonic 


Fig.  345.  Passage  of  bolus.  Contractions  of  longitudinal  coat  (enterograph).  Tlie 
bolus  (of  soap  and  cotton- wool)  was  inserted  into  the  intestine  four  inches  above  the 
recorded  spot  at  a.  The  figures  below  the  tracing  indicate  the  distance  of  the  middle 
of  the  bolus  from  the  recording  levers.  As  the  bolus  arrived  two  inches  above  the 
levers  there  is  cessation  of  the  rhythmic  contractions  and  inhibition  of  the  tone  of 
the  muscle.  This  is  followed,  as  the  bolus  is  forced  past,  by  a  strong  contraction  in 
the  rear  of  the  bolus.  ■ 

inhibitory  influence  on  the  intestinal  movements,  which  can  be  increased  by 
all  manner  of  peripheral  stimuh.  On  this  account  it  is  often  impossible  to, 
obtain  any  movements  in  the  exposed  intestine  so  long  as  these  remain  in 
connection  with  the  central  nervous  system  through  the  splanchnic  nerves. 
The  relaxed  condition  of  the  gut  which  obtains  in  many  abdominal  affections 
is  probably  also  reflex  in  origin,  and  is  due  to  reflex  inhibition  through  the 
splanchnic  nerves. 

As  a  result  of  the  two  sets  of  movements  described  above,  the  food  is 
thoroughly  mixed  with  the  digestive  juices,  and  the  greater  part  of  the 
products  of  digestion  are  brought  into  contact  with  the  intestinal  wall  and 
absorbed.  What  is  left — a  proportion  varying  in  different  animals  according 
to  the  nature  of  the  food — is  passed  on  by  occasional  peristaltic  contractions 
through  the  lower  end  of  the  ileum  into  the  colon,  or  large  intestine.  The 
lowest  two  centimetres  of  the  ileum  present  a  distinct  thickening  of  the  cir- 
cular muscular  coat,  forming  the  ileocoHc  sphincter.  This  sphincter  relaxes 
in  front  of  a  peristaltic  wave  and  so  allows  the  passage  of  food  into  the  colon. 
On  the  other  hand,  it  contracts  as  a  rule  against  any  regurgitation  which 
might  be  caused  by,  contractions  in  the  colon.     Although  thus  falhng  into 


MOVEMENTS  OF  THE  INTESTINES 


729 


line  with  the  rest  of  the  muscular  coat,  as  concerns  its  reaction  to  stimuli 
arising  in  the  gut  above  or  below,  it  presents  a  marked  contrast  to  the  rest  of 
the  gut  in  its  relation  to  the  central  nervous  system.  It  is  unaffected  by 
stimulation  of  the  vagus.     Stimulation  of  the  splanchnic,  however,  which 


Fig.  346.     Effect  of  stimulation  of  right  vagus  on  intestinal  contractions. 


■"Fig.  3-47.     Excitation  of  both  splanchnic  nerves.     Balloon  method, 
returned  to  abdomen. 


Intestine 


causes  complete  relaxation  of  the  lower  part  of  the  ileum  with  the  rest  of  the 
small  intestine,  produces  a  strong  contraction  of  the  muscle-fibres  forming  the 
ileocolic  sphincter  (ElUott). 


MOVEMENTS  OF  THE  LARGE  INTESTINE 
By  means  of  the  occasional  peristaltic  contractions,  accompanied  by 
relaxation  of  the  ileocolic  sphincter,  the  contents  of  the  small  intestine 
are  gradually  transferred  into  the  large.  In  man  these  contents  are  con- 
siderable in  bulk,  aie  semi-fluid,  and  probably  fill  the  ascending  as  well  as  the 
transverse  colon. 


730  PHYSIOLOGY 

The  large  intestine  is  supplied  with  nerves  from  the  central  nervous 
system.  These  run  partly  in  the  sympathetic  system  along  the  colonic 
and  inferior  mesenteric  nerves,  partly  in  the  pelvic  visceral  nerves  or  nervi 
erigentes,  which  come  off  from  the  sacral  cord  and  pass  direct  to  the  pelvic 
viscera.  In  addition  it  possesses  a  local  nervous  system,  presenting  the 
same  structure  as  that  found  in  the  small  intestine.  The  movements  of  the 
large  intestine  differ  considerably  in  various  animals,  as  has  been  shown  by 
EUiott,  according  to  the  nature  of  the  food  and  the  part  played  by  this  portion 
of  the  gut  in  the  processes  of  absorption.  In  the  dog  the  process  of  absorp- 
tion is  almost  complete  at  the  ileocohc  valve,  whereas  in  the  herbivora  a  very 
large  part  of  the  processes  of  digestion  and  absorption  occurs  in  the  colon  and 
caecum.  Man  takes  an  intermediate  position  as  regards  his  large  intestine 
between  these  two  groups  of  animals.  ElUott  and  Barclay  Smith  divide 
the  large  intestine  into  four  parts,  according  to  their  functions,  viz.  the 
caecum,  and  the  proximal,  intermediate,  and  distal  portions  of  the  colon. 
Of  these  the  dog  possesses  practically  only  the  distal  colon.  We  may  take 
Elhott's  account  of  the  movements  as  they  probably  occur  in  man.  They 
agree  very  closely  with  those  observed  by  Cannon  under  normal  circum- 
stances in  the  cat  by  means  of  the  Rontgen  rays.  The  food  as  it  passes  from 
the  ileum  first  fiUs  up  the  proximal  colon.  The  effect  of  this  distension  is  to 
cause  a  contraction  of  the  muscular  wall  at  the  junction  between  the  as- 
cending and  transverse  colon.  This  contraction  travels  slowly  over  the  tube 
in  a  backward  direction  towards  the  caecum,  and  is  quickly  succeeded  by 
another,  so  that  the  colon  may  present  at  the  same  time  several  of  these 
advancing  waves.  These  waves  are  spoken  of  as  anti-peristaltic ;  but  as 
they  do  not  involve  also  an  advancing  wave  of  inhibition,  they  must  not 
be  regarded  as  representing  the  exact  antithesis  of  a  peristaltic  wave,  as  we 
have  defined  it.  The  effect  of  these  waves  is  to  force  the  food  up  into  the 
caecum,  regurgitation  into  the  ileum  being  prevented  partly  by  the  obHquity 
of  the  opening,  partly  by  the  tonic  contraction  of  the  ileocolic  sphincter. 
As  the  whole  of  the  contents  cannot  escape  into  the  caecum,  a  certain  portion 
will  sHp  back  in  the  axis  of  the  tube,  so  that  these  movements  have  the  same 
effect  as  the  similar  contractions  in  the  pyloric  end  of  the  stomach,  causing  a 
thorough  churning  up  of  the  contents  and  its  close  contact  with  the  intestinal 
wall.  The  movements  are  rendered  still  more  effective  by  the  sacculation  of 
the  walls  of  this  part  of  the  large  intestine.  The  distension  of  the  caecum 
caused  by  this  anti- peristalsis  excites  occasionally  a  true  co-ordinated 
peristaltic  wave,  which,  starting  in  the  caecum,  drives  the  food  down  the 
intestine  into  the  transverse  part.  These  waves  die  away  before  they  reach 
the  end  of  the  colon,  and  the  food  is  driven  back  again  by  waves  of  anti- 
peristalsis.  Occasionally  more  food  escapes  through  the  ileocolic  sphincter 
from  the  ileum,  so  that  the  whole  ascending  and  transverse  colon  may  be  filled 
with  the  mass  undergoing  a  constant  kneading  and  mixing  process.  The 
result  of  this  process  is  the  absorption  of  the  greater  part  of  the  water  of  the 
intestinal  contents,  as  well  as  of  any  nutrient  material,  and  the  drier  part  of 
the  intestinal  mass  collects  towards  the  splenic  flexure,  where  it  may  be 


MOVEMENTS  OF  THE  INTESTINES  731 

separated  by  transverse  waves  of  constriction  from  the  more  fluid  parts 
which  are  being  driven  to  and  fro  in  the  proximal  and  intermediate  portions. 
By  means  of  occasional  peristaltic  waves  these  hard  masses  are  driven  into 
the  distal  part  of  the  colon.  The  distal  colon  must  be  regarded  as  a  place 
for  the  storage  of  the  faeces  and  as  the  organ  of  defsecation.  In  the  transverse 
colon,,  in  the  descending  and  iliac-colon,  the  anti- peristaltic  movements  and 
consequent  churning  of  the  contents  are  probably  slight.  These  therefore 
represent  the  intermediate  colon,  with  propulsive  peristalsis  as  its  chief 
activity.     The  descending  colon  is  never  distended,  and  Elliott  therefore 


Fig.  348.  Skiagram  to  show  normal  position  of  colon  in  man,  and  the  position  attained 
by  its  contents  at  different  periods  after  a  meal  containing  bismuth.  The  bismuth 
meal  was  taken  at  8  a.m.  The  times  of  arrival  at  different  levels  are  marked  on  the 
colon.     (Hertz.) 

regarded  it  as  a  transferring  segment  of  exaggerated  irritabihty.  The 
storage  of  the  waste  matter  takes  place  chiefly  in  the  sigmoid  flexure. 
This  with  the  rectum  represents  the  distal  portion  of  the  colon.  The  dis- 
tinguishing feature  of  the  distal  colon  is  its  complete  subordination  to  the 
spinal  centres.  It  probably  remains  inactive  until  an  increasing  distension 
excites  reflexly  through  the  pelvic  visceral  nerves  a  complete  evacuation  of 
this  portion  of  the  gut.  Stimulation  of  these  nerves  in  an  animal,  such  as  the 
cat,  produces  a  rapid  shortening  of  the  distal  part  of  the  colon,  due  to 
contraction  of  the  recto-coccygeus  and  longitudinal  fibres  of  the  gut,  followed 
after  some  seconds  by  a  contraction  of  the  circular  coat.  This  originates 
at  the  lower  limit  of  the  area  of  anti-peristalsis,  i.e.  probably  at  the  upper  end 
of  the  sigmoid  flexure,  and,  spreading  rapidly  downwards,  empties  the  whole 
of  this  segment  of  the  gut.  In  man  the  emptying  of  the  rectum  itself  is 
largely  assisted  by  the  contractions  of  the  voluntary  nniscles  of  the 
abdominal  walls  and  pelvic  floor. 

The  last  section  of  the  rectum  is  emptied  at  the  close  of  the  act  by  a 


732  PHYSIOLOGY 

forcible  contraction  of  the  levator  ani  and  the  other  perinseal  muscles,  and 
this  contraction  also  serves  to  restore  the  everted  mucous  membrane. 

The  carrying  out  of  this  reflex  act  is  dependent  on  the  integrity  of  a  certain 
part  of  the  lumbar  spinal  cord.  If  this  '  centre  '  be  destroyed,  the  tonic  con- 
traction of  the  sphincter  muscles  disappears.  This  centre  may  be  either 
excited  to  increased  action,  or  be  inhibited  by  peripheral  stimulation  of 
various  nerves,  or  by  emotion,  such  as  fear.  Apphcation  of  warmth  to  the 
region  of  the  anus  causes  reflex  relaxation  of  the  sphincter  ;  application  of 
cold  increases  its  tonic  contraction. 

In  man,  as  Hertz  has  shown  by  the  skiagraphic  method,  the  pelvic 
colon  becomes  filled  with  faeces  from  below  upwards,  the  rectum  remaining 
empty  till  just  before  defsecation.  In  individuals  whose  bowels  are  opened 
regularly  every  morning  after  breakfast  the  entry  of  fseces  into  the  rectum 
gives  rise  to  a  sensation  of  fulness  and  acts  as  the  call  to  defsecation.  If 
no  response  be  made,  the  desire  to  defsecate  passes  away,  since  the  rectum 
relaxes  and  the  fsecal  mass  no  longer  exercises  pressure  on  its  wall.  Hertz 
has  shown  that  the  minimal  pressure  required  to  produce  the  call  to  defsecate 
varies  from  30  to  40  mm.  Hg,  according  to  the  length  of  the  gut  which  is  the 
seat  of  distension. 


'■'-i 


SECTION  X 
THE  ABSORPTION  OF  THE  FOOD-STUFFS 

THE  ABSORPTION  OF  WATER  AND  SALTS 

The  intake  of  water,  and  probably  of  salts,  by  the  alimentary  canal,  in 
accordance  with  the  requirements  of  the  organism  as  a  whole,  seems  to 
be  regulated  almost  entirely  by  the  central  nervous  system,  the  higher  parts 
of  this  system,  viz.  those  concerned  with  appetite,  being  particularly  in- 
volved in  the  process.  Thus  in  man  any  large  loss  of  fluid  to  the  body,  as  by 
sweating,  diarrhoea,  haemorrhage,  gives  rise  to  an  intense  thirst  that  has  its 
natural  reaction  in  increased  intake  of  water  by  the  mouth.  On  the  other 
hand,  the  property  possessed  by  the  ahmentary  canal  of  absorbing  water  and 
weak  saline  fluids  contained  in  its  interior  is  very  little  influenced  by  the 
state  of  depletion,  or  otherwise,  of  the  water  depots  of  the  body.  It  is 
practically  impossible,  however  large  the  quantities  of  fluid  ingested,  to 
evoke  the  production  of  fluid  motions,  the  greater  part  of  the  ingested 
fluid  being  absorbed  on  its  way  through  the  ahmentary  canal.  Thus  a 
man  may  keep  himself  in  perfect  health  and  maintain  the  water  content  of 
his  body  constant  whether  he  take  one  litre  or  six  litres  of  water  daily.  The 
whole  process  of  regulation,  apart  from  that  determined  by  appetite,  is 
carried  out  at  the  other  end  of  the  cycle,  viz.  by  the  kidneys.  As  concerns 
absorption  of  water  there  is  no  chemical  solidarity  between  the  ahmentary 
surface  and  the  rest  of  the  body.  Whenever  water  is  presented  to  the 
surface  it  is  absorbed  and  passes  into  the  circulation. 

The  absorption  of  water  in  the  stomach  may  be  regarded  as  nil. 
Although  from  this  viscus  alcohol,  and  possibly  peptone  and  sugar,  may 
be  absorbed  to  a  slight  extent,  water  or  saline  fluids  introduced  into  it 
are  passed  through  the  pylorus  either  without  change  or  increased  by  the 
secretion  of  fluid  from  the  gastric  glands.  In  no  case  is  there  a  diminution 
of  fluid  in  the  stomach. 

The  chief  absorption  of  water  occurs  in  the  small  intestine.  It  is  on 
this  account  that  the  salient  features  of  cases  of  dilatation  of  the  stomach 
with  stenosis,  absolute  or  relative,  of  the  pyloric  orifice  can  be  nearly  all 
referred  to  the  starvation  of  the  body  in  water,  and  can  be  often  relieved 
by  the  administration  of  water  either  subcutaneously  or  by  the  rectum,  i.e. 
by  the  channels  through  which  absorption  is  still  possible.  The  introduction 
of  water  into  the  stomach  simply  increases  the  dilatation,  but  does  not 
relieve  the  intense  thirst  of  the  patient.    Water  that  has  been  swallowed 

733 


734 


PHYSIOLOGY 


to  quench  tkirst  has  first  to  be  passed  from  the  stomach  into  the  small 
intestine  before  it  can  be  absorbed  and  reheve  the  needs  of  the  tissues.  The 
intestinal  contents  at  the  ileocsecal  valve  contain  relatively  nearly  as  much 
water  as  they  do  at  the  upper  part  of  the  jejunum.  Their  absolute  bulk  is, 
however,  much  smaller,  so  that  only  a  small  proportion  of  the  water  that  has 
been  taken  in  by  the  mouth  remains  to  be  absorbed  in  the  large  gut — an 
amount  probably  much  less  than  that  which  has  been  added  to  the  contents 
of  the  small  intestine  in  the  form  of  secretion  by  the  stomach,  liver,  pancreas, 
and  intestinal  tubules. 

The  main  problem  before  us  is  therefore  the  mechanism  of  absorption 
of  water  and  sahne  fluids  by  the  viUi  of  the  small  intestine.     By  means 


Epithelium  of 

villus 


Vein 


Artery 


Lieberkiihn's 

follicle 


Central  lacteal 


'^M^.'c^-. 


Mucosa 
Muscularis  mucosse 

Submucosa 

Lymphatic  plexus 

Circular  muscle 

Lymphatic  plexus 
Longitudinal  muscle 


Fig.  349.     Diagrammatic  section  through  wall  of  small  intestine  to  show  vascular  and 
lymphatic  arrangements  of  mucous  membrane.     (After  Mall.) 


of  these  structures  the  absorbing  surface  of  the  intestine  is  largely  increased. 
It  has  been  calculated  that  each  square  milhmetre  of  intestine  represents 
an  absorbing  surface  of  3  to  12  mm.^  Each  villus  (Fig.  349)  consists  of  a 
framework  of  reticular  tissue  containing  many  leucocytes  in  its  meshes, 
separated  from  the  lumen  of  the  gut  by  a  continuous  layer  of  columnar 
epithehal  cells.  These  cells  rest  on  an  incomplete  basement  membrane  and 
present  on  the  side  turned  towards  the  lumen  of  the  gut  a  striated  basilar 
border.  The  villus  offers  two  channels  by  means  of  which  material,  which 
has  passed  through  the  epithelium,  may  be  carried  into  the  general  circu- 
lation. In  the  centre  of  the  villus  is  the  central  lacteal,  a  club-shaped  vessel 
bounded  by  a  complete  layer  of  delicate  endothehal  cells.  This  leads  into 
a  plexus  of  lymphatics  placed  superficially  to  the  muscularis  mucosae.  From 
the  superficial  plexus  communicating  branches  pass  vertically  to  a  corre- 
sponding plexus  lying  in  the  submucosa.  The  central  lacteal  and  the  super- 
ficial plexus  are  free  from  valves,  which,  however,  are  present  in  abundance 
in  the  deeper  plexus,  so  that  fluid  can  pass  easily  from  the  lacteal  to  the 


THE  ABSORPTION  OF  THE  FOOD-STUFFS  735 

deeper  plexus,  but  not  in  the  reverse  direction.  From  the  muscularis 
mucoscB  unstriated  muscle  fibres  pass  up  through  the  villus  to  be  attached 
partly  to  the  outer  surface  of  the  central  lacteal,  partly  by  expanded 
extremities  to  the  basement  membrane  covering  the  surface  of  the  villus. 
Contraction  of  these  muscle  fibres  mil  tend  to  empty  the  central  lacteal 
into  the  deep  plexus  of  lymphatics  and  may  also  cause  an  expulsion  of 
the  contents  of  the  spaces  of  the  retiform  tissue  of  the  villus  into  the  central 
lacteal.  The  alimentary  canal  represents  one  of  the  few  localities  where  a 
formation  of  lymph  is  constantly  proceeding,  even  in  a  condition  of  complete 
rest.  On  placing  a  cannula  in  the  thoracic  duct  of  a  dog  an  outflow  of 
lymph  is  obtained  which  may  vary  in  different  animals  between  1  c.c.  and 
10  c.c.  in  the  ten  minutes.  The  greater  part  of  this  lymph  is  derived  from 
the  ahmentary  canal,  so  that  any  of  the  intestinal  contents  which  have 
made  their  way  into  the  spaces  of  the  villus  might  be  entrained  in  this 
lymph  current  and  carried  away  with  it  into  the  thoracic  duct  and  so  into  the 
general  blood  system. 

The  other  possible  channel  of  absorption  is  by  the  capillary  blood- 
vessels of  the  villus.  Each  villus  is  supphed  with  blood  from  one  or  two 
arterioles  which  break  up  into  a  rich  plexus  of  capillaries  lying  close  under 
the  basement  membrane  of  the  villus.  The  return  blood  is  collected  into 
one  or  two  veins,  which  join  the  radicles  of  the  portal  vein  in  the  submucosa 
and  in  the  mesentery.  In  these  capillaries  the  blood  is  circulating  rapidly, 
so  that  a  considerable  amount  of  material  may  pass  into  them  from  the 
spaces  of  the  villus  within,  say,  one  hour  without  altering  appreciably  the 
percentage  composition  of  the  blood.  On  the  other  hand,  it  must  be  remem- 
bered that  the  blood  in  these  vessels  is  at  a  high  pressure,  probably  not  less 
than  30  mm.  Hg.,  so  that  any  absorption  into  the  blood  stream  must  occur 
against  this  pressure.  It  is  probable  therefore  that  in  explaining  any 
absorption  by  the  blood-vessels  we  shall  have  to  place  out  of  court  any  possi- 
bihty  of  the  passage  occurring  in  consequence  of  hydrostatic  differences  of 
pressure,  i.e.  by  a  process  of  filtration. 

When  salt  solutions  are  introduced  into  the  small  intestine  they  are 
rapidly  absorbed  without  the  production  of  any  corresponding  increase  in 
the  rate  of  lymph  flow  from  the  thoracic  duct.  On  the  other  hand,  the 
absorption  of  large  amounts  of  fluid  may  cause  an  actual  diminution  of 
the  solids  of  the  plasma,  so  that  we  are  justified  in  regarding  the  capillary 
network  of  blood-vessels  at  the  surface  of  the  villi  as  solely  responsible  for 
the  absorption. 

What  are  the  forces  which  cause  this  transference  of  fluid  and  dissolved 
substances  from  one  side  to  the  other  of  the  membrane  composed  of  epithelial 
cells  ylus  capillary  endothelium  ?  Like  other  cells,  those  of  the  intestinal 
epithelium  are  probably  bounded  on  their  free  surface  by  a  '  lipoid  '  mem- 
brane, i.e.  one  containing  some  complex  of  lecithin  and  cholesterin  and  per- 
meable only  by  such  substances  as  are  soluble  in  lipoids.  On  the  other  hand, 
the  cement  substance  between  the  cells  may  be  of  a  dift'erent  character  and 
possibly  permeable  to  water-soluble  substances.     The  question  has  been 


736  PHYSIOLOGY 

propounded  whether  the  greater  part  of  the  substances  which  enter  the  blood 
plasma  from  the  gut  pass  between  the  cells  or  through  the  cells.  Water  could, 
of  course,  pass  in  either  way.  Most  of  the  inorganic  salts,  such  as  sodium 
chloride,  as  well  as  the  very  important  constituents  of  the  food,  the  sugars, 
are  insoluble  in  hpoids,  and  would  have  to  pass  between  the  cells.  When 
the  question  is  investigated  by  the  use  of  dye-stuffs,  soluble  or  insoluble  in 
Hpoids,  it  is  found  that  the  hpoid-soluble  dye-stuffs,  such  as  neutral  red  or 
toluidin  blue,  pass  into  the  cells,  whereas  the  dye-stuffs  which  are  insoluble 
in  such  substances  pass  into  the  intercellular  spaces.  Too  much  stress,  how- 
ever, must  not  be  laid  on  these  experiments.  All  these  dye-stuffs  are  ab- 
normal so  far  as  the  body  is  concerned.  We  cannot  imagine  that  at  any 
time  in  the  course  of  evolution  of  the  properties  of  the  intestinal  epithehum 
the  cells  were  ever  presented  with  or  had  to  discriminate  between  different 
dye-stuffs.  The  fact  that  absorption  of  these  dye-stuffs  is  determined  by  the 
physical  conditions  of  the  cell  membrane  is  no  proof  that  the  absorption  of 
the  normal  food  constituents  is  determined  in  the  same  way.  In  fact,  it  is 
quite  legitimate  to  assume  that  the  lipoid  membrane  or  hmiting  layer  round 
every  cell  has  as  its  main  office,  not  the  regulation  of  the  access  of  food- stuffs 
to  the  cell,  but  its  protection  from  any  of  the  food-stuffs  which  it  does  not 
require  for  its  metabohsm.  If  it  were  not  for  such  a  membrane  the  assimila- 
tion of  a  salt  would  be  determined  entirely  by  its  concentration  in  the  imme- 
diate surroundings  of  the  cell,  whereas  we  know  that  the  assimilation  of  any 
living  organism,  whether  uni-  or  multi- cellular,  is  regulated  in  the  first  place 
by  the  activity  of  the  organism  itself.  According  to  this  activity  and  the 
needs  thereby  induced  the  uptake  of  food  material  may  be  large  or  small 
whatever  its  concentration  in  the  surrounding  medium.  It  would  indeed 
be  strange  that  the  whole  absorbing  surface  of  the  intestine  should  be  covered 
by  a  membrane,  of  which  the  greater  part  was  useless  for  the  absorption  of  the 
common  food-stuffs,  as  would  be  the  case  if  these  could  only  penetrate  the 
membrane  by  the  narrow  chinks  between  the  cells.  It  seems  more  probable 
that  the  absorption  of  the  different  food-stuffs,  and  probably  also  of  the 
normal  salts  of  the  body,  is  effected  by  the  cells  themselves,  in  accordance 
with  their  nutritional  needs,  and  this  view  is  strengthened  when  we  come 
to  examine  into  the  absorption  even  of  normal  saline  solutions.  If  50  c.c. 
of  normal  sodium  chloride  solution  be  introduced  into  a  loop  of  intestine,  it 
is  absorbed  steadily,  so  that  at  the  end  of  an  hour  not  more  than  about 
20  c.c.  may  be  recoverable.  The  absolute  amounts  absorbed  differ  in 
various  experiments,  but  are  fairly  uniform  for  repeated  observations  on  one 
and  the  same  animal.  The  absorption  of  such  a  solution  could  be  ascribed  to 
the  osmotic  pressure  of  the  colloids  in  the  blood  plasma  or  lymph  within  the 
spaces  of  the  vilh.  If,  instead  of  using  isotonic  solutions,  hypertonic  solutions 
are  employed,  e.g.  a  2  or  3  per  cent.  NaCl  solution,  absorption  still  takes 
place,  but  may  be  preceded  by  an  interval  in  which  there  is  an  actual  in- 
crease of  the  fluid  contained  in  the  gut.  Here,  again,  we  might  ascribe  the 
absorption  to  the  physical  factors  present,  were  it  not  that  absorption  is 
found  to  commence  before  the  fluid  in  the  gut  has  attained  isotonicity  with 


THE  ABSORPTION  OF  THE  F00D-8TLTFS  737 

the  blood.  In  fact,  employing  a  1-5  per  cent,  salt  solution,  absorption  may- 
occur  from  the  very  beginning  of  the  experiment.  If  such  a  solution  is  passed 
through  the  epithelial  membrane  into  the  blood  plasma  with  a  smaller 
tonicity,  it  is  evident  that  work  must  be  done  in  the  process,  work  which  can 
only  be  furnished  by  the  cells  of  the  epithehum.  When  sugar  solutions  are 
employed  they  behave  in  somewhat  similar  fashion  to  sodium  chloride 
solutions,  provided  that  the  sugar  is  one  of  the  absorbable  hexoses,  both 
sugar  and  water  being  rapidly  absorbed.  It  is  important  to  note  that  dex- 
trose is  absorbed  from  the  gut  almost  as  rapidly  as  sodium  chloride,  and 
quite  as  rapidly  as  sodium  iodide,  although  its  diffusibihty  is  very  consider- 
ably less  than  either  of  these  salts.  Moreover  great  differences  are  found 
between  the  rate  at  which  different  sugars  are  absorbed,  differences  which 
are  not  referable  to  the  diffusibihty  of  the  sugars  in  question.  Thus  the 
monosaccharides  glucose,  fructose,  galactose  are  absorbed  with  double  the 
rapidity  of  solutions  of  cane  sugar  and  maltose,  and  it  seems  that  in  the 
absence  of  hydrolytic  splitting  of  the  disaccharides  absorption  from  the  gut 
would  be  entirely  aboUshed.  Thus  lactose  disappears  from  the  intestine 
much  more  slowly  than  either  of  the  other  two  disaccharides,  so  that  large 
doses  may  give  rise  to  a  laxative  effect.  In  animals  devoid  of  lactase, 
the  lactose-sphtting  ferment,  in  their  intestinal  epithehum  milk  sugar  is 
apparently  not  absorbed  at  all. 

The  most  cogent  argument  perhaps  in  favour  of  an  active  intervention 
of  the  cells  of  the  gut  in  the  process  of  absorption  is  furnished  by  the  study 
of  the  absorption  of  blood  serum.  It  has  been  sho^vn  that  if  an  animal's  own 
serum  be  introduced  into  a  loop  of  its  intestine  the  serum  undergoes  absorp- 
tion. This  absorption  affects  the  water  and  salts  more  than  the  protein,  so 
that  the  percentage  of  the  proteins  in  the  fluid  remaining  in  the  intestine 
is  increased.  Finally,  however,  the  whole  of  the  serum  is  absorbed.  In  this 
case  the  fluid  within  the  gut  is  identical  with  the  fluid  within  the  blood-vessels. 
There  are  no  differences  in  concentration,  quality  of  salts,  or  osmotic  pressure 
of  proteins.  Nevertheless  water  passes  through  the  cells  of  the  gut  from 
their  inner  to  their  outer  sides,  entraining  with  it  the  salts  of  the  serum  and 
a  certain  proportion  of  the  indift'usible  proteins.  It  is  impossible  to  explain 
this  result  as  due  to  the  digestion  of  the  proteins  and  their  conversion  into 
diffusible  products,  since  the  intestinal  loops  were  washed  free  of  any  trypsin 
that  they  contained,  and  serum  has  itself  a  strong  antitryptic  action  which 
would  prevent  its  being  attacked  by  even  a  strong  solution  of  trypsin. 

The  active  intervention  of  the  cells  in  the  absorption  of  salt  solutions, 
as  well  as  of  serum,  can  be  abohshed  by  any  means  which  diminishes  or 
destroys  their  vitahty,  such  as  the  addition  of  sodium  fluoride  to  the  fluid 
to  be  absorbed,  or  destruction  of  the  epithelium  by  previous  temporary 
occlusion  of  the  blood-vessels  supplying  the  loop  of  intestine. 

We  must  conclude  that,  when  a  fluid  is  introduced  into  the  intestine,  an 
active  transference  of  water  from  the  lumen  into  the  blood  stream  is  effected 
by  the  intermediation  of  forces  having  their  origin  in  the  metabolism  of  the 
cells  themselves.     This  work  of  absorption  of  the  cells  may  be  aided  or 

24 


738  PHYSIOLOGY 

hindered  according  to  the  physical  conditions  present.  If  these  act  against 
the  cells,  e.g.  if  the  fluid  be  hypertonic,  the  absorption  is  eflected  more  slowly, 
while  with  hypotonic  solutions  the  physical  conditions  concur  with  the  vital 
acti^dty  of  the  cells  in  bringing  about  a  very  rapid  transference  of  fluid  from 
the  gut  into  the  blood-vessels.  Among  these  physical  conditions  we  must 
reckon  the  nature  of  the  salts  present  in  the  solution.  If  these  can  pass 
easily  into  and  through  the  cells,  e.g.  anunonium  salts,  sodium  chloride, 
absorption  is  carried  out  rapidly.  If,  on  the  other  hand,  the  salts  in  the 
intestinal  contents  are  but  shghtly  diffusible  or  have  very  Httle  power  of 
penetrating  into  the  cells,  the  absorption  of  water  by  the  cells  causes  an 
increased  concentration  of  the  salts,  and  therefore  an  increased  osmotic 
pressure,  which  offers  a  resistance  to  any  further  absorption  ;  and  the  process 
comes  to  an  end,  when  the  absorptive  power  of  the  cells  is  exactly  balanced 
by  the  increased  osmotic  pressure,  or  attraction  for  water,  of  the  intestinal 
contents. 

Cushny  and  Wallace,  as  the  result  of  their  experiments  on  the  relative  absorbability 
of  salt  solutions  from  the  gut,  divide  the  salts  into  four  main  classes  as  follows  : 


I 

II 

Ill 

IV 

Sodium  chloride, 

Ethyl  sulphate, 

Sulphate,  phosphate, 

Oxalate, 

bromide,  iodide. 

nitrate,  lactate,  sali- 

ferrocyanide, capry- 

fluoride. 

formate  acetate, 

cylate,  phthalate. 

late,  malonate,  succi- 

propionate,  butyrate, 

'  nate,  malate,  citrate. 

valerianate,  caprate. 

tartrate. 

Of  these  the  first  class  contains  those  salts  which  are  absorbed  with  great  ease 
from  the  intestine.  The  second  group  of  salts  are  absorbed  with  somewhat  greater 
difficulty.  The  third  group  are  absorbed  so  slowly,  i.e.  the  salts  retain  the  water  in 
which  they  are  dissolved  so  long,  that  they  increase  peristalsis  and  act  as  laxatives  or 
purgatives.  The  members  of  the  fourth  class  are  not  absorbed  at  all.  It  is  evident 
that  this  classification  is  independent  of  the  diffusibility  of  the  salts.  Sodium  acetate 
has  a  much  smaller  dissociation  value  and  a  lower  diffusibility  than  sodixun  chloride 
or  iodide,  and  yet  is  absorbed  at  approximately  the  same  rate  as  these  two  salts.  There 
is,  however,  as  Cushny  pointed  out,  one  physical  or  chemical  character  which  apparently 
determines  the  non-absorbability  (relative  or  absolute)  of  the  members  of  the  tlfird 
and  fourth  classes.  All  these  salts  form  insoluble  compounds  with  calcium.  This 
common  character  is  not  an  explanation  of  the  permeability  of  the  cell  wall,  but  is 
simply  a  general  statement  of  one  of  the  conditions  which  affect  the  power  of  the  cells 
to  take  up  salts  from  their  solutions,  tliis  power  being  absent  in  the  case  of  salts  which 
furnish  an  insoluble  calcium  compound. 

THE  ABSORPTION  OF  FATS 

Fats  administered  to  an  animal  in  excess  of  its  diurnal  requirements 
are  stored  up  in  the  body  in  the  form  in  which  they  are  administered.  Each 
cell  of  the  body  probably  possesses  in  itself  the  mechanism  for  the  utihsation 
of  these  neutral  fats,  and  for  eflecting  in  them  the  various  changes  involved 
in  the  successive  stages  of  their  disintegration  and  oxidation  through  which 
they  are  finally  converted  to  CO2  and  water.  The  problem  therefore  of  fat 
absorption  is  ultimately  one  of  the  simplest  with  which  we  have  to  deal, 
and  involves  merely  the  transference  of  the  neutral  fat  of  the  food  to  the 
circulatiug  fluids  in  such  a  form  that  it  can  be  carried  by  them  to  the  place 


THE  ABSORPTION  OF  THE  FOOD-STUFFS  739 

where  it  is  required  for  the  metaboHsm  of  the  body  or  where  it  may  be  stored 
up  as  a  reserve  substance. 

The  processes  of  digestion  of  fat  result  in  the  production  of  glycerin  and 
fatty  acids,  if  the  reaction  be  neutral  or  slightly  acid.  H  the  reaction  of  the 
gut  be  alkahne  the  alkah  will  combine  with  the  fatty  acids  to  produce  soaps. 
Analyses  of  the  contents  of  the  gut  after  a  fatty  meal  show  that  the  greater 
proportion  of  the  fats  are  present  as  a  mixture  of  fatty  acids  and  soaps,  the 
amount  of  these  substances  as  compared  with  unchanged  fat  increasing  as  we 
descend  the  gut. 

In  studying  the  absorption  of  fats  the  investigator  is  able  to  take 
advantage  of  the  fact  that  the  micro-chemical  detection  of  this  substance  is 
usually  very  easy.  Globules  of  fats  or  fatty  acids  containing  any  proportion 
of  the  unsaturated  fatty  acids  have  the  property  of  reducing  osmic  acid, 
and  therefore  of  being  stained  black  by  this  reagent.  Practically  all  the  fats 
which  occur  in  the  food  or  in  the  cells  of  the  body  contain  oleic  acid 
or  the  glyceride  of  this  acid  in  association  with  palmitic  or  stearic  acid,  and 
therefore  give  the  typical  micro- chemical  fat  reactions.  In  many  cases  it  is 
useful  to  employ  the  specific  stains  for  fats,  such  as  Sudan  red  or  alkanna 
red.  It  is  important  to  remember  that  the  intensity  of  the  fat  reaction 
given  by  a  cell  is  only  an  expression  of  the  fat  or  fatty  acid  contained  in  a 
free  state  in  the  cell,  and  is  no  criterion  of  the  total  amount  of  fat  which 
may  be  present.  Thus  a  normal  heart  muscle  in  section  gives  only  a  diffuse 
light  brown  coloration  with  osmic  acid.  After  poisoning  by  phosphorus  or 
by  diphtheria  toxin,  every  muscle- cell  may  be  found  studded  with  minute 
black  granules  of  fat.  Chemical  analysis  shows,  however,  that  the  normal 
heart  muscle  contains  as  much  fat  as  the  degenerated  muscle.  Our  micro- 
chemical  methods  will  therefore  throw  no  hght  on  the  amount  of  fat  which 
is  actually  in  combination  with  the  cell  protoplasm. 

If  an  animal  be  examined  a  few  hours  after  the  administration  of  a 
meal  rich  in  fats,  the  lymphatics  of  the  intestine  are  seen  to  be  distended 
with  a  milky  fluid — chyle — and  the  same  fluid  is  found  filling  the  cisterna 
hjmphatica  magna  and  the  thoracic  duct.  The  lymph  from  the  thoracic 
duct  will  also  be  milky,  and  chemical  analysis  shows  that  the  opacity  is  due 
to  the  presence  of  minute  granules  of  neutral  fat.  The  fat  in  such  chyle 
may  amount  to  over  6  per  cent.,  so  that  in  a  moderate-sized  dog  12  grammes 
of  fat  may  be  carried  in  the  com"se  of  an  hour  from  the  intestine  to  the  blood 
by  tliis  means.  This  great  access  of  fat  to  the  blood  during  fat  absorption 
introduces  corresponding  changes  in  the  blood.  The  plasma  itself  becomes 
milky,  and  if  the  blood  be  allowed  to  clot,  the  sermn  expressed  from  the  clot 
is  also  milky.  On  standing,  a  layer  of  fat  globules  hke  cream  may  rise 
to  the  surface  of  the  serum.  Fat  is  found  in  a  free  state  in  this  finely  divided 
condition  in  the  blood  plasma  so  long  as  it  is  being  absorbed  in  the  intestine. 
During  btarvation  it  disappears  entirely,  the  serum  becoming  perfectly  clear. 
Thus  part,  at  any  rate,  of  the  fat  which  is  absorbed  from  the  gut  is  carried 
thence  by  the  lymphatic  channels  in  the  form  of  neutral  fat  to  the  blood 
stream,  by  which  it  is  distributed  to  the  various  tissues  of  the  body,  gradually 


740  PHYSIOLOGY 

leaving  the  blood  stream  in  a  manner  which  at  present  has  not  been  deter- 
mined. Not  all  the  fat  which  is  absorbed  takes  this  path  by  way  of  the 
lymphatics  and  the  thoracic  duct.  Ligature  of  the  thoracic  duct,  if  effective, 
certainly  impedes  the  absorption  of  fat,  but  does  not  abohsh  it.  If  the 
thoracic  duct  lymph  be  collected  during  the  absorption  of  a  given  quantity  of 
fat  from  the  intestine,  not  more  than  60  per  cent,  of  the  fat  which  has  disap- 
peared from  the  gut  can  be  recovered  from  the  lymph.  What  happens  to 
the  remainder  we  do  not  know.  Apparently  it  does  not  reach  the  blood 
in  a  finely  divided  condition.  If  the  thoracic  duct  be  ligatured  the  per- 
centage of  fat  in  the  blood  rapidly  falls  to  a  minimum  which  remains  con- 
stant, even  during  starvation.  If  now  fat  be  administered,  although  a 
considerable  proportion  of  it  may  be  absorbed,  the  percentage  of  fat  in  the 
A  B 


i 


•V 


Fig.  350.     Columnar  epithelium  from  small  intestine  of  frog  stained  with  osmic 

acid  to  show  fat-absorption. 

A,  five  hours  after  a  meal  of  olive  oil ;   B,  three  hours  later.     It  should  be  noticed 

that  the  fat  globules  first  formed  grow  in  size  in  the  course  of  digestion,  pointing 

to  a  gradual  deposition  of  fat  on  the  globules  from  solution  in  the  protoplasm. 

(SCHAJ'ER.) 

blood  is  not  raised.  If  therefore  the  fat  is  absorbed  directly  into  the  blood 
it  cannot  be  in  the  particulate  condition,  and  it  must  be  in  such  small 
quantities  at  a  time  that  it  is  at  once  removed  from  the  blood  by  the  tissues 
through  which  this  fluid  flows.  It  is  difficult  to  imagine  that  any  large 
proportion  of  this  lost  fraction  of  the  fat  is  absorbed  into  the  blood  stream 
in  the  form  of  soaps,  since,  as  Mmik  has  shown,  soaps  injected  into  the 
blood- stream  act  as  poisons  and  give  rise  to  a  great  fall  of  blood-pressure, 
incoagulability  of  the  blood,  and  a  condition  of  coma.  We  must  therefore 
leave  out  of  account  for  the  present  the  mechanism  of  absorption  of  this  lost 
fraction  and  endeavour  to  trace  the  course  of  the  absorption  of  that  part  of 
the  fat  which  makes  its  way  into  the  lymphatics. 

Microscopic  examination  of  a  section  of  the  villus  during  fat  absorption 
shows  that  the  absorption  occurs  for  the  most  part  through  the  epithelial 
cells.  These  are  found  closely  packed  with  fat  granules  (Fig.  350),  which, 
small  at  the  beginning  of  the  process  of  absorption,  rapidly  enlarge  till  they 
occupy  the  greater  part  of  the  cell  lying  between  the  nucleus  and  the  basilar 
striated  border.  Most  observers  are  agreed  that  no  fat  globules  are  to  be 
seen  within  the  border  itself. 


THE  ABSORPTION"  OF  THE  FOOD-STUFFS 


741 


According  to  Altmann  the  fat  granules  found  in  the  cells  during  absorption  are  them- 
selves produced  by  a  transformation  of  fuchsinophile  granules  -which  are  present  in  the 
cell  even  during  the  fasting  condition.  At  an  early  stage  the  small  fat  granules  can  be 
stained  so  as  to  show  a  distinct  fuchsinophile  envelope.  Altmann  intei'prets  this  ap- 
pearance as  showing  that  the  epithelial  cells  take  up  the  fat  in  a  dissolved  form,  probably 
in  a  hych'olysed  condition,  and  that  a  process  of  synthesis  then  occirrs  in  the  granules 
leading  to  the  formation  and  accumulation  of  fat.  When  the  process  of  absorption  is 
proceeding  actively  the  meshes  of  the  villus  contain  a  number  of  free  fat  granules,  and 
the  leucocytes  in  these  meshes  are  generally  found  also  full  of  these  granules.     According 


Fig.  351.  a.  Vertical  section  through  intestinal  epithelium  of  a  rat  during 
fat  absorption.  B.  Horizontal  section  through  deeper  parts  of  the  cells, 
showing  excretion  of  fine  fat  globules  into  the  interccUular  clefts.  (Retjtek.) 

to  Zawarykin  and  Schafer  an  important  function  in  the  transfer  of  the  granules  from 
epithelial  cells  to  central  lacteal  was  performed  by  the  leucocytes.  These  were  supposed  to 
take  up  the  fat  granules  extruded  bj'  the  epithelial  cells  at  the  base  of  the  villi,  to  wander 
into  the  central  lacteal  where  they  broke  down,  fmnishing  in  this  way  the  molecular 
basis  of  the  chyle  as  well  as  its  protein  constituents.  This  view  was  strongly  combated 
by  Heidenhain,  who  pointed  out  that  many  of  the  granules  staining  darkly  with  osmic 
acid  were  not  necessarily  fat,  and  that  the  number  of  leucocytes  within  the  villi  were 
hardly  sufficient  to  account  for  the  amount  of  material  observed.  According  to  Renter 
the  epithelial  cells  take  up  fat  in  a  dissolved  condition  through  the  striated  border, 
and  deposit  it  as  granules  of  neutral  fat  in  the  inner  portion  of  the  protoplasm.  From 
here  the  fat  is  passed  on  by  the  protoplasm  by  the  side  of  the  nucleus  and  extruded  in 
the  form  of  very  fine  granules  in  the  deeper  parts  of  the  inter-epithelial  clefts,  which 
thus  function  as  true  excretory  chamiels  for  the  epithelial  cells  (Fig.  351). 

It  is  probable  that  the  muscular  mechanism  of  absorption  described 
many  years  ago  by  Briicke  plays  an  important  part  in  the  absorption  of  fats, 
but  it  is  difficult  to  furnish  any  experimental  proof  of  the  manner  in  which 
this  mechanism  works.  Repeated  contractions  of  the  muscle  fibres  of  the 
villus  would  tend  to  empty  the  spaces  into  the  central  lacteal,  and  this  in  its 
turn  into  the  submucous  plexus  of  lymphatics,  so  that  the  hniiph  in  the 
spaces  is  constantly  renewed  and  passes  laden  with  absorbed  fat  particles  into 
the  valved  lymphatics  of  the  mesentery. 


742  PHYSIOLOGY 

It  was  long  considered  that  the  fats  were  taken  up  by  the  epithehal  cells 
from  the  intestine  as  fine  particles  of  neutral  fat,  the  chief  use  of  the  pan- 
creatic juice  being  to  aid  the  formation  of  an  emulsion  of  fat  in  the  intestines. 
There  seems  to  be  httle  doubt  that  this  was  an  error,  and  that  the  fats  are 
absorbed,  dissolved  in  the  bile,  either  as  soap  or  as  fatty  acid.  The  arguments 
for  this  view  can  be  shortly  summarised  as  follows  ; 

(1)  Although  the  bile  does  not  dissolve  neutral  fats,  it  has  a  strong  solvent 
action  on  fatty  acids,  on  soaps,  and  even  on  the  insoluble  calcium  soaps. 
This  solvent  power  is  greatest  in  the  case  of  oleic  acid,  of  which  bile  can  dis- 
solve 19  per  cent.  It  is  very  small  in  the  case  of  pure  stearic  acid,  but  the 
solubihty  of  the  latter  acid  is  largely  increased  if  it  be  associated  as  usual  with 
oleic  acid.  Moore  has  shown  that  this  solvent  action  is  chiefly  conditioned 
by  the  bile  salts,  aided  by  the  lecithin  and  cholesterin  also  present  in  the  bile, 
a  solution  of  lecithin  and  cholesterin  in  bile  salts  having  a  greater  solvent 
power  than  the  salts  alone. 

(2)  The  presence  of  bile  in  the  intestine  is  essential  for  the  normal 
absorption  of  fat.  If  the  bile  be  cut  off  by  occlusion  of  the  bile  ducts  or  by 
the  establishment  of  a  biliary  fistula,  the  utihsation  of  fat  sinks  from  about 
98  per  cent,  to  about  40  per  cent.,  the  unabsorbed  fat  appearing  in  the 
faeces.  This  large  undigested  residue  of  fat  hinders  also  the  absorption  of 
the  other  food-stufls  by  covering  them  with  an  insoluble  layer,  so  that 
nutrition  as  a  whole  may  suffer  considerably. 

(3)  Absorption  may  also  be  interfered  with  by  ligature  of  the  pancreatic 
duct.  This  result  is  probably  due  to  the  absence  of  the  fat-splitting  ferments 
of  the  pancreatic  juice  from  the  intestine.  If  the  faeces  be  analysed  it  is  found 
that  a  very  large  proportion  of  the  fat  has  been  spht  into  fatty  acids  in  the 
course  of  its  passage  through  the  ahmentary  canal.  This  lipolysis  has,  how- 
ever, been  carried  out  by  the  agency  of  micro-organisms,  i.e.  in  the  lower 
segments  of  the  gut  where  the  greater  part  of  the  bile  has  been  already  re- 
absorbed into  the  portal  circulation.  If  fat  be  given  to  animals  deprived 
of  their  pancreas,  in  a  finely  divided  form,  such  as  cream  or  milk,  a  certain 
proportion  of  it  is  absorbed.  Under  these  conditions  a  considerable  degree 
of  hpolysis  may  occur  in  the  stomach  itself,  so  that  the  fats  would  be  already 
hydrolysed  when  they  came  in  contact  with  the  bile  in  the  duodenum. 

(4)  It  was  shown  by  Schiff,  by  means  of  his  amphibohc  fistula,  that  the 
bile  which  is  poured  into  the  gut  undergoes  a  circulation,  being  re-absorbed 
from  the  lower  parts  of  the  digestive  tube,  carried  to  the  hver  by  the  portal 
vein,  and  re-secreted  in  the  bile.  The  same  quantity  of  bile  salts  may 
therefore  be  used  over  and  over  again  as  a  vehicle  for  the  transfer  of  the  fatty 
acid  and  soaps  from  the  lumen  of  the  gut  into  the  epithelial  cells. 

(5)  Substances  which  are  physically  almost  identical  with  fats,  e.g. 
petroleum  or  paraffin,  are  not  absorbed  even  when  introduced  into  the  intes- 
tine in  the  finest  possible  emulsion.  If  neutral  fat  be  melted  with  a  soft 
paraffin  and  the  resulting  mixture  made  into  a  fine  emulsion  and  administered 
it  is  found  that  the  intestine  rejects  the  paraffin,  but  takes  up  the  neutral 
fat.     This  result  can  only  be  explained  by  assuming  that  the  fat  in  the 


THE  ABSOKPTION  OF  THE  FOOD-STUFFS  743 

particles  has  been  actually  dissolved  out  by  the  digestive  juices  and  has 
been  absorbed  in  a  state  of  solution. 

We  may  sum  up  the  processes  involved  in  digestion  and  absorption  of 
fat  as  follows.  Neutral  fat  is  hydrolysed  into  fatty  acid  and  glycerin  under 
the  action  of  the  gastric  juice,  the  pancreatic  juice,  and  the  succus  entericus, 
the  efiect  of  the  gastric  juice  being,  however,  extremely  Umited  unless  the 
fat  be  presented  to  it  in  a  finely  divided  condition.  The  Hpolytic  action  of 
the  pancreatic  juice  and  succus  entericus  is  largely  aided  and  increased  by 
the  simultaneous  presence  of  bile,  which,  in  virtue  of  the  bile  salts  lecithin 
and  cholesterin  it  contains,  enables  the  pancreatic  juice  to  enter  into  close 
relation  with  the  fat,  and  dissolves  the  products  of  the  activity  of  the  ferment, 
and  so  enables  it  to  attack  renewed  portions  of  the  neutral  fat.  As  the  result 
of  this  hpolysis  there  are  formed  glycerin,  which  is  soluble  in  water,  and 
fatty  acids  or  soaps,  according  as  the  reaction  of  the  medium  is  acid  or 
alkahne.  The  alkaline  soaps  are  soluble  in  water,  the  soaps  of  magnesium 
and  calcium  are  soluble  in  bile,  free  fatty  acids  are  soluble  in  bile  acids.  The 
fat  is  thu5  reduced  to"  a  condition  in  which  it  is  soluble  in  the  intestinal 
contents  whatever  their  reaction.  In  this  state  of  solution  its  constituents 
are  taken  up  by  the  cells  of  the  intestinal  mucosa.  Within  the  cells  a 
process  of  sjTithesis  takes  place,  the  soaps  being  spht  and  the  fatty  acids  thus 
set  free  or  absorbed,  being  combined  with  glycerin  with  the  elimination  of 
water  to  form  neutral  fat,  which  appears  as  fine  granules  in  the  cell  proto- 
plasm. By  an  active  process  of  excretion  these  granules  are  extruded  in  a 
somewhat  more  finely  divided  form  into  the  intercellular  clefts  and  into  the 
spaces  of  the  villus,  whence  by  the  contractions  of  the  musculature  of  the 
villus  they  are  forced  with  the  lymph  transuding  from  the  capillary  blood- 
vessels into  the  central  lacteal,  and  thence  along  the  mesenteric  lymphatics 
to  the  thoracic  duct.  This  description  would  apply  to  about  60  per  cent,  of 
the  fat  which  is  absorbed.  It  is  probable  that  all  the  fat  which  is  absorbed 
is  taken  up  in  a  dissolved  condition,  but  whether  the  remaining  40  per  cent, 
enters  the  blood  stream,  or  is  utihsed  and  broken  down  in  the  tissues  of  the 
intestinal  wall  itself,  we  have  no  means  of  judging.  Under  normal  circum- 
stances the  utilisation  of  fat  is  almost  complete.  By  the  time  the  intestinal 
contents  have  arrived  at  the  lower  end  of  the  ilemn  95  per  cent,  of  the  fat 
has  been  absorbed.  Removal  of  the  whole  large  intestine  was  found  by 
Vaughan  Harley  not  to  afiect  fat  absorption. 

THE  ABSORPTION  OF  CARBOHYDRATES 

As  a  result  of  the  action  of  the  various  digestive  juices  all  the  carbo- 
hydrate constituents  of  the  normal  diet  of  man  are  reduced  to  the  state  of 
monosaccharides.  The  absorption  of  these  digestive  products  may  take 
place  at  any  part  of  the  ahmentary  canal,  the  greatest  part  in  the  act  of 
absorption  being  taken  by  the  small  intestine.  By  the  time  that  the  food 
has  arrived  at  the  ileocsecal  valve  practically  the  whole  of  the  carbohydrate 
constituents  of  the  food  have  been  absorbed.  All  experimenters  are  agreed 
that  the  carbohydrates  pass  into  the  body  by  way  of  the  vessels  of  the  portal 


744  PHYSIOLOGY 

system.  The  lymph  from  the  thoracic  duct  contains  no  more  sugar  than 
does  the  arterial  blood  taken  at  the  same  time,  whereas  several  observers 
have  obtained  an  increased  percentage  of  sugar  in  the  portal  blood  during  the 
absorption  of  a  big  carbohydrate  meal. 

Of  the  carbohydrates  of  the  food,  some,  Hke  starch,  dextrin,  glycogen, 
are  colloidal  and  indiffusible  ;  others,  such  as  the  disaccharide3  cane  sugar, 
milk  sugar,  and  maltose,  are  soluble  and  diffusible,  and  the  products  of  the 
action  of  digestive  ferments  on  these  two  classes,  namely,  monosaccharides, 
mannose,  fructose,  glucose,  galactose,  are  also  soluble  and  diffusible.  The 
problem  as  to  the  mechanism  involved  in  the  passage  of  these  substances 
across  the  intestinal  waU  into  the  blood-vessels  has  been  already  dealt  with 
in  treating  of  the  absorption  of  water  and  salts.  The  most  striking  fact  is  the 
relative  impermeabihty  of  the  intestinal  wall  to  the  disaccharides  as  compared 
with  the  monosaccharides.  The  intestinal  wall  is  apparently  only  able  to 
take  up  in  any  quantity  such  sugars  as  can  be  utilised  by  the  cells  of  the 
organism.  For  this  purpose  the  disaccharides  are  useless ;  cane  sugar  or 
lactose  introduced  into  the  blood-vessels  or  subcutaneously  is  excreted  quan- 
titatively in  the  urine,  and,  as  might  be  expected,  does  not  increase  in  any 
way  the  glycogen  of  the  Hver.  When  maltose  is  injected  in  the  same 
manner  a  certain  proportion  of  it  is  utihsed  owing  to  the  fact  that  the  blood 
and  fluids  of  the  body  contain  a  ferment,  maltase,  capable  of  converting  the 
disaccharide  into  the  monosaccharide,  glucose.  The  absorption  of  these 
disaccharides  occurs  therefore  much  more  slowly  from  the  intestine  than  does 
the  absorption  of  monosaccharides,  the  process  of  absorption  being  always 
preceded  by  and  waiting  for  the  process  of  hydrolysis.  Thus  huge  doses 
of  cane  sugar  may  be  taken  without  causing  the  appearance  of  cane  sugar 
in  the  blood  or  urine.  It  has  been  found  that  sugar  does  not  appear  in  the 
urine  until  as  much  as  320  grm.  of  cane  sugar  have  been  ingested,  whereas 
any  quantity  of  glucose  over  100  grm.  may  give  rise  to  glycosuria.  Lactose 
is  absorbed  still  more  slowly,  and  in  animals  whose  intestine  is  free  from  the 
ferment  lactase,  is  not  absorbed  ;  large  doses  of  lactose  in  such  animals 
therefore  give  rise  to  diarrhoea.  The  behaviour  of  the  intestinal  wall  to 
the  non-assimilable  sugars  of  artificial  origin  has  not  yet  been  suflB.ciently 
investigated.  It  would  be  interesting  to  inquire  whether  the  rate  of 
absorption  of  the  different  sugars  was  in  any  way  determined  by  their 
stereomeric  configuration,  whether,  for  instance,  Z- glucose  would  be 
absorbed  as  rapidly  as  the  ordinary  d-g\\\cose. 

THE  ABSORPTION  OF  PROTEINS 
In  very  few  departments  of  physiology  has  there  been  so  great  a  revo- 
lution in  our  ideas  as  in  that  relating  to  protein  absorption,  especially  as  to 
the  form  in  which  it  is  absorbed  from  the  alimentary  canal,  and  its  fate  after 
absorption.  As  to  the  channel  by  which  it  obtains  entry  into  the  circulation, 
practical  agreement  reigns  that  it  is  absorbed  by  the  blood-vessels.  Almost 
every  physiologist  who  has  occupied  himself  with  the  investigation  of  the 
lymph  flow  from  the  thoracic  duct  has  been  impressed  by  the  fact  that  the 


THE  ABSOKPTION  OF  THE  FOOD-STUFFS  745 

variations  in  the  amount  of  lymph  to  be  obtained  in  this  way  bear  no 
relation  to  the  condition  of  the  animal  as  regards  the  state  of  digestion.  Nor 
do  we  find  any  appreciable  increase  in  the  amount  of  lymph  flow  or  in  the 
amount  of  proteins  contained  in  this  lymph  during  digestion.  The  small 
increase  observed  by  Asher  and  Barbara  would  be  sufficiently  accounted  for 
by  the  increased  blood-supply  to  the  intestines  during  digestion,  and  is 
insufficient  to  account  for  the  absorption  of  any  appreciable  quantity  of  the 
protein  which  is  being  taken  up  from  the  alimentary  canal.  Moreover  it  was 
shown  by  Schmidt  Miilheim  that  the  absorption  of  proteins  was  not  inter- 
fered with  as  the  result  of  Hgature  of  the  thoracic  duct,  and  that  after  this 
duct  had  been  ligatured  the  ingestion  of  proteins  was  followed  at  the  usual 
interval  by  the  increased  output  of  urea  which  is  the  invariable  concomitant 
of  protein  absorption  and  assimilation.  We  must  therefore  conclude  that 
the  products  of  protein  digestion  are  taken  up  by  the  epithehal  cells  and 
passed  on  by  these  into  the  blood-vessels. 

During  the  absorption  of  a  protein  meal  changes  have  been  described  by  various 
observers  in  the  structures  of  the  villus.  In  nearly  every  case  there  is  marked  increase 
in  the  number  of  mitotic  figures  in  the  epithelium  lining  the  follicles  of  Lieberkiihn. 
According  to  Hofmeister  there  is  during  absorption  an  increase  in  the  number  of 
leucocytes  in  the  villi,  and  this  observer  ascribed  an  important  function  to  these 
ecUs  in  the  absorption  of  protein.  Heidenhain  showed  that  this  increase  of 
leucocytes  was  not  constant  in  all  animals,  and  bore  no  relation  to  the  amount  of 
absorption  that  was  taking  place,  and  was  quite  inadequate  to  account  for  the  total 
absorption  that  was  carried  on.  On  the  other  hand,  several  observers  have  described 
changes  in  the  epithelium  as  the  result  of  protein  digestion.  According  to  Renter  the 
epithelial  cells  become  swollen,  their  protoplasm  stains  less  deeply,  and  at  their  basal 
ends  the  cells'  limits  disappear,  the  protoplasm  being  apparently  distended  -nith  hyaline 
coagulable  material  (Fig.  352).  Reuter  regards  this  appearance  as  a  direct  expression 
of  the  taking  up  of  proteins  in  a  dissolved  form  and  their  conversion  near  the  bases 
of  the  cells  into  coagulable  proteins  ;  but  further  evidence  on  this  subject  is  necessary 
before  we  can  attach  much  importance  to  such  an  interpretation  of  the  appearances 
observed. 

Under  the  influence  of  the  gastric  juice  the  proteins  of  the  food  are 
resolved  during  their  stay  in  the  stomach  into  albumoses  and  peptones.  In 
the  small  intestine  the  process  of  hydration  is  carried  further,  the  tr}^sin  of 
the  pancreatic  juice  carrying  the  proteins  through  the  stage  of  secondary 
albumoses  and  peptones,  and  converting  them  into  a  mixture  of  amino-acids 
and  polypeptides.  The  same  end-products  result  from  the  action  of  the 
erepsin  of  the  intestinal  wall  on  the  albumoses  and  peptones  produced  by 
gastric  digestion.  The  digestive  juices  finally  reduce  the  proteins  therefore 
to  a  mixture  of  amino-acids,  with  a  certain  remainder  of  polj'peptides  con- 
sisting of  two  or  three  of  the  amino-acids  associated  together,  wliich  do  not 
undergo  further  disiritegration  under  the  action  of  the  intestinal  ferments. 
The  final  products  give  no  biuret  test.  The  first  question  we  have  to  decide 
is  to  what  extent  the  proteins  are  reduced  to  their  ultimate  hydration  pro- 
ducts before  absorption.  We  have  evidence  that  protein  may  be  absorbed 
by  the  small  intestine  without  having  imdergone  any  hydration  whatsoever. 
The  absorption  of  serum  protein  has  been  discussed  already  in  dealing  with 
the  mechanism  of  absorption  of  salt  solutions  from  the  gut.     In  a  series  of 

24* 


746 


PHYSIOLOGY 


experiments  made  by  Friedlander  tke  absorptions  of  various  proteins  were 
compared  after  their  introduction  into  loops  of  the  small  intestine  which  had 
been  washed  free  from  ferment.  During  a  period  of  three  hours  this  author 
found  that  21  per  cent,  of  the  proteins  of  egg  white  or  of  blood  serum  were 
absorbed.  During  the  same  period,  of  alkah-albumen  which  had  been  intro- 
duced into  the  loops,  69  per  cent,  was  absorbed.     On  the  other  hand,  when 


■N^ 


n 


^  »i€ 


Fig.  352.     Figures  (from  Reuter)  showing  changes  in  intestinal  epithelium 

induced  by  absorption  of  protein. 

I,  epithelium  of  fasting  rat ;    II,  initial  stage  ;    III,  later  stage  of  protein 

absorption. 

syntonin  and  casein  were  introduced  into  the  intestine,  no  absorption  what- 
ever was  observed.  As  to  the  condition  in  which  such  unchanged  protein 
reaches  the  blood  stream  our  knowledge  is  still  imperfect.  Foreign  proteins, 
such  as  egg  albumin,  or  the  serum  of  other  species  introduced  into  the  blood 
stream,  may  cause  poisonous  effects,  and  give  rise  to  albuminuria,  to  lowering 
of  blood  pressure,  or  to  alteration  of  the  coagulability  of  the  blood.  If 
injected  in  small  quantities  they  excite,  as  a  reaction  on  the  part  of  the 
organism,  the  production  in  the  blood  serum  of  a  'precipitin,  and  the  presence 
of  the  precipitin  may  be  looked  upon  therefore  as  a  test  by  which  we  may 
decide  whether  these  proteins  have  passed  through  the  intestinal  wall 
unchanged.  In  most  cases  it  is  found  that,  however  abundant  the  amount 
of  protein  administered  in  the  soluble  form,  none  of  it  appears  in  the  urine, 


THE  ABSOEPTION  OF  THE  FOOD-STUFFS  747 

nor  is  any  precipitin  formation  aroused.  Ascoli  has,  however,  observed  such 
events  occasionally  to  follow  the  administration  of  large  doses  of  egg  white, 
and  it  has  been  showTi  that  there  is  a  difference  in  the  behaviour  of  animals  to 
the  introduction  of  soluble  protein  into  their  ahmentary  canal,  according  as 
they  are  new  born  or  are  more  than  a  few  days  old.  It  seems  that  during  the 
first  few  days  of  life  the  cellular  lining  of  the  alimentary  canal  is  permeable 
to  foreign  proteins,  whereas  later  on  any  protein  which  is  taken  up  unchanged 
from  the  gut  does  not  arrive  in  the  same  unchanged  condition  in  the  blood 
stream. 

The  absorption,  however,  of  unchanged  proteins  can  play  but  a  small 
part  in  the  assimilation  of  protein  as  a  whole.  Animals  very  rarely  take 
coagulable  proteins  in  a  condition  in  which  they  will  arrive  at  the  small 
intestine  in  a  state  of  solution  unchanged.  Even  in  the  carnivora  the  Hving 
tissues  taken  into  the  stomach  will  undergo  coagulation  by  the  acid,  and  wiU 
then  be  dissolved  by  the  gastric  juice.  In  man  practically  all  the  proteins  of 
the  food  Are  either  insoluble  or  are  rendered  insoluble  by  the  process  of 
cooking.  For  absorption  to  take  place  it  is  therefore  necessary  that  this 
insoluble  or  coagulated  protein  should  be  brought  into  solution,  and  this 
process  is  accomphshed,  together  with  hydration,  by  means  of  the  ferments 
of  the  gastric  and  pancreatic  juices.  This  process  of  solution  has  long  been 
regarded  as  the  chief  object  of  the  digestive  ferments.  Although  both  Kiihne 
and  Schmidt  MiiHieim  were  aware  of  the  production  of  amino-acids,  such 
as  leucine  and  tyrosine,  as  the  result  of  digestion,  they  regarded  their  pro- 
duction as  evidence  of  a  waste  of  material.  Proteoses  and  peptones  are 
soluble,  diffusible,  and  rapidly  absorbed  from  the  alimentary  canal,  and  there 
is  no  doubt  that  a  large  proportion  of  the  products  of  protein  digestion  are 
taken  up  by  the  absorbing  membrane  in  this  form.  For  many  years  phy- 
siologists were  occupied  with  the  problem  as  to  the  fate  of  these  peptones 
and  proteoses  after  their  entrance  into  the  mucous  membrane.  '  They  do  not 
pass  as  such  into  the  blood.  The  injection  of  small  quantities  of  proteose 
and  peptone  into  the  blood  gives  rise  to  the  excretion  of  these  substances  by 
the  kidneys  ;  injection  of  larger  quantities  has  pronoimced  poisonous  effects, 
which  were  first  studied  by  Schmidt  Miilheim  and  Fano.  If  samples  of 
blood  be  taken  either  from  the  portal  vein  or  from  the  general  circulation 
after  a  heav)''  protein  meal,  no  trace  either  of  proteose  or  of  peptone  is  to 
be  found  in  the  blood.  The  observations  of  Hofmeister  and  others  to  the 
contrary  depend  on  the  fact  that  these  observers  employed  a  method  for  the 
separation  of  coagulable  protein,  as  an  antecedent  to  the  testing  for  pro- 
teoses, which  was  in  itself  capable  of  producing  small  traces  of  these  sub- 
stances. Hofmeister  showed  that  during  the  absorption  of  a  protein  meal 
the  mucous  membrane  either  of  the  stomach  or  of  the  intestine,  if  rapidly 
killed  by  plunging  into  boiling  water  directly  it  was  taken  from  the  animal, 
always  contained  a  considerable  amount  of  peptone,  and  similar  observations 
were  made  by  Neumeister.  If,  however,  the  mucous  membrane  was  kept 
warm  for  half  an  hour  after  removal  from  the  body,  the  peptone  disappeared. 
Salvioh,  imder  Ludwig's  guidance,  introduced  peptone  into  a  loop  of  gut 


748  PHYSIOLOGY 

wliich  was  kept  alive  by  passing  defibrinated  blood  through  its  vessels. 
At  the  end  of  some  hours  the  loop  was  found  to  contain  a  certain  amount 
of  coagulable  protein,  but  no  trace  of  peptone,  nor  was  any  trace  of  the 
latter  substance  found  in  the  blood  which  had  been  passed  through  the 
vessels.  These  observations  were  interpreted  as  pointing  to  a  regeneration 
in  the  intestinal  wall  of  coagulable  protein  from  the  proteose  and  peptone 
taken  up  from  the  gut,  and  opinions  were  divided  whether  the  most  important 
part  of  this  regeneration  was  to  be  ascribed  to  the  leucocytes  of  the  vilU 
(Hofmeister),  or  to  the  epithelial  cells  of  the  mucous  membrane  itself. 

It  is  evident  that  such  a  conclusion  was  not  justified  by  the  experiments. 
AU  that  these  experiments  showed  was  that  the  proteoses  and  peptones 
disappeared,  i.e.  were  converted  into  something  which  did  not  give  the 
biuret  test.  The  discovery  of  the  ferment  erepsin  by  Cohnheim  led  this 
observer  to  repeat  the  experiments  of  Hofmeister  and  Neumeister  with  a  view 
to  testing  the  conclusions  drawn  by  these  physiologists.  Cohnheim  found 
that,  although  it  was  perfectly  true  that  proteose  and  peptone  disappeared 
when  intestinal  mucous  membrane  and  peptone  were  placed  together  in  the 
presence  of  either  blood  or  of  Ringer's  fluid,  this  disappearance  was  due,  not 
to  a  regeneration  of  coagulable  protein,  but  to  the  fact  that  the  erepsin  of 
the  mucous  membrane  carried  the  process  of  hydrolysis  a  step  further,  con- 
verting the  proteoses  and  peptones  into  the  ultimate  crystalHne  products  of 
protein  hydrolysis.  Similar  observations  were  made  by  Kutscher  and  See- 
mann,  who  showed  that  at  anytime  after  a  protein  meal  these  end-products, 
especially  leucine,  tyrosine,  lysine,  and  arginine,  were  to  be  found  in  the 
contents  of  the  small  intestine.  A  repetition  of  SalvioU's  experiment  by 
Cathcart  and  Leathes  deprived  this  also  of  much  of  its  significance.  It  was 
found  that  the  artificial  circulation,  although  sufficient  to  maintain  the 
activity  of  the  muscular  wall  of  the  intestine,  as  evidenced  by  the  peristaltic 
movements,  was  insufficient  to  keep  the  mucous  membrane  ahve.  After  one 
hour's  experiment  the  loop  contained  a  mass  of  epithelial  cells  mixed  with  the 
products  of  the  action  of  erepsin  on  the  introduced  peptone  solution.  In 
no  case  was  there  any  diminution  in  the  amount  of  uncoagulable  nitrogen, 
i.e.  there  was  no  formation  of  coagulable  protein,  while  the  processes  of 
absorption  had  been  brought  by  the  desquamation  entirely  to  a  standstill. 

These  additional  experiments  caused  a  complete  revolution  in  the  attitude 
of  physiologists  towards  the  problem  of  protein  absorption.  All  this  evidence 
went  to  show  that  protein,  however  introduced,  whether  as  coagulated  protein 
or  as  albumose  and  peptone,  underwent  complete  hydrolysis  either  in  the 
gut  or  in  the  wall  of  the  gut  before  entering  the  blood  stream.  If  this  were 
the  case  it  should  be  possible  to  feed  an  animal  on  a  diet  in  which  the  neces- 
sary protein  had  been  replaced  by  the  corresponding  amount  of  ultimate 
products  of  protein  hydrolysis,  i.e.  by  a  mixture  which  would  give  no  biuret 
reaction.  Such  a  possibility  had  previously  been  negatived  on  theoretical 
grounds  by  Kiihne  and  by  Bunge.  It  was  thought  by  these  observers 
either  that  the  animal  body  lacked  the  power  of  synthesis  of  proteins  from 
these   crystalHne   products   (hydration  products),   or  that   any   complete 


THE  ABSORPTION  OF  THE  FOOD-STUFFS  749 

hydration  occurring  in  the  intestine  would  involve  such  a  loss  of  energy  to  the 
body  as  to  be  unteleological.  Neither  of  these  theoretical  objections  is 
justified  in  fact.  We  know  from  the  researches  of  Fischer  and  others  that 
although  the  difi'erent  proteins  in  our  food  present  a  marvellous  quahtative 
simihtude,  in  that  all  of  them  yield  on  hydrolysis  the  same  kinds  of  amino- 
acids,  there  are  great  differences  in  the  relative  amounts  of  these  amino-acids 
contained  in  different  proteins.  Thus,  in  gelatin,  glycine  is  contained  in 
considerable  quantities,  but  is  absent  in  many  of  the  other  proteins. 
Caseinogen  is  distinguished  by  the  large  amount  of  leucine  that  it  yields, 
while  ghadin,  the  chief  protein  of  wheat  flour,  contains  very  large  amounts 
of  glutamic  acid.  It  is  difiicult  to  imagine  how,  for  instance,  muscle  protein 
could  be  formed  from  wheat  protein,  a  process  continually  occurring  in  the 
growing  animal,  unless  we  assumed  that  the  protein  molecule  is  first  entirely 
taken  to  pieces,  and  that  its  constituent  molecules  are  then  selected  by  the 
growing  cells  of  the  body  and  built  up  in  the  order  and  proportions  which  are 
characteristic  of  muscle  protein.  Moreover,  when  we  measure  the  amount 
of  energy  change  involved  in  the  hydrolysis  of  the  proteins,  we  find  it  is  rela- 
tively small.  There  is  not  a  loss  of  5  per  cent,  of  the  total  energy  available 
i.e.  the  heat  of  combustion  of  the  products  of  pancreatic  digestion  would  differ 
from  that  of  the  original  protein  submitted  to  digestion  by  less  than  5  per 
cent.  The  energy  of  the  protein  as  evolved  in  the  body  Hes,  not  in  the 
couphng  of  the  amino-acids  with  one  another,  or  indeed  in  the  coupUng  of 
the  nitrogen  to  the  carbon,  but,  hke  that  of  the  other  food-stuff s,  in  the  carbon 
itself,  and  is  derived  from  the  combustion  of  the  carbon  of  the  molecule  under 
the  influence  of  the  oxidising  processes  of  the  body  into  carbon  dioxide. 
The  experimental  decision  of  this  question  was  first  attempted  by  0.  Loewi, 
who  found  that  it  was  possible  to  keep  a  dog  in  a  state  of  nitrogenous  equiU- 
brium  on  a  diet  containing  fat,  starch,  and  a  pancreatic  digest  of  protein 
which  contained  no  substances  which  would  give  the  biuret  test.  These 
results  have  been  confirmed  for  carnivora  by  Henderson,  by  Liithje,  by 
Abderhalden  and  Rona,  and  by  Hemiques  and  Hansen.  According  to 
Abderhalden,  it  is  possible  to  keep  an  animal  alive  when  the  nitrogen  in  his 
food  is  represented  entirely  by  the  end-products  of  pancreatic  digestion. 
The  same  result  cannot  be  attained  by  the  administration  of  the  products 
of  acid  hydrolysis  of  protein,  but  this  may  be  due  either  to  the  racemisation  of 
the  amino-acids  under  the  action  of  the  strong  acid,  or  to  the  fact  that  the  acid 
spHts  up  certain  pol}^eptide  groupings  which  are  still  contained  in  the  tr}^sin 
digest,  and  which  possibly  cannot  be  synthetised  by  the  cells  of  the  body. 

We  are  justified  therefore  in  concluding  that  while  a  certain  small 
proportion  of  the  proteins  of  the  food  may  be  absorbed  imchanged,  a  much 
larger  proportion  is  taken  up  as  proteoses  and  peptones  or  as  amino-acids. 
The  proteoses  and  peptones  are,  however,  rapidly  changed  in  the 
mucous  membrane  itself  into  amino-acids,  which  we  may  regard  as  the  form 
in  which  practically  all  the  protein  of  the  body  is  presented  to  the  absorbing 
mechanisms  of  the  alimentary  canal  for  absorption  and  for  passing  on 
into  the  circulating  fluids. 


750  PHYSIOLOGY 

THE  FATE  OF   THE   AMINO- ACIDS   AFTER   ABSORPTION   BY   THE 

INTESTINAL  EPITHELIUM.  During  a  condition  of  starvation  the  normal 
protein  requirements  of  the  body,  or  rather  of  the  active  tissues,  are  met 
at  the  expense  of  the  less  active  tissues.  The  protein  characteristic  of  any  ■ 
tissue  can  be  taken  down,  removed  to  another  part  of  the  body,  and  built 
up  into  the  protein  characteristic  of  some  other  active  tissue.  It  is  diflS.cult 
to  conceive  that  such  a  transference  and  transformation  could  occur  in  any 
other  way  than  by  a  more  or  less  thorough  disintegration  of  the  protein 
molecule  at  one  place  and  its  synthesis  at  the  other,  and  we  know  from  the 
researches  of  Hedin  and  others  that  every  tissue  contains  intracellular 
ferments  which  are  capable  of  effecting  the  disintegration  of  the  protein 
molecule,  and  are  responsible  for  the  autolytic  degeneration  of  tissues  after 
death.  If  therefore  the  normal  interchange  of  protein  between  the  tissues 
is  accompHshed,  as  we  know  it  to  be  in  plants,  by  the  disintegration  of  the 
proteins  into  their  constituent  amino-acids  and  their  subsequent  reintegra- 
tion, there  is  no  a  priori  reason  to  beheve  that  the  blood  carries  the  proteins 
from  the  ahmentary  canal  to  the  tissues  in  any  other  form  than  that  of 
amino-acids.  The  experimental  proof  of  this  conclusion  was  hardly  possible 
before  the  invention  of  a  rehable  method  for  the  detection  of  small 
quantities  of  amino-acids  in  the  blood  and  tissues.  This  is  rendered  possible 
by  van  Slyke's  method,  in  which  after  the  separation  of  coagulable  proteins 
by  alcohol  the  amino-acids  are  determined  by  measuring  the  nitrogen  evolved 
on  addition  of  nitrous  acid.  Van  Slyke  has  shown  that  the  blood  always 
contains  a  certain  amount  of  amino-acids  even  during  fasting.  After  a  pro- 
tein meal  there  is  a  considerable  increase  in  the  amount  of  amino-acids. 
Thus  the  blood  of  fasting  animals  contains  from  3-1  to  5*4  milligrams  amino- 
acid  nitrogen  per  100  c.c.  Blood  taken  after  food  contains  8*6  to  10*2 
milligrams  amino-acid  nitrogen  per  100  c.c.  of  blood.  The  question  of  the 
fate  of  amino-acids  thus  absorbed  from  the  intestine  to  the  blood  is  decided 
by  an  estimation  of  the  amino-acid  content  of  the  different  tissues  after 
the  injection  of  amino-acids  into  the  blood.  Van  Slyke  has  found  that 
after  the  injection  of  amino-acids  only  a  certain  proportion  is  excreted 
with  the  urine,  and  that  the  rest  of  the  amino-acids  rapidly  disappeared 
from  the  blood  and  are  taken  up  by  the  tissues  without  undergoing  any 
immediate  chemical  change,  though  in  the  case  of  certain  tissues,  such 
as  the  muscles,  a  definite  saturation  point  exists  which  sets  the  limit  to  the 
amount  of  amino-acids  that  can  be  absorbed.  On  the  other  hand  the 
capacity  of  the  internal  organs,  and  especially  of  the  hver,  for  the  absorption 
of  amino-acid  is  much  greater. 

It  is  worthy  of  note,  however,  that  the  absorption  of  amino-acids  by  the 
tissues  from  the  blood  is  never  complete,  i.e.  the  amino-acids  of  the  blood 
must  be  in  a  state  of  equilibrium  with  those  of  the  tissues,  although  the  con- 
centration in  the  latter  may  be  much  greater  than  in  the  former.  If  several 
hours  be  allowed  to  elapse  after  the  injection  of  amino-acids  before  the 
analysis  of  the  tissue  is  undertaken,  it  is  found  that  the  amino-acid  nitrogen 
content  of  the  hver  may  have  returned  to  normal  although  the  concentration 


THE  ABSORPTION  OF  THE  FOOD-STUFFS  751 

in  the  muscles  has  suffered  no  appreciable  fall.  Since  we  have  evidence 
that  the  circulation  of  amino-acids  through  the  liver  gives  rise  in  this  organ 
to  the  formation  of  urea,  we  must  conclude  that  this  organ  is  especially 
■  responsible  for  the  breakdown  of  the  products  of  protein  digestion  which  are 
not  directly  required  for  replacing  tissue  waste.  This  breakdown  must 
involve  a  process  of  deamination.  We  may  therefore  conclude  that  the 
amino-acids  normally  produced  by  a  protein  digestion  are  absorbed  without 
further  change  into  the  blood  stream.  They  then  circulate  throughout  the 
body,  a  certain  proportion  of  them  being  built  up  in  each  tissue  into  the 
proteins  characteristic  of  that  tissue  in  order  to  replace  the  waste  caused  by 
wear  and  tear.  The  rest,  probably  the  major  part  of  the  protein,  is  taken  up 
by  the  liver,  where  it  undergoes  deamination,  the  nitrogen  moiety  being 
rapidly  converted  into  urea  and  excreted  by  the  kidneys,  while  the  non- 
nitrogenous  moiety  is  carried  to  the  working  tissues  to  which  it  serves  as  a 
ready  and  immediate  source  of  energy. 

The  fact  that  not  only  the  blood  but  also  the  tissues  contain  amino-acids, 
even  after  complete  starvation  for  some  days,  shows  that  these  substances 
are  intermediate  steps  not  only  in  the  synthesis  but  in  the  breaking  do^vn  of 
body  proteins.  Free  amino-acids  are  thus  the  protein  currency  of  the  body, 
just  as  glucose  is  the  carbohydrate  currency.  In  the  fasting  body  we  must 
regard  the  processes  of  autolysis  as  the  main  source  of  the  amino-acids  found 
in  the  tissues,  and  it  is  by  autolysis  that  the  proteins  of  the  resting  tissues  are 
made  available  in  starvation  for  those  whose  continued  working  is  essential 
for  the  maintenance  of  hfe.  The  fact  that  high  protein  feeding  does  not 
appreciably  increase  the  amino-acid  content  of  the  tissues,  shows  that  any 
storage  of  nitrogen  in  the  organism  must  take  place,  not  in  the  form  of 
amino-acids,  but  as  body  protein. 

It  was  formerly  thought  that  the  deamination  of  amino-acids  occvirred  on  a  large 
scale  in  the  wall  of  the  alimentary  canal,  on  the  gromids  that  a  larger  amount  of 
ammonia  was  present  in  the  portal  blood  than  in  the  arterial  blood.  It  seems,  probable, 
however,  that  the  sovu-ce  of  this  excess  of  ammonia  is  to  be  found  in  intestinal  bacterial 
changes,  and  that  the  major  portion  of  the  amino-acids  is  actually  absorbed  unchanged. 
The  view  of  Abderhalden  that  the  amino-acids  are  synthetised  in  the  intestinal  wall 
to  serum  proteins,  and  absorbed  in  that  form  into  the  blood-stream,  need  here  only 
be  mentioned,  since  it  lacks  experimental  support. 

THE  ACTUAL  COURSE  OF  DIGESTION 

In  a  recent  series  of  papers  London  describes  the  com'sc  of  digestion  of  meals  of 
Various  characters  in  dogs  wliich  had  been  provided  with  fistulas  in  one  of  the  following 
places  :  (a)  gastric  fistula  (into  the  fundus  of  the  stomach)  ;  (b)  pyloric  fistula  (on  the 
duodenal  side  of  the  pylorus) ;  (c)  duodenal  fistula  (about  one  foot  below  the  pylorus)  ; 
{d)  jejunal  fistula  (about  the  middle  of  the  small  intestine)  ;  (e)  ileum  fistula  (just 
above  the  caecum). 

We  may  take  as  an  example  the  course  of  digestion  of  a  meal  comixjsed  of  200  grm. 
of  bread.  This  is  eaten  by  the  animal,  mixed  with  the  saliva  and  swallowed.  On 
arriving  at  the  stomach  it  gives  rise  to  the  secretion  of  gastric  juice.  In  a  series 
of  special  experiments  London  found  that  on  the  average  200  grm.  of  bread  evoked 
the  secretion  of  20  grm.  of  saliva,  about  10  grm.  of  mucus  from  (he  coats  of  the  stomach, 
and  about  315  grm.  of  gastric  juice.     The  secretion  of  gastric  juice  is  continuous  dui'ing 


752 


PHYSIOLOGY 


the  whole  time  that  the  food  remaiBS  in  the  stomach.  In  the  animal  Tvith  a  pyloric 
fistula,  one  to  two  minutes  after  the  meal  had  been  taken,  a  few  drops  of  alkaline  fluid 
were  extruded  from  the  opening.  Erom  three  to  eight  minutes  after  the  conclusion 
of  the  meal  small  quantities  of  clear  acid  gastric  juice  were  repeatedly  extruded.  The 
first  admixture  of  the  food  with  the  outflow  from  the  fistula  occurred  at  eight  to  twelve 
minutes  after  the  completion  of  the  meal,  and  after  this  time  the  pylorus  continued 
to  open  at  regular  intervals  of  ten  to  forty  seconds,  discharging  each  time  a  small 
amount  of  fluid  composed  of  particles  of  undigested  bread  mixed  with  gastric  juice. 
One  and  a  half  houi"s  later  the  pylorus  began  to  open  less  regularly  and  the  fluid  became 
of  a  more  pasty  consistence,  devoid  of  lumps  of  undigested  bread.  In  the  fourth, 
fifth,  and  sixth  hom's  after  the  meal  the  pylorus  opened  only  once  every  one  or  two 
minutes,  and  towards  the  end  of  this  period  the  fluid  extruded  was  clear.  The  follow- 
ing Table  shows  the  percentage  amount  of  food  taken  which  had  left  the  stomach  at 
the  end  of  each  hoiu'  after  the  meal : 


First  hoiu* 

.     32-6    perc 

Second  hour    . 

.     17-9 

Third  hour 

.     29-5 

Foiu'th  hour   . 

1-87 

Fifth  hour 

6-66 

Sixth  hour 

.       4-21 

The  large  proportion  of  the  ingested  food  leaving  the  stomach  during  the  first  two 
or  three  houi's  can  hardly  be  regarded  as  normal.  Since  in  these  experiments  there  was 
a  free  outflow  from  the  pylorus  and  the  food  was  not  allowed  to  enter  the  duodenimi, 
the  local  reflex,  evoked  by  the  presence  of  acid  in  the  duodenum,  was  absent.  The 
gastric  contents  obtained  in  this  way  were  analysed  in  order  to  find  what  changes 
had  been  wi'ought  on  the  food  by  the  gastric  juice.  It  was  found  that  32  per  cent. 
of  the  bread  had  been  brought  into  solution.  This  solution  had  aftected  the  proteins 
more  than  the  carbohydrates.  Thus  67  per  cent,  of  the  nitrogen  had  been  brought 
into  soluble  form,  consisting  chieflj'  of  proteoses  and  peptones.  Ko  amino-acids 
were  formed.  Only  25  per  cent,  of  the  starch  of  the  bread  had  been  rendered  soluble, 
and  of  this,  21  per  cent,  was  in  the  form  of  dextrine  and  4  per  cent,  in  the  form  of 
sugar.  Xo  absorption,  however,  either  of  the  digested  proteins  or  of  the  digested 
carbohydrates  was  ever  foimd  to  take  place  in  the  stomach. 

DUODENAL  DIGESTION.  The  influence  exerted  by  the  pancreatic  juice,  bile, 
and  succus  entericus,  poui'ed  out  on  the  food  in  the  duodenum,  was  studied  by  analybis 
of  the  intestinal  contents  leaving  the  intestine  by  a  fistula,  either  at  the  lower  end  of 
the  duodenum,  or  in  the  jejimum,  or  in  the  ilemn.  From  the  duodenal  fistifla  Ihe 
expulsion  of  food  occurs  at  repeated  inteiwals,  but  in  a  somewhat  irregiflar  fashion, 
its  movements  being  determined  partly  by  the  contractions  of  the  stomach  and  partly 
by  those  of  the  duodenal  wall.  Usually  a  large  gush  is  followed  by  a  series  of  small 
gushes.  Although  only  a  foot  intervenes  between  the  duodenal  fistifla  and  the  pyloric 
fistula,  a  great  difference  is  observed  in  the  character  of  the  intestinal  contents  obtained 
in  the  two  cases.  The  outflow  fi-om  the  duodenmn,  being  mixed  with  the  pancreatic 
juice  and  the  bile  is  yellow  in  colom-  and  increased  in  amoimt.  With  a  meal  of  200  grm. 
there  is  secreted  on  the  average  130  grm.  of  bile  and  140  grm.  of  pancreatic  juice. 
During  its  passage  through  the  duodenum  the  carbohydrates  of  the  food  undergo  con- 
siderable changes,  so  that  even  one  foot  below  the  in'lorus  we  find  that  one-half  to 
three-fifths  of  the  carbohydi'ates  have  been  converted  into  dextrine  and  sugar.  A 
further  digestion  of  the  proteins  also  takes  place  amomiting  to  about  one-tenth  of  the 
whole  protein  taken  with  the  food. 

On  deducting  the  amount  of  juices  which  have  been  added  to  the  food  it  is  found 
that  even  in  this  short  length  of  intestine  absorption  has  taken  place  of  about  one-sixth 
of  the  ingested  food,  about  one-fourth  of  the  carbohydi'ates  having  been  absorbed 
and  about  one-eighth  of  the  proteins. 

In  a  dog  A\ith  a  fistifla  about  the  middle  of  its  small  intestine,  the  outflow  began 
six  to  fiifteen  minutes  after  the  meal,  and  lasted  six  or  seven  hours.     The  outflow  was 


THE  ABSORPTION  OF  THE  FOOD-STUFFS 


753 


by  small  gushes  repeated  at  intervals  of  five  to  ten  seconds  separated  by  intervals  of 
one  to  five  minutes,  dm-ing  which  nothing  appeared  at  the  orifice  of  the  cannula.  The 
material  obtained  was  quite  different  in  character  from  that  flowing  from  the  duodenal 
fistula.  The  pasty  character  had  disappeared,  the  material  forming  a  frothy,  orange- 
yellow,  even  jelly-like  mass  with  practically  no  trace  of  undigested  bread. 

From  a  fistula  in  the  ileum  the  outflow  occurred  at  long  intervals  of  three  to  fifteen 
minutes  and  was  much  scantier  than  that  obtained  from  the  jejunal  fistula,  consist- 
ing of  a  thick  jelly-like,  orange-coloured  mass.  Both  proteins  and  carbohydi'ates  were 
entirely  digested,  and  in  the  case  of  the  former  the  chief  products  of  digestion  consisted 
of  amino-acids.  Thus  in  one  experiment,  after  four  large  meals  of  500  grm.  of  meat 
each  had  been  given,  in  order  to  obtain  sufficient  quantity  for  analysis,  175  grm.  of 
soluble  substances  were  obtained.  From  this  were  isolated  tyrosine,  leucine,  alanire, 
aspartic  acid,  lysine,  and  traces  of  arginine  and  histidine. 

From  a  fistula  in  the  caecum  there  was  no  outflow  until  fom:  or  five  hours  after  the 
meal  had  been  taken.  The  material  from  the  gut  was  then  extruded  in  foecal  like 
masses  at  long  intervals  of  one  half  to  one  hour.  This  regular  outflow  lasted  lor  about 
six  hours.  The  reaction  of  the  contents  was  strongly  alkaline,  with  no  food  particles, 
and  the  material  contained  merely  debris  of  cells,  with  small  traces  of  sugar,  dextrine 
and  unaltered  starch.  The  absorption  of  the  food-stuffs  is  thus  practically  complete 
by  the  time  that  the  food  has  reached  the  lower  end  of  the  small  intestine. 

The  following  Table  gives  the  total  amounts  obtained  in  a  series  of  experiments 
from  the  different  fistulse  after  administration  of  200  grm.  of  bread,  and  also  the  per- 
centage amoimt  of  food-stuffs  which  had  been  absorbed  before  the  food  had  arrived  at 
the  level  of  the  fistula  in  question  : 


Total  amounts  obtained 

Absorbed 

from  200  grm. 

of  bread 

per  cent. 

Pyloric  fistula 

691  gr 

m. 

0 

Duodenal  fistula     . 

691     „ 

17-45 

Jejunal  fistula 

585     ,. 

37-77 

Ileum  fistula 

412     .„ 

67-65 

Csecal  fistula 

80     „ 

94-34 

SECTION  X 

THE    F^CES 

The  fseces  are  often  regarded  as  representing  the  undigested  or  indigestible 
constituents  of  the  food  which  have  escaped  solution  and  absorption  in  their 
passage  through  the  aUmentary  canal.  This  view  is  hardly  correct  as  appMed 
to  man  or  to  the  carnivora.  In  these  the  absorption  of  the  constituents  of 
a  meal,  whether  consisting  of  fats,  proteins,  or  carbohydrates,  is  practically 
complete  by  the  time  that  the  food  has  arrived  at  the  lower  end  of  the 
ileum.  The  faeces,  in  fact,  are  not  derived  from  the  food,  but  are  produced  in 
the  ahmentary  canal  itself.  This  is  shown  by  the  fact  that  on  analysing 
the  faeces  no  soluble  carbohydrates  or  proteins,  albumoses,  peptones,  or 
amino-acids  are  to  be  found.  After  a  meal  of  meat  microscopic  examination 
of  the  faeces  reveals  no  trace  of  striated  muscle  fibres.  Moreover  animals 
in  a  state  of  complete  starvation  form  faeces  which  do  not  differ  in  their 
composition  from  the  fasces  which  are  found  after  feeding  with  meat,  eggs, 
sugar,  or  cooked  starch,  though  the  amount  is  less  in  a  state  of  inanition  than 
under  normal  circumstances.  In  one  experiment  Hermann  isolated  a  loop 
of  gut,  joining  its  ends  together  so  that  a  continuous  ring  was  formed.  The 
continuity  of  the  gut  was  then  restored  by  suturing  the  two  free  ends.  After 
some  weeks  the  isolated  loop  was  found  to  contain  a  semi-sohd  material 
similar  to  faeces  in  appearance,  consistence,  and  chemical  composition.  It 
contained  a  large  amount  of  phosphoric  acid,  Kme,  and  iron. 

So  long  as  vegetables  or  coarsely  ground  cereals  are  excluded  from  the 
diet,  the  nature  of  the  latter  does  not  alter  the  chemical  constitution  or 
appearance  of  the  faeces.  Under  these  circumstances  the  faeces  have  the 
following  composition  : 

Water  .  .  .  .  65  to  67  per  cent. 

Nitrogen      .  ...  .  5  to    9       „ 

Ether  extract        .  .  .  12  to  18       ,. 

Ash 11  to  22       „ 

The  ash  consists  chiefly  of  lime  and  phosphoric  acid  with  some  iron  and 
magnesia.  The  ethereal  extract  contains  fatty  acids  and  a  small  amount 
of  lecithin.  Neutral  fat  is  present  in  very  small  proportions.  The  faeces  also 
contain  small  (Quantities  of  cholahc  acid  and  its  products  of  decomposition, 
dyslysin,  and  coprosterin,  a  body  allied  to  cholesterin,  and  a  certain  amount 
of  purine  bases  consisting  of  guanine,  adenine,  xanthine,  and  hypoxanthine. 
On  the  average  the  faeces  contain  about  0-11  grm.  of  purine  bases  per  diem, 

754 


THE  F^CES 


755 


about  seven  times  as  much  as  is  contained  in  the  urine  passed  in  the  same 
time.  The  material  basis  of  the  faeces  seems  to  be  largely  desquamated 
epitheHal  cells  from  the  intestinal  wall,  and  bacteria,  of  which  countless 
numbers,  chiefly  dead,  are  present.  It  has  been  reckoned  that  as  much  as 
50  per  cent,  of  the  faeces  may  consist  of  the  dead  bodies  of  bacteria. 

Very  different  is  the  composition  of  faeces  if  the  food  contains  a  large 
amount  of  cellulose.  Not  only  does  the  ingested  cellulose  pass  unchanged 
into  the  faeces,  but  large  quantities  of  other  substances  enclosed  in  the  cellu- 
lose walls  may  also  escape  digestion  and  absorption.  Moreover  the  in- 
creased bulk  of  the  undigested  residue  stimulates  peristalsis,  and  thus 
quickens  the  passage  of  the  food  through  the  gut  to  such  an  extent  that  the 
digestive  ferments  have  not  time  to  exert  their  full  action  on  the  digestible 
constituents  of  the  food.  The  influence  of  the  character  of  the  food  is  well 
illustrated  by  a  comparison  of  the  amount  and  composition  of  the  faeces  on 
different  kinds  of  bread  (Rubuer)  : 


Eind  of  bread 

Weight  of 
moist  fasces 

Weight  of 
faeces  dried 

Percentage  of 
ingested  food 

Nitrogen 
(grm.) 

Bread  from  fine  flour 
Bread  from  coarse  flour     . 
Bro'mi  bread  . 

132-7 
252-8 
317-8 

24-8 
40-8 
75-79 

4-03 

6-66 

12-23 

2-17 
3-24 

3-80 

The  following  Table  is  also  instructive.  In  this  Table  Rubner  calculates 
the  amount  of  faeces  which  a  man  would  pass  in  twenty-four  hours  if  he 
satisfied  his  energy  requirements  at  the  expense  of  one  only  of  the  difl'erent 
kinds  of  food  enumerated, 
material  which  would  be  excreted  in  the  faeces 


The  numbers  refer  to  the  amount  of  organic 


Meat  . 

.     26  grm. 

Rice   . 

. 

60  grm 

Eggs  . 

.     26     „ 

Maize 

.       51      „ 

Macaroni      . 

.     27     „ 

Turnips 

.     101      „ 

Wheaten  bread 

.     36     „ 

Potatoes 

.     133     „ 

Milk   . 

•     42     „ 

Coarse  brown 

bread 

.     146     „ 

The  indigestible  cellulose  in  the  food  is  not  without  value.  It  has  been 
shown  previously  that  the  peristaltic  contractions  of  the  intestine  are  roused 
primarily  by  the  mechanical  stimulus  of  distension.  If  the  food  is  capable 
of  entire  digestion  and  absorption  the  amount  of  faeces  formed  is  limited 
to  that  produced  by  the  intestinal  wall  itself.  The  small  bidk  exercises 
very  Httle  stimulating  effect  on  the  intestine,  and  the  movements  of  the 
latter  will  therefore  tend  to  be  sluggish,  especially  in  the  absence  of  the 
mechanical  stimulus  determined  by  muscular  exercise.  The  presence  of  a 
certain  amount  of  cellulose  in  the  diet  may  therefore  be  of  considerable 
advantage  by  giving  bulk  to  the  faeces  and  ensuring  the  proper  regular  evacu- 
ation of  the  lower  gut.  It  is  probable  that  the  constipation  which  is  so 
common  a  disorder  in  civiHsed  communities  is  due  as  much  to  the  refinement 
in  the  preparation  of  the  food  as  to  the  prevalence  of  sedentary  occupations 
incident  on  the  working  of  such  a  community. 


CHAPTER  XI 

THE  HISTORY  OF  THE  FOOD-STUFFS 

SECTION  I 

PROTEIN   METABOLISM 

A  PEOTEiN  consists  of  the  elements  carbon,  hydrogen,  oxygen,  nitrogen,  and 
sulphur.  In  the  oxidation  which  these  bodies,  in  common  with  the  other 
food-stuiis,  undergo  in  the  body,  the  carbon  and  hydrogen  are  converted  to 
carbon  dioxide  and  water.  A  certain  proportion  escapes  this  complete 
oxidation,  being  excreted  by  the  kidneys  in  combination  with  nitrogen  as 
the  essential  constituents  of  the  urine  (chiefly  urea).  When  proteins  are 
oxidised  in  the  body  there  is  a  definite  relation  between  the  carbon  dioxide 

.      CO2 

which  is  produced  and  the  oxygen  consumed.     This  respiratory  quotient  -jr- 

in  the  case  of  proteins  equals  0-81.  Since  the  respiratory  quotient  on  a  pure 
consumption  of  fats  is  only  0-71  and  on  carbohydrates  equals  1,  we  may,  by 
a  study  of  the  respiratory  exchanges,  arrive  at  some  idea  of  the  extent  to 
which  protein  metabolism  is  responsible  for  the  energy  exchanges  of  the  body 
as  a  whole.  Such  information  by  itself  will  always  be  somewhat  uncertain, 
since  it  is  possible,  by  a  combination  of  fat  and  carbohydrate  metaboUsm  in 
proper  proportions,  to  produce  a  respiratory  quotient  identical  with  that 
obtaining  when  the  metaboHsm  is  purely  of  protein.  On  the  other  hand,  the 
specific  constituents  of  proteins,  namely,  nitrogen  and  sulphur,  are  excreted 
entirely  by  the  urine  (if  we  exclude  the  small  traces  which  may  leave  the 
body  in  the  sweat,  or  as  scales  of  epidermis,  hair,  nails,  &c.).  It  has 
therefore  been  customary  to  take  the  nitrogen  output  in  the  urine  as  an  index 
of  the  protein  metabohsm.  This  proceeding  is  only  justified  if  we  remember 
that  we  are  deahng  in  the  urine  merely  with  the  nitrogen  and  sulphur  of  the 
protein  molecule,  and  that  a  large  proportion  of  the  carbon  and  hydrogen 
moiety  of  this  molecule  is  being  left  unregarded. 

Since  we  cannot  follow  all  the  stages  in  the  changes  undergone  by  proteins 
on  their  way  through  the  body,  it  will  be  convenient  to  take  the  nitrogenous 
end-products  of  protein  metabolism  such  as  appear  in  the  urine,  and  to  deter- 
mine, where  possible,  their  precursors,  and  the  conditions  which  determine 
their  formation  in  the  body.  The  chief  nitrogenous  constituents  of  urine  are 
urea,  ammonia,  uiic  acid,  creatinine,  hippuric  acid.     There  is  a  small  residue 

756 


PROTEIN  METABOLISM 


757 


of  undetermined  nitrogen  which  may  include  traces  of  purine  bases,  such  as 
xanthine  and  hypoxanthine,  traces  of  amino-acids,  small  amounts  of  pig- 
ment and  of  nucleo-protein  from  the  wall  of  the  bladder.  The  relative  pro- 
portions in  which  these  bodies  occur  are  not  invariable,  but  differ  according 
to  the  nature  of  the  protein  foods  taken  and  also  according  to  the  proportion 
which  the  protein  metabohsm  bears  towards  the  total  energy  requirements 
of  the  body.  In  the  following  Tables  (Folin)  are  given  the  average  composi- 
tion of  two  specimens  of  urine  from  the  same  individual,  one  on  a  diet  con- 
taining the  ordinary  proportion,  and  the  other  on  a  diet  containing  only  a 
minimal  amount  of  protein  : 

TABLES  I  AND  II 

Distribution  of  Nitrogen  in  Urine  on  Various  Diets 


July  13 

July  20 

Ordinary  diet 

Low  protein  diet 

Vol.  of  m'ine 

1170  c.c. 

385  c.c. 

Total  nitrogen 

16-8  grm. 

3-60  grm. 

Urea   . 

14-70  grm.  =  S7-5  % 

2-20  grm.  =  61-7% 

Ammonia     . 

0-49  grm.  =     3-0  % 

0-42  grm.  =  11-3% 

Uric  acid 

0-18  grm.  =     M  % 

0-09  grm.  =    2-5  % 

Creatinine    . 

0-58  grm.  =     3-6  % 

0-60  grm.  =  17-2  % 

Undetermined 

0-85  grm.  =    4-9  % 

0-27  grm.  =    7-3  % 

Total  SO3     . 

3-64  grm. 

0-76  grm. 

Laorganic  SO3 

3-27  grm.  =  90-0  % 

0-46  grm.  =  60-5  % 

Ethereal  SO3 

0-19  grm.  =     5-2  % 

0-10  grm.  =  13-2  % 

Neutral  S     • 

0-18  grm.  =    4-8  % 

0-20  grm.  =  26-3  % 

111  dealing  with  the  metabolism  of  the  body  as  a  whole  we  saw  reason  to 
beheve  that  the  proteins  taken  in  with  the  food  might  be  regarded  as  having 
a  twofold  destiny.  One  part,  and  under  normal  circumstances  the  greater 
part,  is  apphed  to  the  production  of  energy,  in  this  respect  discharging  a 
function  which  might  equally  well  be  performed  by  the  fats  and  carbohy- 
drates of  the  food.  In  its  second  function  protein  cannot  be  replaced  by  any 
other  food-stuff,  since  it  alone  contains  the  necessary  elements  as  well  as  the 
groupings  of  these  elements  which  are  essential  for  the  building  up  of  the 
living  tissues.  We  saw  reason  to  believe  that  this  tissue  metabolism  onlv 
accounted,  however,  for  a  small  part  of  the  nitrogen  of  the  food.  On  this 
account  it  is  "possible  to  ensure  health  and  a  condition  of  nitrogenous  equili- 
brium with  amounts  of  protein  in  the  diet  of  man  which  might  varv  between 
40  and  200  grm.  per  diem.  The  more  protein  that  is  taken  in  with  the  food 
the  greater  is  the  relative  amount  which  is  apphed  to  the  energy  needs  of 
the  body.  If  therefore  we  would  attempt  to  find  out  what  are  the  end- 
products  of  the  tissue  metabolism  we  should  confine  the  energy  metabolism 
of  proteins  within  the  smallest  possible  limits  by  reducing  the  quota  of  pro- 
tein in  the  diet  to  its  minimum.  Folin  has  shown  that  if  we  compare'the  com- 
position of  the  urine  obtained  under  these  two  conditions,  namely,  on  a  diet 
containing  a  normal  quantity  of  protein  and  on  a  diet  coutaioiug  a  minimal 


758 


PHYSIOLOGY 


amount,  we  find  evidence  of  a  qualitative  difference  between  the  two 
kinds  of  metabolism.  The  difference  is  well  brought  out  in  the  Tables  just 
quoted.  On  a  large  diet  the  greater  part  of  the  nitrogen  can  be  regarded 
as  derived  directly  from  the  food,  whereas  on  a  small  diet  a  relatively  larger 
proportion  of  it  must  come  from  protein  which  has  been  previously  built  up 
into  the  tissues.  Fohn  distinguishes  these  two  sources  of  the  nitrogen 
of  the  urine  as  exogenous,  i.e.  that  from  the  food,  and  endogenous,  i.e.  derived 
from  the  tissues.     Two  facts  stand  out  in  comparing  these  two  urinary 


24H0L 


Pig.  353.  The  hourly  variation  in  the  excretion  of  nitrogen  after  a  meal. 
The  meal  was  given  at  0.  The  thick  line  represents  the  average  ab- 
sorption of  the  food  from  the  alimentary  canal.  The  thin-lined  curves 
represent  the  N.  excretion  (1)  after  a  meal  of  1000  grm.  meat ;  (2)  after  500 
grm.  meat  and  150  grm.  fat ;  (3)  after  a  meal  of  500  grm.  meat ;  (4)  and 
(5)  both  represent  the  excretion  in  a  fasting  animal.  (From  Tigebstedt 
after  Feder.) 

analyses.  In  the  first  place,  on  a  normal  protein  diet  the  urea  accounts  for 
87  per  cent,  of  the  total  nitrogen  of  the  urine.  On  an  excessive  protein  diet 
this  percentage  may  rise  to  90  or  95.  On  the  low  protein  diet  the  percentage 
of  nitrogen  appearing  as  urea  is  reduced  to  60.  On  the  other  hand,  practi- 
cally identical  amounts  of  creatinine  are  obtained  under  the  two  conditions, 
so  that  whereas  on  the  full  diet  it  amounts  only  to  3-6  per  cent.,  on  the  low 
protein  diet  it  forms  as  much  as  17  per  cent,  of  the  total  nitrogen  output. 
We  are  therefore  justified  in  regarding  urea  as  to  a  large  extent  exogenous  in 
origin,  and  as  derived  directly  from  the  nitrogenous  moiety  of  the  protein 
molecule,  which  may  not  at  any  time  have  formed  part  of  the  living  tissues 
of  the  body. 

On  giving  a  large  protein  meal  to  a  dog  the  urea  in  the  urine  rapidly 
rises,  and  at  the  end  of  four  or  five  hours  50  per  cent,  of  the  total  nitrogen 
taken  in  with  the  food  has  appeared  in  the  urine  as  urea  (Fig.  353).  If  we 
take  into  account  that  the  digestion  of  a  meat  meal  in  this  animal  may  go 
on  for  eight  hours,  we  are  justified  in  the  statement  that  by  far  the  greater 


PROTEIN  METABOLISM  759 

poi-tion  of  the  protein  nitrogen  taken  with  the  food  is  excreted  almost 
directly  after  absorption  as  urea  in  the  urine.  Urea  is  therefore  to  be  re- 
garded in  the  first  place  as  an  index  to  the  amount  of  protein  absorbed.  We 
have  seen  that  the  end-products  of  protein  digestion  in  the  intestine  are 
the  amino-acids  ;  and  that  these  are  the  immediate  precursors  of  the  urea 
is  shown  by  the  fact  that  the  administration  of  these  bodies  is  followed  very 
rapidly  by  the  appearance  of  the  whole  of  their  nitrogen  in  the  urine  as 
urea.  Many  attempts  have  been  made  to  explain  the  method  by  which  urea 
may  be  derived  from  the  amino-acids. 

F.  Hofmeister  succeeded  in  preparing  urea  by  oxidising  amino-acids 
with  potassium  permanganate  in  the  presence  of  ammonia  and  ammonium 
sulphate.  He  assumes  that  urea  is  formed  by  an  oxidation  synthesis. 
The  first  step  would  be  the  formation,  by  oxidation  of  protein  or  amino-acids, 
of  the  group  CONHg,  and  this  at  the  moment  of  formation  would  combine 
with  the  NH2  left  over  in  the  oxidation  of  the  ammonia  to  form  urea, 

According  to  Drechsel  and  Nencki,  the  immediate  precursor  of  the  urea 
is  probably  ammonium  carbamate,  which  loses  a  molecule  of  water,  thus  : 

C0<^H.-H,0-CO<™= 

Schroder,  on  the  other  hand,  suggested  that  the  urea  was  formed  from 
ammonium  carbonate  by  the  loss  of  two  molecules  of  water. 

°°<om:-2h,o-co<™^ 

In  all  these  views  it  is  assimaed  that  before  urea  can  make  its  appearance 
in  the  urine  there  must  be  a  complete  destruction  of  the  amino-acid.  If 
we  compare  the  structure  of  any  amino-acid  with  that  of  urea  we  see  that  the 
proportion  of  carbon  to  nitrogen  is  very  much  greater  in  the  former  than  in 
the  latter,  and  that  even  after  splitting  off  from  two  molecules  of  amino-acid 
the  necessary  elements  to  form  urea,  00^2114,  almost  the  whole  of  the 
molecule  will  be  left  in  an  unoxidised  condition.  A  complete  oxidation 
of  the  amino-acid  would  result  in  the  production  of  ammonia,  carbon  dioxide, 
and  water,  so  that  if  oxidation  were  the  method  adopted  for  the  production  of 
urea  the  immediate  precursor  of  this  substance  would  be  a  combination 
of  ammonia  and  carbonic  acid,  either  ammonium  carbonate  as  sugorested 
by  Schroder,  or  carbamate  as  thought  by  Dreschel.  We  have  distinct  evi- 
dence that  ammonia  in  one  of  these  two  forms  is  an  important  precursor  of 
urea.  If  ammonium  carbonate  or  carbamate  be  administered  to  man  or 
to  an  animal  the  whole  of  it  is  turned  out  in  the  urine  as  urea.  Although 
there  is  normally  a  small  amount  of  ammonia  in  the  urine,  it  is  not  in- 
creased by  injections  of  ammonium  carbonate.  Schroder  has  sho^\^l  that 
the  liver,  even  after  removal  from  the  body,  has  the  power  of  transforming 
ammonium  carbonate  into  urea.  Defibrinated  blood  mixed  with  ammonium 
carbonate  was  passed  through  a  surviving  liver.     After  a  little  time  it  was 


760  PHYSIOLOGY 

found  that  the  ammonium  carbonate  had  disappeared  and  that  its  place  was 
taken  by  urea.  If  the  liver  is  necessary  for  this  conversion  to  take  place  and 
ammonia  is  a  constant  precursor  of  urea,  we  should  expect  to  find  that  the 
abohtion  of  the  hepatic  functions  would  cause  the  appearance  in  the  urine 
of  ammonium  carbonate  or  carbamate  in  the  place  of  urea.  The  cutting  out 
of  the  hver  is  not,  however,  an  easy  matter  in  mammals.  Ligature  of  the 
portal  vein,  which  would  be  a  necessary  step  in  the  extirpation  of  the  hver, 
causes  the  blood  to  be  dammed  up  behind  the  ligature  in  the  portal  area. 
The  intestinal  wall  gets  full  of  effused  blood,  the  blood  pressure  falls  steadily, 
and  the  animal  dies  within  a  few  hours,  being  bled  to  death,  so  to  speak,  into 
its  portal  vessels.  A  way  of  obviating  this  difficulty  was  suggested  by  a 
Kussian  surgeon,  Eck,  and  was  successfully  carried  out  by  Pawlow.  Before 
ligature  of  the  portal  vein,  this  vessel  was  joined  to  the  vena  cava  and  an 
artificial  opening  made  connecting  the  lumen  of  the  two  vessels,  so  that, 
after  the  ligature,  the  blood  could  flow  directly  into  the  general  circulation 
without  passing  through  the  Hver.  Some  animals  operated  on  in  this  way 
showed  no  abnormal  symptoms  whatsoever.  There  was  a  rapid  formation 
of  a  collateral  circulation  so  that  the  blood  could  get  round  the  Kgature  to 
the  hver.  Under  all  circumstances  a  path  to  the  liver  was  still  open  by  the 
hepatic  artery,  but  to  arrive  here  the  blood  from  the  alimentary  canal  had 
fijst  to  pass  through  the  general  circulation.  A  certain  number  of  animals 
were  found  to  be  particularly  susceptible  to  the  nature  of  their  diet.  On  a 
diet  largely  consisting  of  carbohydrates  they  maintained  good  health.  After 
a  large  meat  meal,  however,  they  became  ill,  and  in  many  cases  suffered  from 
tremors  and  convulsions  ending  in  coma.  At  the  same  time  there  was  a  defi- 
nite increase  of  ammonia  in  the  urine,  chiefly  in  the  form  of  ammonium 
carbamate.  Analysis  of  the  blood  from  a  normal  animal  showed  that 
during  protein  digestion  there  was  a  constant  excess  of  ammonia  in  the 
blood  of  the  portal  vein  above  that  in  any  other  part  of  the  vascular  system. 
In  the  carotid  blood  the  normal  amount,  according  to  Nencki,  is  about 
2  mg.  per  100  c.c,  in  the  portal  blood  4  to  6  mg.*  During  the  morbid 
symptoms  brought  on  by  a  protein  meal  in  the  animals  in  whom  an  Eck 
fistula  had  been  produced,  the  ammonia  in  the  carotid  blood  may  rise  to  as 
much  as  4  mg.,  i.e.  to  the  amount  normally  found  in  portal  blood,  Pawlow 
and  Nencki  therefore  ascribed  the  symptoms  observed  in  these  dogs  after 
a  heavy  meat  meal  to  a  condition  of  '  ammonisemia,'  and  regarded  the  liver 
as  an  organ  which  is  normally  concerned  in  protecting  the  rest  of  the  body 
from  ammonia  produced  in  the  alimentary  tract  by  converting  this  substance 
into  the  innocuous  neutral  body,  urea. 

This  view  of  the  function  of  the  liver  is  confirmed  by  Schroder's  experi- 
ments on  birds.  In  these  animals  the  chief  nitrogenous  excretion  is  not  urea, 
but  ammonium  urate,  60  per  cent,  of  the  nitrogen  of  the  urine  appearing  in 
the  form  of  uric  acid.  In  birds  there  is  naturally  a  communication  between 
the  portal  system  and  the  general  venous  system  by  means  of  the  vein  of 

*  According  to  Folin  this  excess  of  ammonia  in  the  portal  blood,  when  present, 
is  due  to  bacterial  fermentation  processes  occurring  within  the  intestine. 


PROTEIN  METABOLISM  761 

Jacobson,  which  connects  the  lower  branches  of  the  portal  vein  with,  as  a 
rule,  the  left  renal  vein  (Fig.  354).  On  this  account  the  liver  can  be  cut 
out  of  the  body  or  of  the  circulation  without  entailing  the  rapid  death  of  the 
bird,  which  may  live  for  three  or  four  days,  and  pass  urine  after  the  opera- 
tion. The  urine  is,  however,  fluid,  and  the  uric  acid,  instead  of  accounting 
for  60  per  cent,  of  the  total  nitrogen,  now  forms  only  5  per  cent.  The  place 
of  the  greater  part  of  the  uric  acid  has  been  taken  by  ammonium  lactate, 
which  therefore  seems  to  be  the  chief  immediate  precursor  of  the  uric  acid  in 


l^-lnf.  Vena  Cava 


Iliac  vein- 
Kidney 


V.  of  Jacobson 
Inf.  mes.  V, 


Caudal  v. — 


PoKtal  V. 


Fig.  354.     Diagram  to  show  the  arrangement  of  the  veins  in  the  bird, 
with   the   communication   of   the   renal   and   portal  veins.     (After 

MORAT.) 

the  urine  of  birds.  We  shall  have  occasion  to  consider  the  method  of  trans- 
formation of  ammonium  lactate  to  uric  acid  more  fully  when  dealing  with 
the  origin  of  the  latter  body. 

Of  late  years  evidence  has  been  brought  forward  that  the  formation  of 
ammonia  from  the  amino- acids  may  involve  no  such  profound  changes  of 
oxidative  disintegration  as  were  suggested  in  the  theories  of  Hofmeister  or 
Schrdder.  If  amino-acids  be  treated  with  the  pulp  of  various  organs  the 
amount  of  ammonia  in  the  mixture  is  increased,  an  increase  which  is  absent 
when  no  amino-acids  are  added.  More  ammonia,  for  instance,  was  found 
when  leucine,  glycine,  tyrosine,  or  cystine  was  added  to  the  pulp.  On  the 
other  hand,  phenylalanine  gave  rise  to  no  production  of  ammonia.  This 
conversion  was  ascribed  by  Lang  to  the  presence  of  a  deaminising  ferment  in 
the  cells  of  these  different  tissues,*  and  Leathes  and  Folin  have  suggested 
that  this  process  of  deamination  is  the  essential  factor  in  the  rapid  con- 
version  of  the  nitrogen  of  the  ingested  protein  into  urea.     Viewed  in  this  light, 

*  According  to  van  Slyke,  the  liver  plays  the  chief  part  in  the  brcakdowu  of  the 
amino-acids,  though  there  is  no  reason  to  denj'  the  possession  of  similar  power  to  the 
other  tissue?  {e.g.  mascles)  of  the  animal  body. 


762  PHYSIOLOGY 

these  results  of  Lang,  and  Folin,  effect  an  entire  revolution  in  our  views 

of  protein  metabolism.     Instead  of  regarding  the  urea  which  appears  in  the 

urine  after  protein  ingestion  as  produced  by  the  total  disintegration  of  the 

protein  molecule,  we  see  now  that  it  represents  merely  the  throwing  off 

of  the  nitrogenous  part  of  this  molecule.     This  deamination  may  be  a 

purely  hydrolytic  change  or  it  may  be  associated  with  oxidation  or  reduction. 

Deamination  of  alanine,  for  instance,  by  simple  hydrolysis  would  result  in  the 

formation  of  lactic  acid  (an  oxy- fatty  acid). 

CH3  CII3 

I  I 

.      CH.NH2  +  H2O  =  NH3  +  CHOH 

COOH  COOH 

If  the  deamination  were  accompanied  with  oxidation  the  corresponding 
keto-fatty  acid  would  be  formed,  thus 

CH3.CHNH2.COOH  +  0  =  NHg  +  CH3CO.COOH 

If  reduction  took  place  at  the  same  time,  the  result  would  be  the  production  of 
a  saturated  fatty  acid.  Knoop  has  shown  that  aU  three  cases  may  occur. 
The  investigation  of  the  stages  in  deamination,  and  indeed  in  the  disintegra- 
tion of  fatty  derivatives  generally,  is  rendered  difficult  by  the  fact  that  aU  the 
intermediate  products  undergo  further  change  and  leave  the  body  in  a  state 
of  complete  oxidation,  as  carbon  dioxide  and  water.  If,  however,  an  amino- 
acid  group  be  administered  as  part  of  an  aromatic  compound,  i.e.  forming 
a  side-chain  of  the  benzene  ring,  it  is  protected  from  complete  oxidation  by 
the  stabiHty  of  this  ring.  The  oxidation  of  the  fatty  side-chain  may  proceed 
to  a  certain  degree,  so  that  intermediate  products  of  metaboHsm  may  be 
excreted  still  attached  to  the  benzene  nucleus.  In  the  a-amino-acids 
the  point  where  disintegration  first  occurs  is  the  o-group.  Deamination 
Knoop  finds  most  usually  associated  with  oxidation.     The  primary  product 

I 
is  therefore  an  a-keto-acid.     Further  oxidation  affects  the  CO  group,  so  that 

carbon  dioxide  is  eliminated  and  the  next  lower  acid  in  the  fatty  acid  series, 
is  produced.  Thus  from  alanine  the  body  would  produce  pyruvic  acid, 
CHg.CO.COOH,  and  this  on  further  oxidation  would  form  acetic  acid, 
CHg.COOH,  and  carbon  dioxide.  On  the  other  hand,  these  keto-acids  may 
undergo  reduction  to  an  oxy-acid,  or  even  a  step  further,  to  a  fatty  acid, 
though  the  conditions  which  determine  whether  oxidation  or  reduction  shall 
take  place  have  not  yet  been  fully  studied. 

Of  very  great  importance  is  Knoop's  discovery  that  deamination  is  a 
reversible  process,  so  that,  given  a  right  molecular  grouping,  a  fatty  acid 
residue  may  react  with  ammonia  to  form  an  amino-acid.  The  proof  of  this 
fact  was  facilitated  by  the  discovery  that  the  next  higher  homologue  of 
phenylalanine,  namely,  phenyl- a-amino-butyric  acid,  when  administered  to 
an  animal,  was  excreted  in  large  quantities  in  the  urine  as  an  ether-soluble 
acetyl  derivative,  which  was  easily  isolated  in  a  state  of  purity.    If  then  this 


PROTEIN  METABOLISM 


763 


amino-acid  were  formed  in  the  body,  one  might  expect  to  jSnd  it  without 
difficulty  in  the  urine.  Knoop  found  that  the  administration  of  either 
phenyl- a-keto-butyric  acid  or  phenyl- a-oxybut>Tic  acid  led  to  the  excretion 
of  the  corresponding  amino-acid  in  the  urine.  Since  keto-acids  occur  as  the 
ordinary  products  of  the  breakdown  of  amino-acids  and  also  as  the  inter- 
mediate products  of  oxidation  of  oxy-acids,  e.g.  lactic  acid,  it  is  evident  that 
the  animal  body  can  assimilate  ammonia  and  form  amino-acids,  provided 
only  that  it  is  supphed  with  the  proper  non- nitrogenous  acids.  These  latter 
need  not  be  derived  from  proteins  at  all,  but,  hke  lactic  acid,  be  a  result  of 
carbohydrate  metabolism.  Thus,  if  the  fitting  non-nitrogenous  food  be  given 
(e.g.  oxy-fatty  acids,  or  carbohydrates,  from  which  these  bodies  may  be 
formed),  part  of  the  nitrogen  set  free  by  protein  disintegration  might  be 
recombined  with  the  formation  of  amino-fatty  acids  without  gi^^ng  rise  to 
urea  or  appearing  in  any  way  in  the  nitrogen  balance-sheet  of  the  body. 
This  possibility  enjoins  the  necessity  of  caution  in  interpreting  the  results  of 
metabolism  experiments  where  the  nitrogen  excreted  is  taken  to  represent  the 
total  protein  metabohsm  of  the  body.  The  fate  of  the  nitrogen  does  not, 
however,  matter  much  to  the  energy  balance-sheet  of  the  body,  since  so  far 
as  regards  energy  the  residue  of  the  protein  molecule  or  the  amino-acid 
molecule  which  is  left  behind  after  the  process  of  deainination  has  taken  place, 
has  lost  only  from  one-fifth  to  one-tenth  of  the  total  energy  of  the  original 
molecule.  This  is  shown  in  the  following  Table  of  the  heat  equivalents  of 
some  of  the  amino-acids  and  their  corresponding  fatty  and  oxy-acids  : 

Calories 


Substance 
Leucine 

per  grm.  molecule 
855 

Isobutylacetic  acid    . 
Alanine    .... 

837 
389 

Propionic  acid  . 
Lactic  acid 

367 
329 

Pyruvic  acid 

not  dstermined 

Even  in  the  case  of  the  smallest  molecule  the  loss  of  energy  attendant 
on  simple  deamination  and  conversion  into  the  corresponding  oxy-acid  only 
amounts  to  about  20  per  cent.  We  thus  come  to  the  conclusion  that  the 
urea  output  in  the  urine  after  a  protein  meal  teUs  us  nothing  whatever  about 
the  fate  of  that  part  of  the  protein  which  contains  80  to  90  per  cent,  of  the 
total  energy  of  the  protein  food.  So  far  as  concerns  the  output  of  energy,  the 
exogenous  protein  metabolism  may  be  regarded  as  practically  non-nitrogen- 
ous. The  rise  in  the  rate  of  excretion  of  urea  after  a  protein  meal  was 
regarded  both  by  Voit  and  Pfliiger  as  a  sign  that  the  cells  of  the  body  pre- 
ferred to  use  proteins  for  all  their  requirements  if  this  substance  were 
available.  We  see  now  that  the  big  output  of  urea  after  a  protein  meal 
affords  no  basis  for  this  view,  but  is  rather  a  sign  that  the  body  has  no  need 
for  all  the  nitrogen  contained  in  its  food  and  that  this  must  be  got  rid 
of  before  the  really  valuable  part,  the  energy-giving  part  of  the  protein 
molecule,  is  admitted  into  the  metabolic  cycle  of  the  cells. 

The  important  problem  in  the  energy  metabolism  of  protein  is  thus,  not 


764 


PHYSIOLOGY 


the  origin  of  the  urea,  but  the  nature  of  the  substances  that  are  left  after 
deamination  and  their  subsequent  fate  in  the  body.  Since  they  contain 
only  the  elements  carbon,  hydrogen,  oxygen,  one  would  expect  to  find  that 
they  could  replace  either  fat  or  carbohydrate.  So  far  as  concerns  the  pro- 
duction of  energy  this  is  true.  Moreover,  as  we  shall  see  in  deahng  with  the 
metaboHsm  of  carbohydrates,  we  have  definite  evidence  that  part  of  this  non- 
nitrogenous  moiety  of  the  protein  molecule  may  be  converted  into  sugar  or 
glycogen.  Thus,  of  the  amino-acids  formed  by  the  digestion  of  proteins, 
glycine,  alanine,  aspartic  acid  and  glutamic  acid  can  be  converted  quanti- 
tatively under  appropriate  circumstances  into  glucose.  On  the  other  hand, 
leucine,  phenylalanine  and  tyrosine  yield  no  glucose,  even  in  the  diabetic 
animal,  but  may  in  the  Hver  undergo  conversion  into  aceto-acetic  acid,  which 
is  a  stage  in  the  oxidative  disintegration  of  fats.  In  spite  of  this  latter  fact 
we  have  no  evidence  that  fat  may  be  formed  from  this  part  of  the  protein 
molecule  ;  at  any  rate,  no  fat  which  can  be  stored  in  the  body  and  give  rise 
to  the  production  of  adipose  tissue.  On  the  other  hand,  the  proteins,  more 
than  either  of  the  other  two  food-stufis,  cause  a  direct  augmentation  of  the 
respiratory  exchanges  of  the  body.  This  is  shown  in  the  following  Table 
by  Rubner,  in  which  isodynamic  quantities  of  proteins,  fats,  and  carbo- 
hydrates were  administered  during  a  period  of  starvation  : 


Day 

Food 

Calories 

Energy  metabolism 

N.  grm. 

Fat  grm. 

Carbohydrate 
grm. 

Total 
calories 

Per  kilo 

body  weight 

calories 

2       .       . 

_ 

_ 

_ 

_ 

969 

40-2 

3      .       . 

56-8 

— 

— 

1543 

1072 

44-8 

4      .      . 

— 

— 

— 

947 

39-9 

5      .      . 

— 

167 

— 

1536 

963 

40-9 

6      .       . 

-^ 

— 

— 

• — • 

922 

39-6 

7      .       . 

— 

— 

411 

1446 

982 

42-3 

8      .      . 

— 

• — 

— 

— 

977 

42-1 

It  will  be  seen  that  the  metabolism,  i.e.  the  caloric  output,  of  the  body 
on  administration  of  protein  increased  11 -9  per  cent.,  whereas  with  fat  the 
increase  amounted  only  to  1-2  per  cent.,  and  with  carbohydrate  to  4-7  per 
cent.  In  another  similar  experiment  the  animal  received  57-4  calories 
protein,  54*2  calories  fat,  and  57  calories  carbohydrate  respectively  per 
kilo  body  weight.  During  hunger  the  total  metabolism  per  kilo  body 
weight  amounted  to  37-5  calories ;  with  meat,  to  46  calories ;  with 
fat,  to  39-4  calories  ;  with  carbohydrates,  to  39-4  calories.  Compared 
with  the  metabohsm  during  starvation  the  rise  per  cent,  with  protein  was 
24-3,  and  with  fat  and  carbohydrates  5-1.  This  surplus  output  of  energy 
resulting  from  the  administration  of  protein  cannot  be  ascribed  to  increased 
work  thrown  on  the  digestive  organs.  There  is  no  evidence  that  this  is 
greater  in  the  case  of  proteins  than  it  would  be  with  carbohydrates  or  fats  ; 


PROTEIN  METABOLISM  765 

and  even  if  the  capacity  of  these  organs  be  strained  to  their  utmost  by 
administration  of  large  quantities  of  bones,  the  increase  in  the  carbon  dioxide 
output  which  results  is  not  so  great  as  that  following  a  large  protein  meal.  It 
seems  therefore  that  the  CHO  moiety  of  the  protein  undergoes  oxidation  more 
rapidly  than  either  dextrose  or  the  ordinary  fats  of  the  diet,  and  that,  as  we 
concluded  in  an  earUer  chapter,  the  metabolism  of  these  substances  is  really 
to  a  considerable  extent  dependent  on  the  quantity  presented  to  the  organ- 
ism rather  than  on  the  actual  needs  of  the  cells  of  the  body.  It  is  this  rise 
in  metabolism  and  respiratory  exchanges  after  protein  ingestion  which 
justifies  to  a  certain  extent  the  idea  that  the  proteins,  more  than  any  other 
food-stuff,  have  a  stimulant  action  on  metabohsm.  The  reason  why  the 
CHO  remainder  of  the  protein  molecule  is  so  prone  to  oxidation  and  does  not, 
like  an  excess  of  carbohydrates,  undergo  conversion  into  fats  in  the  body,  we 
shall  have  to  consider  in  greater  detail  in  deahng  with  the  fate  of  this  latter 
class  of  substances.  We  need,  however,  considerably  more  evidence  as  to  the 
extent  to  which  deamination  occurs  and  as  to  its  conditions  and  end-products 
before  we  can  hope  to  determine  the  cause  for  the  rapid  breakdown  of  these 
end-products  in  the  body. 

ARE  THE  AMINO-ACIDS  INTERCONVERTIBLE  i 
Although  the  animal  organism  is  apparently  capable  of  synthetising 
amino-acids  from  ammonia  and  the  corresponding  keto-  or  oxy-fatty  acid, 
it  is  unable  to  convert  one  amino-acid  into  another.  On  this  account  many 
proteins  are  inadequate  as  food  substances  since  they  do  not  contain  the 
necessary  amino-acid  groups.  Life  cannot  be  supported  on  such  bodies  as 
zein  or  gelatin,  which  are  lacking  in  the  tr}^tophane  and  tyrosine  groups. 
The  failure  in  these  cases  is  not,  as  has  been  generally  supposed,  owing  to 
an  inabiUty  to  assimilate,  i.e.  synthetise,  nitrogen  as  ammonia,  but  to  the 
fact  that  in  the  animal  the  apparatus  is  wanting  for  the  manufactm*e  of  some 
of  the  oxy-fatty  acids  and  other  radicals  which  form  the  non-nitrogenous 
part  of  the  amino-acids.  This  view  receives  confirmation  from  the  fact  that 
the  simplest  of  the  amino-fatty  acids,  namely,  glycine,  can  be  easily  manu- 
factured in  the  body,  acetic  acid  being  one  of  the  latest  stages  in  the  oxidation 
of  most  carbohydrates  and  fats.  It  has  been  shown  that  alanine  too  can 
be  easily  manufactured  by  the  body,  by  the  amination  of  the  three  carbon 
acids  or  oxy-acids  derived  from  the  breakdown  of  glucose  or  glycogen. 

THE  EXCRETION  OF  AMMONIA 
A  large  proportion  of  the  urea  appearing  in  the  urine  after  a  protein 
meal  is  exogenous  and  is  derived  by  a  rapid  separation  of  ammonia  from  the 
proteins  or  their  disintegration  products  ahnost  immediately  after  their 
absorption.  The  greater  part  of  the  ammonia  is  converted  in  the  hver  into 
urea,  which  is  excreted  by  the  kidney.  A  certain  small  proportion  of  the 
nitrogen  in  the  urine  is  generally  turned  out  in  the  form  of  ammonia.  This 
proportion  is  not  increased  by  the  administration  of  ammonium  carbonate. 
If  ammonium  chloride  be  given  to  a  starving  rabbit  it  appears  in  the  urine 


766  PHYSIOLOaY 

"imclianged,  and  so  increases  the  proportion  of  ammonia  in  this  fluid.  If, 
however,  the  ammonimn  chloride  be  administered  at  the  same  time  as  the 
animal  is  receiving  its  ordinary  vegetable  diet  there  is  no  increase  in  the 
ammonia  in  the  urine,  the  whole  of  the  ammonium  chloride  being  converted 
into  urea.  The  factor  which  determines  the  proportion  of  ammonia  in  the 
urine  is  the  relative  proportion  of  acids  and  bases  which  have  to  be  ehminated 
from  the  body.  The  normal  reaction  of  urine,  though  acid  as  regards  certain 
indicators,  can  be  regarded  as  neutral,  since  it  contains  no  free  hydrogen  ions, 
the  '  acidity  '  being  due  to  the  presence  of  such  substances  in  solution  as  acid 
sodium  phosphate.  If  the  fixed  alkaUes  in  the  food  are  sufficient  to  combine 
with  the  whole  of  the  acids  excreted  from  the  body,  then  the  ammonia  will  be 
completely  converted  into  urea  and  ehminated  as  such.  If,  however,  a  dose 
of  mineral  acid  be  administered  to  an  animal,  this  must  be  excreted  in  com- 
bination with  a  base.  If  the  fixed  alkahes  available  do  not  suffice  for  this 
purpose,  the  neutrahsation  of  the  acid  is  efiected  by  couphng  with  ammonia. 
The  ammonia  of  the  urine  is  therefore  an  index  to  the  amount  of  acids  which 
are  excreted.  These  acids  may  be  introduced  directly  with  the  food,  as  when 
mineral  acids  are  administered  by  the  mouth,  or  may  be  the  product  of 
abnormal  metabohc  processes  occurring  in  the  body.  Thus  under  certain 
circumstances,  e.g.  in  complete  carbohydrate  starvation,  there  is  a  failure 
in  the  last  stages  of  the  oxidation  of  fats,  and  oxy- fatty  acids,  viz.  oxybutyric 
acid  and  aceto-acetic  acid,  are  produced  in  the  body  in  large  quantities,  but 
cannot  undergo  further  disintegration.  The  alkalescence  (electrical  neu- 
trahty)  of  the  fluid  media  of  the  body  is  a  necessary  condition  for  the  con- 
tinuance of  the  Hfe  of  the  cells  and  especially  of  the  normal  processes  of 
oxidation.  It  is  therefore  essential  for  the  preservation  of  Hfe  that  the 
acids  thus  formed  and  accumulating  as  a  result  of  the  impaired  oxidative 
processes  should  be  neutralised,  carried  to  the  kidneys,  and  excreted  by  them 
in  combination  with  some  base.  When  these  acids  are  produced  in  large 
quantities  the  alkahes  of  the  food  and  of  the  tissues  do  not  suffice  for  their 
neutrahsation.  Ammonia,  which  is  a  constant  intermediate  stage  in  the 
production  of  urea,  is  then  utihsed  for  this  purpose  and  the  acids  appear  in  the 
urine  together  with  the  corresponding  amount  of  ammonia.  The  ammonia 
therefore  of  the  urine  gives  valuable  information,  not  as  to  the  total  nitro- 
genous exchanges  of  the  body,  but  as  to  the  formation  of  acids  in  abnormal 
quantities  during  the  processes  of  metabohsm. 

There  is  one  other  method  in  which  urea  may  be  formed  by  a  rapid 
alteration  of  the  proteins  taken  in  with  the  food.  Nearly  all  the  ordinary 
proteins  contain  arginine  as  an  integral  part  of  their  molecule.  This  sub- 
stance can  be  regarded  as  formed  by  a  couphng  of  guanidine  with  amino- 
valerianic  acid  and  as  analogous  to  the  most  prominent  extractive  of  muscle, 
namely,  creatine,  which  is  methyl  guanidine  acetic  acid.  On  heating  either 
of  these  substances  with  baryta  water  it  undergoes  hydrolysis  and  is  decom- 
posed with  the  formation  of  urea  and,  in  the  case  of  arginine,  a-^-diamino- 
valerianic  acid ;  in  the  case  of  creatine,  methyl  amino-acetic  acid  or  sarco- 
sine.     It  has  been  shown  by  Dakin  and  Kossel  that  the  same  change  may  be 


PROTEIN  METABOLISM  767 

efiected  under  the  agency  of  a  ferment,  arginase,  which  is  contained  in 
extracts  of  the  intestinal  wall  or  of  the  hver.  We  have  every  reason  to 
beheve  therefore  that  a  certain  small  proportion  of  the  urea  which  appears 
in  the  urine  after  the  ingestion  of  protein  is  due  to  this  hydi'olytic  sphtting 
of  the  arginine  contained  in  the  protein  molecule.  The  other  moiety  of  the 
arginine,  namely,  the  diamino-valerianic  acid,  probably  undergoes  the  same 
changes  as  the  other  amino-acids,  such  proportion  of  it  as  is  not  required  for 
the  building  up  of  the  tissues  of  the  body  being  deaminised  and  giving  rise  to 
urea  and  some  CHO  group  in  the  manner  already  discussed. 

THE  ENDOGENOUS  OR  TISSUE  METABOLISM  OF  PROTEINS 
On  comparing  the  output  of  the  various  nitrogenous  excreta  given  in 
Fohn's  Tables  quoted  above  (p.  757),  we  see  that  on  a  low  protein  diet,  when 
the  exogenous  or  energy  metabohsm  of  this  food-stuff  is  reduced  to  a  mini- 
mum, the  only  substance  which  does  not  undergo  simultaneous  diminution 
is  the  creatinine.  Whereas  on  an  ordinary  diet  free  from  meat  it  only  ac- 
counts for  about  3  per  cent,  of  the  total  nitrogen  output,  on  the  low  diet  it 
contains  as  much  as  17  per  cent.  The  conclusion  at  once  suggests  itself  that 
creatinine,  more  than  all  the  other  constituents  of  the  mine,  must  be  regarded 
as  an  index  of  the  tissue  metabohsm  of  protein.  Let  us  see  what  facts  can 
be  adduced  in  favour  of  this  view. 
Creatinine  has  the  formula  : 

NH  =  C.N(CH3).CH2 

I  I 

NH CO 

and  may  be  regarded  as  derived  by  a  process  of  dehydration  from  creatine 

(methyl  guanidine  acetic  acid). 

NH  =C.N(CH3).CHoC00H 

I 
NHg 

It  may  be  formed  from  this  latter  substance  by  boihng  for  three  hours  with 
strong  hydrochloric  acid.  Creatine  has  long  been  known  as  the  most 
abimdant  nitrogenous  extractive  in  the  body.  It  exists  in  relatively  large 
quantities  in  muscle,  and  in  meat  extracts,  such  as  Liebig's,  it  occurs  to  the 
extent  of  10  or  12  per  cent.  It  has  been  calculated  that  the  body  of  a  man 
at  any  time  contains  about  90  grm.  of  this  substance.  On  boihng  creatine 
with  baryta  water  it  undergoes  hydrolysis  A\ith  the  formation  of  urea  and 
sarcosine  or  methyl  glycine. 

CHa  CH3 

NH         I  NH,  I 

^C.N.CHoCOOH  +  HoO  =  >C0  +  HN.CH2COOH 

NHg/  NHg/ 

Creatine  Urea  Methyl  glyci  no 

Owing  to  the  ease  with  which  this  formation  of  urea  from  creatine  may  be 
brought  about  outside  the  body,  it  was  natural  that  this  substance  should 
be  regarded  as  an  important  precm'sor  of  the  urea  in  the  urine.     The  view 


768  PHYSIOLOGY 

was  held  till  recently,  however,  on  the  ground  of  experiments  by  Voit,  that 
creatine  administered  in  the  food  appeared  in  its  entirety  as  creatinine  in  the 
urine,  so  that  if  creatine  were  hberated  from  the  muscles  in  their  normal 
processes  of  metabohsm  it  would  pass  to  the  kidneys  and  be  excreted  as 
creatinine  without  undergoing  further  decomposition.  On  this  account  too 
the  creatinine  in  the  urine  was  regarded  as  derived  almost  exclusively  from 
the  creatine  taken  in  with  the  food.  The  analyses  given  in  Fohn's  Tables 
show  that  in  one  respect  at  any  rate  this  view  was  incorrect.  Creatinine  is 
excreted  in  considerable  quantities  even  when  the  man  is  on  a  creatine-free 
diet,  or  even  when  his  food  is  almost  free  from  protein.  It  has  been  found 
moreover  by  Fohn  that  creatine  administered  by  the  mouth  may  disappear 
in  the  body.  This  is  especially  the  case  if  the  animal  or  man  is  on  an  in- 
sufficient protein  diet,  but  there  is  no  evidence  of  a  corresponding  increase 
in  urea  formation.  If  a  larger  amount  be  given  creatine  appears  as  such  in 
the  urine.  In  most  cases  a  certain  minute  proportion  escapes  and  causes  an 
increase  in  the  quantity  of  creatinine.  Under  abnormal  circumstances,  e.g. 
during  illness,  when  the  physiological  activities  of  the  body  are  lowered,  a 
portion  of  the  creatine  may  be  found  in  the  urine  in  an  unchanged  con- 
dition. If  creatinine  is  to  be  regarded  in  any  way  as  the  index  of  tissue 
metabohsm  its  amount  ought  to  vary  with  the  extent  of  this  metabohsm. 
Thus  it  should  be  increased  when  there  is  an  exaggeration  of  the  disintegrative 
processes  in  the  tissues,  and  should  be  diminished  when  the  nutritive  changes 
in  these  tissues,  especially  in  the  muscles,  are  reduced  to  a  minimum.  The 
end-products  of  tissue  metabohsm  therefore  should  be  increased  under  the 
following  conditions  : 

(1)  Increased  motor  activity  involving  increased  wear  and  tear  of  the 
muscular  tissues. 

(2)  In  fevers,  especially  in  those  where  there  is  severe  toxsemia  and  rapid 
wasting  of  the  muscles  of  the  body. 

On  the  other  hand,  it  should  be  diminished  where  the  activity  of  the 
muscular  tissue  is  reduced  to  a  minimum,  as  under  the  influence  of  sleep  or 
soporifics,  or  where  the  bulk  of  the  muscular  tissue  is  reduced  as  well  as  its 
activity,  as  in  cases  of  widespread  muscular  atrophy  and  paralysis. 

The  excretion  of  creatinine  has  been  investigated  under  these  various 
conditions  by  Van  Hoogenhuyze  and  Verploegh,  and  their  results  fully  bear 
out  the  view  expressed  above  as  to  the  intimate  relation  of  creatinine  with 
the  tissue  metabohsm  of  protein. 

L;  During  protein  starvation  the  uric  acid  output,  though  diminished,  does 
not  show  a  change  which  is  at  all  proportional  to  that  shown  by  the  urea. 
This  substance  also  might  therefore  represent  an  end-product  of  tissue 
metabohsm.  Since,  however,  uric  acid  is  an  outcome  of  the  metabohsm  of 
a  special  group  of  bodies,  the  nucleins  and  purine  bases,  we  shall  have  to 
devote  a  complete  section  to  its  consideration. 

Although  the  urea  is  diminished  in  protein  starvation,  it  still  remains  the 
most  abimdant  nitrogenous  constituent  of  the  urine.  We  are  therefore  not 
justified  in  excluding  this  substance  from  the  products  of  tissue  metabohsm. 


PROTEIN  METABOLISM  ^6D 

If  any  creatine  undergoes  complete  oxidation  in  the  body  during  protein 
starvation  a  certain  proportion  of  the  urea  might  be  derived  in  this  way. 
We  shall  see  later  that  uric  acid  may  possibly  also  undergo  further  oxidation 
with  the  formation  of  urea.  Even  during  complete  protein  starvation  some 
of  the  urea  which  is  turned  out  may  be  the  expression  of  a  utilisation  of  pro- 
tein through  deamination  for  the  energy  needs  of  the  body.  The  active  cells 
are  bathed  everywhere  with  a  tissue  fluid  in  which  prciceins  form  a  prepon- 
derating constituent,  and  it  is  possible  that,  even  in  the  times  of  greatest 
protein  need,  these  cells  utilise  the  proteins  of  their  surrounding  medium, 
though  in  a  reduced  degree,  for  the  production  of  energy.  In  this  case  the 
active  cell  would  initiate  the  utilisation  by  throwing  off  that  part  of  the 
protein  molecule,  namely,  NHg,  which  is  useless  to  the  cell  as  a  source  of 
energy,  so  that  deamination  would  be  carried  out  in  the  working  tissues,  and 
not,  as  in  the  rapid  formation  of  urea  after  a  heavy  meal,  in  the  liver. 

SULPHUR 
Sulphur  occurs  in  the  urine  in  three  forms,  namely,  as  ordinarv  inorganic 
sulphates,  as  ethereal  sulphates  (indoxyl-  and  skatoxyl-sulphates),  and  in  an 
unoxidised  condition  often  termed  neutral  sulphur.  There  is  no  doubt  that 
part  of  the  latter  consists  of  cystine,  part  of  sulphocyanates,  and  in  some 
animals  mercaptan  compounds.  The  excretion  of  the  inorganic  sulphates 
rises  fari  passu  with  that  of  the  urea,  so  that  very  soon  after  the  throwing 
off  of  the  NH2  group  there  must  be  also  a  removal  and  oxidation  of  the  greater 
part  of  the  sulphur  contained  in  the  cystine  group  of  the  ^^rotein  molecule. 
So  far  as  regards  the  metabolism  of  the  body  as  a  whole,  the  ethereal  sulphates 
may  be  classed  with  the  inorganic  sulphates.  They  arc  excreted  in  varying 
quantity  accordiiig  to  the  extent  of  the  decomposition  processes  which  are 
occurring  in  the  intestine.  Under  the  influence  of  these  processes  the  trypto- 
phane, produced  in  the  pancreatic  digestion  of  proteins,  is  converted  into 
indol  and  skatol.  These  two  substances  after  absorption  are  deprived  of 
their  poisonous  qualities  by  oxidation  and  conjugation  with  sulphuric  acid 
to  form  the  indoxyl-  and  skatoxyl-sulphates  of  the  urine,  both  of  which  are 
innocuous.  If  the  processes  of  putrefaction  are  increased,  as  in  intestinal 
obstruction,  the  relative  amount  of  sulphate  appearing  in  the  conjugated 
form  is  also  increased.  On  administration  of  phenol  a  large  proportion  of 
the  sulphate  appears  in  the  urine  conjugated  with  phenol  or  with  products  of 
its  oxidation.  If  the  normal  putrefactive  processes  which  go  on  in  the 
intestine  are  abolished  by  the  administration  of  intestinal  antisejitics  such 
as  naphthalene  or  calomel,  the  ethereal  sulphates  practically  disappear 
from  the  urine.  We  cannot  therefore  regard  the  absence  or  diminution  of 
the  ethereal  sulphates  during  protein  starvation  as  throwing  any  light  on  the 
endogenous  protein  metabolism.  On  the  other  hand,  the  fact  that  the 
neutral  sulphur  undergoes  no  decrease  suggests  that  this  part  of  the  sulphur 
output  of  the  organism  may  be  connected  with  tissue  metabolism.  Further 
observations  on  the  output  of  neutral  sulphur  during  fever  or  wasting  diseases 
are  necessary  before  a  definite  conclusion  can  be  arrived  at  on  this  point. 


770  PHYSIOLOGY 

THE  FATE  OF  THE  AROMATIC  AND  OTHER  CYCLIC 
GROUPS  IN  THE  PROTEIN  MOLECULE 

A  t5rpical  protein  such  as  can  be  utilised  as  a  complete  food-stuff  con- 
tains, in  addition  to  the  amino-acids  of  the  fatty  series,  a  number  of  other 
nitrogenous  derivatives  of  cycHc  compomids,  including  benzene,  indol,  pjnrrol, 
and  iminazol.  Substances  such  as  gelatin,  from  which  some  of  these 
groupings  are  absent,  cannot,  as  we  have  seen,  entirely  replace  protein  in  the 
food.  So  far  we  are  acquainted  with  three  compounds  of  the  aromatic 
series  among  the  products  of  disintegration  of  the  protein  molecule.  These 
are  tyrosine,  phenylalanine,  and  tryptophane.  Since  these  substances 
are  also  contained  in  the  protein  constituents  of  the  tissues  we  may  assume 
that,  after  they  have  been  set  free  by  the  digestive  hydrolysis  of  proteins,  they 
are  absorbed  and  built  up  again  with  the  other  amino-acids  in  appropriate 
groupings.  Like  these  they  are  susceptible  of  complete  oxidation  in  the 
body,  so  that  they  can  contribute  to  the  supply  of  energy.  Any  one  of  these 
substances,  administered  with  the  food  or  subcutaneously,  is  entirely  de- 
stroyed, with  the  production  of  urea,  carbon  dioxide,  and  water.  In  this 
respect  they  present  a  marked  contrast  to  abnost  all  other  compounds  of 
the  aromatic  series.  In  these  we  find  that  the  benzene  ring  is  extremely 
stable,  so  that,  although  changes  may  occur  in  its  side-chains,  the  benzene 
ring  itself  appears  intact  in  the  urine,  and  is  not  broken  up  in  the  body. 
Thus  benzoic  acid,  benzylalcohol,  and  phenyl  propionic  acid,  when 
administered,  are  passed  in  the  urine  as  hippuric  acid  (benzoyl  glycine). 
Indol  and  skatol,  which  are  closely  alhed  to  tryptophane,  undergo  oxida- 
tion in  the  body  without  further  modification  and  appear  in  the  urine  as 
conjugated  aromatic  sulphates. 

Some  light  is  thrown  on  the  conditions  of  breakdown  of  these  aromatic 
bodies  by  the  study  of  a  rare  disorder  in  metaboHsm,  which  may  occur  in 
certain  famiUes  and  is  known  as  alcaptonuria.  In  this  condition,  which  is 
congenital  and  lasts  throughout  "hfe,  the  urine  darkens  considerably  when 
made  alkahne  and  exposed  to  the  air.  It  has  the  power  of  reducing  Fehhng's 
solution,  so  that  the  presence  of  sugar  might  be  suspected.  On  analysis 
the  pecuharities  of  the  urine  are  found  to  be  due  to  the  presence  in  it  of  a 
substance  known  as  homogentisic  acid.     This  is  dioxyphenyl  acetic  acid. 

HO  /\ 

CH2COOH 

The  amount  of  this  substance  in  the  urine  bears  a  constant  ratio  to  the 
nitrogen  excreted.  It  does  not  disappear  during  starvation,  and  is  much 
increased  on  a  large  protein  diet.  It  must  therefore  be  derived  from  the 
disintegration  of  proteins  both  exogenous  and  endogenous.  If  tyrosine  or 
phenylalanine  be  administered  to  patients  affected  with  this  disorder,  both 
substances  are  quantitatively  converted  into  homogentisic  acid.     The  ratio 


PROTEIN  METABOLISM  771 

of  this  acid  to  the  total  nitrogen  indicates  that  the  wliolc  of  the  tyrosine  and 
phenylalanine  of  the  protein  molecule,  whether  set  free  in  the  alimentary 
canal  or  in  the  tissue  metabohsm,  is  converted  into  homogentisic  acid.  It 
is  not  possible  to  conceive  of  the  direct  conversion  of 


tyrosine 


°«  HO 

into  homogentisic  acid 


OH 
CHoCOOH 


CH2.CHNH2.COOH 

The  tyrosine  must  first  be  reduced  to  phenylalanine 


CH0.CHNH..COOH 


and  then  this  substance  must  undergo  oxidation  into  homogentisic  acid. 
Since  phenyl  lactic  acid  and  phenyl  pyruvic  acid,  but  not  phenyl  acetic 
acid,  are  also  converted  in  alcaptonuric  patients  to  homogentisic  acid,  it 
has  been  suggested  that  these  two  substances  form  stages  in  the  conversion  of 
phenylalanine  into  homogentisic  acid.     Thus 


OH 

CH,CHOH.COOH  CHgCO.COOH  CH,COOH 

Phenyl  lactic  Phenyl  pyruvic  Homogentisic 

It  is  further  thought  that  under  normal  circumstances  the  phenyl  deriva- 
tives, tyrosine  and  phenylalanine,  are  oxidised  to  homogentisic  acid  as  in  the 
alcaptonuric  patient.  In  the  normal  individual,  however,  the  introduction  of 
two  hydroxyl  groups  into  the  benzene  ring  leads  to  some  process,  perhaps 
of  a  ferment  character,  which  breaks  up  the  ring.  This  ferment  is  absent 
in  the  alcaptonuric,  so  that  the  transformation  of  the  phenyl  derivatives 
stops  short  at  the  stage  of  homogentisic  acid  (Garrod).  The  eminently 
specific  character  of  this  process  is  shown  by  the  fact  that  although  these 
various  substances  undergo  complete  oxidation  in  the  body,  a  shght  modifi- 
cation in  the  chain  of  the  processes  renders  the  change  impossible.  Thus 
if  the  side  group  in  phenyl  lactic  or  phenyl  pyi-uvic  acid  be  converted  to 
acetic  acid  before  the  introduction  of  the  two  OH  groups  into  the  phenyl 
ring,  the  phenyl  acetic  acid  thus  produced  is  incapable  of  undergoing  further 
oxidation.  TjTosine  in  the  intestine  undergoes  dcamination  to  form 
ox}^henyl  propionic  acid  and  oxyphenyl  acetic  acid.  These  cannot  be 
further  oxidised,  but  appear  in  the  urine  as  such  or,  after  conversion  into 
kresol  or  phenol,  as  sulphuric  acid  esters. 

Somewhat  similar  conditions  apply  to  the  oxidation  of  tr^'ptophane. 


772  mY^IOLOGY 

This  body  is  an  indoi  derivative  and  consists  of  a  benzene  ring  and  a  pyrrol 
ring  having  two  of  their  carbon  atoms  in  common.     Its  formula  is 

HC  C C.CH2CHNH2.COOH 

I  II  II 

HC  C  CH 


i.e.  it  is  indol  amino-propionic  acid.  It  undergoes,  like  tyrosine,  complete 
oxidation  in  the  body.  On  the  other  hand,  a  very  slight  alteration  in  the 
molecule  renders  it  incapable  of  this  change.  Thus  the  tryptophane  set 
free  by  the  tryptic  digestion  of  proteins  under  the  influence  of  the  putre- 
factive bacteria  of  the  intestine  may  undergo  deamination  and  reduction 
with  the  production  of  indol  propionic  acid,  and  this  by  oxidation  may  be 
converted  to  indol  acetic  acid.  The  latter  substance  by  decarboxylation  may 
be  converted  into  skatol,  or  by  oxidation  nearer  the  chain  and  further  loss  of 
carbon  dioxide  into  indol.  Of  these  products  of  bacterial  change,  indol 
acetic  acid  may  be  found  in  the  urine,  and  indol  and  skatol  are  oxidised  to 
the  corresponding  phenols  and  pass  into  the  urine  conjugated  either  with 
sulphuric  acid  or  with  glycuronic  acid.  Apart,  however,  from  these  putre- 
factive changes  due  to  bacteria,  no  indol  derivatives  pass  into  the  urine. 
The  amount  of  the  indol  and  skatol  esters  serves  therefore  merely  as  an  index 
of  bacterial  decomposition  in  the  alimentary  canal,  and  gives  us  no  clue  to 
the  total  tryptophane  metabolism  of  the  body.  If  putrefaction  be  prevented 
by  the  administration  of  calomel  or  other  intestinal  antiseptic  these  esters 
may  entirely  disappear  from  the  urine.  On  the  other  hand,  the  partial 
obstruction  to  the  onward  passage  of  food,  caused  by  dividing  the  small 
intestine  in  two  places  a  few  inches  apart  and  replacing  the  intervening 
length  of  intestine  the  wrong  way  round,  causes  the  indican  excretion  to  be 
increased  twenty  or  thirty  fold.  Subcutaneous  injection  of  tryptophane  in 
rabbits  does  not  increase  the  indoxyl  and  skatoxyl  sulphates  (urinary 
indican)  in  the  urine,  whereas  a  considerable  increase  is  brought  about  by 
subcutaneous  injection  of  indol. 

The  pyrrol  ring  which  occurs  in  proteins  as  proline  and  oxyproline  {i.e. 
pyrrohdine  carboxylic  acid  and  oxypyrrolidine  carboxylic  acid)  appears  to 
undergo  complete  disintegration  in  the  body.  The  steps  in  this  conversion 
are  unknown,  though  it  is  possible  that  the  ring  may  be  unlinked  so  as  to 
produce  from  the  pyrrol  ring  amino- valerianic  acid,  which  would  then  under- 
go the  process  of  deamination  with  which  we  are  already  famihar.  This  ring 
is  of  interest  since  it  appears  to  take  an  important  part  in  the  building  up  of 
the  molecule  of  hsematin,  the  essential  prosthetic  group  of  the  haemoglobin 
molecule. 

Another  ring  grouping,  iminazol,  occurs  in  histidine,  which  is  iminazol 
c(-amino-propionic  acid.  This  too  undergoes  complete  oxidation  in  the 
body.  It  is  important  to  bear  in  mind  that  this  ring  may  be  produced 
synthetically  by  very  simple  means,  i.e.  by  the  action  of  zinc  oxide  and 


PROTEIN  METABOLISM  773 

ammonia  on  glucose,  which  results  in  a  rich  yield  of  methyl  iniinazol  {v. 
p.  117).  The  same  grouping  is  found  in  creatinine,  as  is  seen  by  comparing 
the  formula)  : 

H2C-N<r  HC-X< 

I       /^-^^  !l       >0H 

OC-NH  HC-N^ 

Creatinino  IMcthyl-iminaxoI 

and  it  is  possible  that  this  may  furnish  a  clue  to  the  mode  of  formation  of 
creatinine  in  muscle.  Creatine  has  generally  been  regarded  as  the  primary 
product  of  muscular  metabolism,  but  it  is  possible  that  the  ring-grouping  is 
the  original  one  and  that  creatine  is  produced  by  hydrolysis  occurring  in  this 
ring. 

The  iniinazol  group  is  at  present  chiefly  interesting  in  that  it  contributes 
to  the  formation  of  the  complex  ring  compounds  known  as  the  purines.  Since 
the  purine  metabolism  is  closely  connected  with  the  question  of  the  origin 
of  uric  acid  we  may  consider  these  questions  together. 


SECTION   II 
NUCLEIN  OR  PURINE  METABOLISM 

In  an  undifferentiated  cell  the  proteins,  as  such,  form  but  a  small  part,  the 
mass  of  the  cell  being  composed  of  conjugated  proteins.  The  nucleo-proteins 
are  especially  abundant  constituents  of  nuclei,  and  therefore  occur  to  a 
greater  or  less  extent  in  all  the  ordinary  animal  foods,  eggs  and  milk  excepted. 
Just  as  the  metabolism  of  proteins  is  the  metabohsm  of  the  amino-acids,  so 
the  metabolism  of  the  nucleo-proteins  and  nucleins  is  essentially  comprised 
in  the  history  of  its  main  constituents,  i.e.  the  purines. 

The  nucleo-proteins  themselves  are  bodies  of  very  varjdng  composition. 
If  any  cellular  tissue  such  as  thymus  or  liver  be  extracted  with  water  or  salt 
solution,  a  fluid  is  obtained  from  which  a  precipitate  can  be  thrown  down 
by  the  addition  of  acid.  This  precipitate  as  a  rule  is  soluble  in  excess  of 
acid  or  in  alkahes.  If  subjected  to  gastric  digestion  it  undergoes  solution, 
leaving  behind  a  residue  of  nuclein  which  is  rich  in  phosphorus.  The  amount 
of  this  residue  varies  with  the  strength  of  the  artificial  gastric  juice  employed, 
so  that  the  method  cannot  be  looked  upon  as  in  any  way  quantitative, 
and  the  question  arises  whether  the  original  nucleo-protein  is  to  be  regarded 
as  an  association  or  a  combination  of  nuclein  with  ordinary  protein.  The 
most  convenient  source  for  the  preparation  of  nucleins  is  the  heads  of  fish 
spermatozoa.  All  nucleins  are  associations  or  compounds  of  nucleic  acids 
with  proteins  belonging  to  the  class  of  protamines  or  histones.  The  nucleins 
of  fish  spermatozoa  contain  protamine  as  one  of  their  constituents.  On 
separating  off  the  protamine,  nucleic  acids  can  be  isolated.  These  acids 
have  been  named  either  according  to  their  source  or  according  to  the  purine 
base  which  is  their  most  prominent  constituent.  Only  from  inosinic  acid,  the 
nucleic  acid  of  muscle,  has  it  been  found  possible  to  prepare  crystalline  deriva- 
tives, so  that  in  all  other  cases  it  is  difficult  to  decide  whether  we  are  deahng 
with  chemical  individuals  or  with  mixtures. 

On  hydrolysing  any  of  the  nucleic  acids  by  heating  with  strong  mineral 
acid,  they  are  broken  down  into  a  series  of  bodies  belonging  to  the  following 
four  groups  :  (1)  phosphoric  acid,  (2)  purine  bases,  (3)  pyrimidine  bases, 
(4)  a  carbohydrate.  The  chief  purine  bases  obtained  from  the  hydrolysis 
of  nucleic  acid  are  guanine  and  adenine. 

Hypoxanthine  and  xanthine  are  often  obtained  as  products  of  decom- 
position of  nucleic  acid,  but  are  generally  formed  by  the  deamination  and 
oxidation  of  guanine  and  adenine.    Fischer  has  shown  that  all  these  bodies 

774 


NUCLEIN  OR  PURINE  METABOLISM  775 

are  derivatives  of  a  base  purine.  They  contain  a  central  chain  of  three 
carbon  atoms  to  which  is  attached  on  each  side  a  urea  group,  so  that  they 
may  be  regarded  as  diureides.     Purine  itself  has  the  formula 

N=CH 

I  I 

HC      C~NH 

II  II       \CH 

N— C— nX 

Purine 

The  relation  of  the  purine  bases  obtained  from  disintegration  of  nucleic  acid 

to  purine  itself  has  been  given  on  p.  103.     From  these  formulae  we  see  that 

adenine  and  hypoxanthine  are  related  to   one  another,   adenine   being 

6-aminopurine,   while   hypoxanthine  is   6-oxypurine.     In   the   same   way 

guanine  and  xanthine   are  related,   guanine  being  2-amino-6-oxypurine, 

while  xanthine  is  2- 6-dioxypurine.     The  investigation  of  the  relationships  of 

these  bases  was  of  interest  to  physiologists  since  it  brought  to  light  the  close 

relation  which  they  have  to  uric  acid,  a  substance  which  has  been  known  as 

a  constituent  of  urine  and  urinary  calculi  for  a  long  time,  having  been 

discovered  in  1776  by  Scheele.     Uric  acid  is  2-6-8-trioxypurine  and  has 

the  formula 

HN— CO 

I      I 
CO  C— NH. 

I     II        >o 

HN— C— NH/ 
Uric  acid  =  2-6-8-trioxypurine 

In  uric  acid  the  two  urea  groups  are  attached  to  a  central  3-carbon 
chain,  and  it  is  interesting  to  note  that  one  of  the  first  syntheses  of  uric 
acid,  namely,  that  by  Horbaczewski,  was  accomplished  by  melting  together 
trichlorlactamide  and  urea  in  a  sealed  tube. 

Belonging  to  the  same  group  of  purines  are  the  two  bases  which  form  the  essential 
constituents  of  tea,  coffee,  and  cocoa.  In  tea  and  cofEee  is  found  caffeine,  which  is 
l-3-7-trimethyl-2-6-dioxypurine,  and  in  cocoa  occurs  the  closely  allied  theobromine, 
which  is  3-7-diinethyl-2-6-dioxypuriue.     Caffeine  is  thus  methyltheobromine. 

CH3.N— CO  HN— CO 

I       I          /CH3  [       I           /CH3 

CO  C— N(  CO  C— N< 

I      II        >CH  I      II         >CH 

CH3.N— C— N^  CH3N— C— N^ 

Caffeine  =  1-3-7-trimethyl-  Theobromine  =  3-7-dimethyl- 

2-6-dioxypurine  2-6-dioxypurine 

The  pyrimidine  bases  which  are  also  obtained  from  the  hydrolysis  of 
nucleic  acid  are  derived  from  a  pyi'imidine  nucleus  which  is,  so  to  speak, 

half  a  purine  nucleus,  consisting  of  a  C.    ^  chain  joined  to  a  3-carbon 


770  PHYSIOLOGY 

chain.     Three  pyrimidine  bases  have  been  isolated  from  the  decomposition 
products  of  nuclein,  namely,  thymine,  cytosine,  and  uracil. 

NH— CO  XH  — CO  N   =   C.XHa 

CO       CH  CO      C.CH3  CO       CH 

I  II  I  II  I  II 

NH  — CH  NH  — CH  NH  — CH 

Uracil  2-6-diosy-  Thymine  5-niethyl-  Cytosine  6-amino- 

pyrimidine  uracil  2-oxyi3yrimidine 

Cjiiosine  is  easily  converted  by  oxidation  into  uracil. 

After  separation  of  the  purine  and  pyrimidine  bases  and  phosphoric  acid 

a  substance  is  left  over  which  gives  the  reactions  of  a  carbohydrate, 

TMs  carbohjTlrate  differs  in  different  nucleic  acids.  In  plant  nucleic  acid,  as  "well 
as  in  guaiwlic  acid  from  the  pancreas  and  inosinic  acid  from  muscle,  the  carbohydrate 
is  a  pentose,  d-ribose.  Most  nucleic  acids  of  animal  origin  yield  Isevulinic  acid  en 
hydrolysis  and  must  therefore  contain  a  hexose.  The  researches  of  Levene,  Jones, 
and  others  have  shown  that  the  nucleic  acids  vary  in  complexity  and  consist  of  one 
or  more  so-called  nucleotides  linked  together.  The  simplest  nucleic  acids  are  mono- 
nucleotides. Examples  of  these  are  inosinic  and  guanylic  acid.  Each  consists  of 
phosphoric  acid  and  a  pm'ine  or  pyrimidine  base  linked  together  by  carbohydrate. 
Upon  hydrolysis  with  boiling  mineral  acid  they  are  decomposed  into  their  three 
constituents : 

HO. 

0=P0  -  C5H8O3  -  C5H4X5O  +  2H2O  =  H3PO4  +  C5H10O5  +  CsHgNsO 
^guanylic  acid  '  d-ribose         guanine 

HO. 

0=P0  -  C5H8O3  -  C5H3N4O  +  H2O  =  H3PO4  -f  CgHioOs  +  C5H4N4O 
/  inosinic  acid  d-ribose        hypoxanthine 

When  submitted  to  neutral  hydrolysis  at  175°  C  under  pressure,  decomposition 
occurs  in  a  different  way,  the  phosphoric  acid  is  split  off  and  a  glucoside-like  body 
is  left  which  is  called  a  nucleoside.  Thus  guanylic  acid  yields  guanosine,  inosinic  acid 
yields  a  body  known  as  inosine  or  hypoxanthosine.  Under  the  action  of  ferments, 
known  as  nucleases,  which  may  occur  in  animal  tissues,  the  mono-nucleotides  may 
be  split  in  one  of  two  ways.  The  phosphonuclease  removes  the  phosphoric  acid,  leav- 
ing a  compound  of  purine  and  carbohydrate,  while  the  pm'ine  nuclease  sets  free  the 
])urine  base  and  leaves  a  hexose-  or  pentose-phosphoric  acid.  Of  the  more  complex 
nucleic  acids  which  occur  in  cell  nuclei,  yeast  nucleic  acid  has  been  the  most  carefully 
studied.  According  to  Levene  this  nucleic  acid  is  a  tetranucleotide,  having  a  structure 
represented  by  tlie  following  formula  : 

HO. 

O  =  PO.C5H8O3.C5H4N5O 

/  guanine  group 

\ 

0=      PO.C5H803.C5H,N5 

adenine  group 


0/ 


O  =  PO .  C'sHgOs .  C4H3X2O., 
y"  uracil  group 

0=   PO.C5HSO3.C4H4N3O 

/  cytosine  group 


NUCLEIN  OR  PURINE  METABOLISM  777 

If  this  is  subjected  to  neutral  hydrolysis,  it  loses  the  whole  of  its  phosphoric  acid  and 
sets  free  four  nucleosides,  viz.  :  guauosine,  adenosine,  uridine,  and  cytidine. 

FORMATION  OF  NUCLEINS  IN  THE   BODY 

In  the  case  of  the  proteins  we  saw  reason  to  beheve  that  in  the  higher 
animals,  at  any  rate,  there  was  no  power  of  converting  one  amino-acid  into 
another  (with  the  exception  of  the  lowest  member  of  the  series,  namely, 
glycine),  and  that  on  this  accomit  the  food  had  to  contain  representatives 
of  every  amino-acid  (or  perhaps  of  the  corresponding  oxy-fatty  acid) 
necessary  to  the  building  up  of  the  tissue  proteins.  The  nucleins,  on  the 
other  hand,  can  certainly  be  synthesised  by  the  animal.  This  is  shown  by 
the  fact  that  the  hen's  egg  before  incubation  contains  practically  no  nuclein 
or  purine  bases.  During  incubation  tissues  are  formed,  and  there  is  a 
rapid  increase  in  the  number  of  nuclei,  so  that  the  chick  just  before  it  is 
hatched  contains  a  considerable  amount  of  nuclein  from  which  purine  bases 
can  be  extracted.  This  nuclein  must  have  been  formed  by  a  synthesis 
from  the  phospho-proteins  and  phosphatides  (phosphorised  fats)  which  form 
so  prominent  a  constituent  of  the  egg- yolk,  and  in  the  same  way  the  purines 
must  have  been  formed  by  a  process  of  synthesis.  This  synthesis  may 
occur  by  a  conjugation  of  two  urea  molecules  with  the  3-carbon  chain 
which  is  so  prominent  a  feature  in  the  proximate  principles  of  the  body 
{e.g.  in  lactic  acid,  alanine,  and  all  the  compoimd  amino-acids  of  which 
alanine  is  a  constituent).  Methyliminazol,  representing  one-half  of  the 
purine  ring,  can  be  formed  simply  by  allowing  ammonia  and  glucose  to 
stand  in  contact  with  zinc  hydroxide.  The  power  of  synthesis  of  purines 
possessed  by  the  body  must  comphcate  the  question  of  their  fate  after 
ingestion,  since  it  is  evident  that  they  can  either  be  destroyed  and  excreted 
in  some  other  form  or  that  the  products  of  their  destruction  may  be  built 
up  into  fresh  purine  or  nuclein  molecules.  In  the  same  way,  in  the  growing 
child  there  is  a  rapid  increase  in  the  nuclein  of  the  body,  although  the  only 
food  ingested  is  milk,  which  contains  but  an  insignificant  amount  of  nuclein. 

FATE  OF  NUCLEINS  IN  THE  BODY 

Nucleins  and  nucleic  acids  are  dissolved  by  the  pancreatic  juice,  but  no 
digestion  of  the  nucleic  acid  occurs  in  the  alimentary  tract  other  than  by 
the  action  of  micro-organisms.  We  must  assume  therefore  that  the  nucleic 
acid  is  taken  up  by  the  cells  of  the  intestinal  wall  unchanged. 

Ingestion  of  nucleic  acid  is  followed  by  an  increased  excretion  of  uric 
acid  in  the  urine,  so  that  we  regard  this  substance  as  the  end-product  of 
nuclein  metabolism  in  the  body.  It  is  evident  that  the  uric  acid  of  the 
urine  may  be  derived  either  from  the  nucleins  of  the  food  or  from  the 
nucleins  of  the  tissues  of  the  body,  the  uric  acid  in  these  two  cases  being 
spoken  of  as  exogenous  and  endogenous  respectively.  By  digestion  of 
nucleic  acids  with  animal  tissues  or  extracts  of  animal  tissues  under  varying 
conditions,  it  is  possible  to  bring  about  all  the  changes  involved  in  the 
conversion  of  the  purine  base  contained  in  tliem  into  uric  acid.     In  the 

25* 


778  PHYSIOLOGY 

intestinal  wall,  or  after  absorption  into  other  tissues  of  the  body,  the  nucleic 
acid  is  subjected  to  hydrolytic  changes  by  the  agency  of  ferments  which 
may  be  classed  as  nucleases.  These  are,  however,  of  different  kinds,  the 
phosphonuclease  sphtting  off  the  phosphoric  acid  and  leaving  the  nucleo- 
sides, while  the  purine  nucleases,  which  are  more  effective  in  a  sHghtly 
alkahne  medium,  split  off  the  purines,  leaving  the  phosphoric  acid  com- 
bined vnth.  the  carbohydrate.  The  purines  set  free  in  this  way  undergo 
further  changes.  The  hypoxanthin  derived  from  inosinic  acid  is  converted 
under  the  action  of  an  oxidase  first  into  xanthine  and  then  into  uric  acid. 

This  was  one  of  the  eai'liest  facts  discovered  in  the  metabolism  of  purines. 
Horbaczewski  showed  that  if  spleen  pulp  be  digested  with  blood  for  some  time,  it  is 
possible  to  extract  a  considerable  amount  of  xanthine  from  the  mixture.  If,  however, 
oxygen  be  bubbled  through  the  fluid,  the  xanthine  disappears,  its  place  being  taken 
by  uric  acid. 

From  the  more  complex  nucleic  acids  the  amino-purines,  adenine,  and 
guanine,  are  set  free.  These  first  undergo  deamination  under  the  action 
of  special  ferments,  adenase  and  guanase,  and  are  thus  converted  into 
hypoxanthine  and  xanthine  respectively.  These  bodies  then,  under  the 
action  of  oxidases,  may  be  converted  into  uric  acid. 

All  these  changes  occur  in  the  living  body,  though  not  necessarily  in  the  order  just 
set  out.  Thus  when  the  pyrimidine  derivatives  are  administered  to  dogs,  they  pass 
out  unchanged.  If,  however,  free  nucleic  acid  be  administered  to  the  animal,  no  trace 
of  these  derivatives  can  be  found  in  the  urine,  so  that  they  must  have  undergone  com- 
plete oxidation.  In  the  same  way  the  dog's  liver  is  able  to  deaminise  completely 
the  adenine  group  of  nucleic  acid,  converting  it  into  hypoxanthine,  but  is  without 
effect  on  free  adenine.  It  is  evident,  therefore,  that  the  various  ferments  which  have 
been  described  act  partly  on  the  whole  nucleoside  molecule,  partly  on  the  products 
of  its  decomposition,  and  that  the  results  of  the  action  of  the  body  ferments  are  not 
the  same  in  the  two  cases. 

If  we  make  this  reservation,  namely,  that  the  constituent  parts  of  the  nucleic  acid 
molecule  may  undergo  changes  while  still  bound  to  the  other  parts,  we  may  represent 
diagrammatically  the  formation  of  uric  acid  from  nucleic  acid  as  follows  : 


Ferments 
Nuclease 


Nucleic  acid 


Phosphoric  acid        guanosine         adenosine         m-idine        cytidine 
deaminase  xanthosine  inosine  fate  unknown 

hydrolysis  xanthine     hypoxanthine 


oxidase 
oxidase 

oxidase 
(uricase) 


xanthine 


uric  acid 
allantoin  (in  dogs) 


NUCLEIN  OR  PURIXE  METABOLISM  779 

or  nucleic  acid 

I 
auclcase  4  mononucleotides 

\ 

purine  nuclease  |  III 

pentose-phosphoric  acid        guanine         adenine        pyrimidine  bases 
deaminase  |  I 

(guanase  and  adenase)  xanthin    hypoxanthine 

oxidase  xanthine 

.       .  I 

oxidase  | 

ui'ic  acid 

The  question  arises  whether  the  uric  acid  excreted  by  a  man  represents 
the  whole  of  the  nucleins  which  have  been  destroyed  in  the  body.  Although 
complete  equivalence  has  been  found  between  the  amount  of  hypoxanthine 
ingested  and  the  amount  of  uric  acid  excreted,  the  same  equivalence  has 
not  been  established  in  the  case  of  nucleic  acid,  and  the  important  question 
arises  whether  uric  acid  once  formed  is  stable  or  whether  it  may  undergo 
further  changes  before  being  excreted.  In  many  animals,  such  as  the  dog, 
the  amount  of  uric  acid  in  the  urine  is  only  minute,  the  chief  purine 
derivative  in  this  fluid  being  allantoin.  AUantoin  is  formed  when  uric 
acid  is  oxidised  with  potassium  permanganate,  the  follo^^ing  changes 
taking  place  : 

NH— CO  NH— CO 


CO     C— NH^  +  0  +  H2O  =  CO  XH2       +  COo 

^CO  I  >C0 

NH— C— XH/  NH— €H— NH 

The  same  transformation  can  be  effected  by  extracts  made  fi"om  the 
liver  of  the  dog  and  probably  of  other  animals.  The  ferment  carrying  out 
this  change  is  known  as  uricase.  No  such  ferment  is  found  in  human  hver 
or  any  human  organs,  and,  according  to  Jones  and  others,  uric  acid  once 
formed  in  the  human  organism  is  not  further  oxidised.  The  small  trace 
of  allantoin  which  may  occur  in  himaan  urine  is  directly  derived  from  the 
food.  Modern  research  does  not  confirm  the  idea  which  was  "formerly 
held  that  a  portion  of  the  uric  acid  formed  might  undergo  further  oxidation 
in  man  with  the  production  of  urea. 

On  the  other  hand  it  is  important  to  bear  in  mind  the  possibility  that 
some  of  the  uric  acid  which  occurs  in  human  urine  may  be  formed  by  a 
process  of  synthesis.  We  have  seen  already  that  in  the  bird  the  greater 
part  of  the  uric  acid  is  formed  not  from  purines  at  all  but  by  a  process  of 
synthesis  from  lactic  acid  and  ammonia,  and  though  we  have  no  evidence 
of  a  similar  change  occurring  in  the  mammal,  we  are  not  able  definitely  to 
exclude  its  possibility. 

EXCRETION  OF   URIC  ACID 

The  complexity  of  these  various  processes  in  man  renders  it  a  difficult 
task  to  form  a  clear  idea  of  the  origin  of  the  urinary  uric  acid  and  of  the 
conditions   which  determine  the  variations  in  the  amount   excreted  at 


780  PHYSIOLOGY 

different  times.  Under  ordinary  circumstances  a  man  excretes  about  half 
a  gramme  of  uric  acid  per  day.  In  addition  the  urine  contains  a  certain 
small  amomit  of  purine  bases,  the  ratio  of  these  bases  to  the  uric  acid  being 
generally  about  1:6.  From  10,000  Htres  of  human  urine  Kriiger  and 
Salomon  succeeded  in  isolating  the  following  purine  bases  ; 


Xanthine 

Hypoxanthine 

Adenine 


10-1  grm. 
8-5     „ 
3-5     „ 


The  same  urine  would  probably  have  contained  about  500  grm.  of  uric 
acid.  As  we  should  expect,  the  amount  of  uric  acid  in  the  urine  varies  with 
the  diet.  The  following  Tables  from  Bunge  give  the  composition  of  the 
urine  secreted  (1)  on  a  mixed  diet,  (2)  on  a  diet  mainly  composed  of  meat, 
(3)  on  a  diet  mainly  composed  of  bread  : 


Twenty-four  hours 

Mixed 

Meat 

Bread 

Quantity  c.c.        .         . 
Urea         .... 

grm. 

1500 

1672 

1920 

33 

67 

20 

Uric  acid 

,, 

•55 

1-3 

•25 

Ammonia 

,, 

•9 

2-1 

•9 

Creatinine 

,, 

•77 

•9 

•4 

Hippuric  acid   . 

,, 

•4 

— 

— 

Sulphates 

2 

4-6 

1-2 

Sodium  chloride 

,, 

16-5 

7-5 

8^2 

Phosphates 

,, 

3-16 

3-4 

1-6 

Potassium 

» 

2-5 

3-3 

1-3 

Calcium,  ma 

gnesii 

ini,  ir 

on,  colo 

uring-matter, 

gases,  fermeni 

s. 

An  attempt  has  been  made  to  arrive  at  the  amount  of  uric  acid  produced 
endogenously,  i.e.  from  the  breakdown  of  the  tissues,  from  a  study  of  the 
quant'ty  of  uric  acid  in  the  urine  under  varying  conditions  of  food.  During 
starvation,  when  the  man  is  living  on  his  own  tissues,  one  might  expect  the 
uric  acid  to  be  increased  in  consequence  of  disintegration  of  the  tissues. 
It  has  been  suggested  that  the  amount  of  the  endogenous  uric  acid  in  the 
urine  would  be  obtained  by  an  analysis  of  the  urine  from  patients  taking 
a  diet  free  from  purine  bases,  but  containing  sufficient  nitrogen  to  maintain 
nitrogenous  equilibrium.  It  is  impossible,  however,  to  arrive  at  any 
constant  figure  for  the  endogenous  uric  acid.  Even  in  the  entire  absence 
of  purine  derivatives  from  the  diet  the  amount  of  uric  acid  increases' 
with  the  total  nitrogenous  metabolism.  This  fact  is  well  shown  in 
the  Tables  by  Folin  (already  quoted)  of  the  composition  of  the  urine 
on  a  low  and  a  high  protein  diet  respectively.  Although  in  each  case 
care  was  taken  to  exclude  purine-containing  bodies  from  the  food, 
the  output  of  uric  acid  on  the  high  nitrogenous  diet  was  double  as 
much  as  on  the  low  diet.     All  we  can  say  i§  that  uric  acid  is  constantly 


NUCLEIN  or  purine  metabolism  781 

being  derived  from  the  tissue  disintegration,  but  that  it  varies  under 
different  conditions  of  nutrition  as  well  as  under  different  conditions  of 
activity  of  the  body. 

There  are  two  main  conditions  which  give  rise  to  a  marked  increase  in 
the  output  of  endogenous  uric  acid.  These  are  (1)  severe  muscular  activity, 
(2)  febrile  states  accompanied  by  increased  nitrogenous  metabolism.  Since 
both  these  conditions  are  associated  with  an  increased  breakdown  of  muscle 
substance  we  may  regard  the  uric  acid  as  derived  especially  from  the 
hypoxanthine  or  its  precursors,   such  as  inosinic  acid,  contained  in  the 

muscle. 

The  foods  which  are  especially  effective  in  causing  increase  in  the 
exogenous  uric  acid  are  those  rich  in  nuclein,  such  as  sweetbreads  or  liver, 


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Fig.  355.  Curves  showing  the  hourly  excretion  of  uric  acid  and  urea  after  a  single 
meal.  (Hopkiss.)  The  continuous  line  =  uric  acid  output;  the  dotted 
line  =  urea  output. 

and  those  rich  in  hypoxanthine  or  its  precursors,  such  as  meat  or  meat 

extract. 

When  these  foods  are  taken,  or  when  nucleic  acid  itself  is  administered,  a  con- 
dition of  leucocytosis  is  generally  produced,  the  number  of  leucocytes  in  the  blood 
being  increased  as  much  as  three  times.  It  has  been  suggested  that  the  uric  acid  is 
actually  formed  by  a  disintegration  of  the  newly  formed  leucocytes  and  not  by  a  direct 
conversion  of  the  purines  of  the  food.  It  is  quite  possible,  as  suggested  by  Schittenhelm, 
that  the  leucocytes  play  a  part  in  the  transference  of  the  nucleins  from  the  intestine 
to  the  circulation.  But  the  absence  of  any  absolute  proportionality  between  the  degree 
of  leucocytosis  and  the  amount  of  uric  acid  excreted  points  to  the  probability  of  a  direct 
conversion  of  the  purines  of  the  food  into  uric  acid. 


URIC  ACID  IN  GOUT 
Gout  is  a  condition  in  which  deposits  of  urate  of  soda  occui-  in  the  cartilages  of  the 
joints,  the  great  toe  joint  being  the  seat  of  predilection  for  this  disorder.  The  deposit 
is  generally  associated  with  an  acute  inflammation  of  the  joint.  In  normal  individuals 
the  amouilt  of  uric  acid  in  the  blood  is  too  small  to  be  detected.  Uric  acid  is  readily 
excreted  by  the  healthy  kidneys.  If  the  production  of  uric  acid  be  largely  increased 
by  the  administration  in  large  quantities  of  food-stuffs  rich  in  pm-ines,  it  becomes 


782  PHYSIOLOGY 

possible  to  demonstrate  the  actual  presence  of  uric  acid  in  the  blood.  In  gout  there 
is  constantly  an  increased  amount  of  uric  acid  in  the  blood,  probably  in  the  form  of 
sodium  m-ate,  even  when  the  patient  is  on  a  pmine-free  diet,  so  that  gout  may  be  re- 
garded, from  one  point  of  view  at  any  rate,  as  a  uricaemia  of  endogenous  origin.  On 
the  other  hand,  the  output  of  uric  acid  in  the  urine  is  not  increased,  and  may  in  fact 
be  somewhat  smaller  than  normal.  It  might  be  thought  that  the  presence  of  uric 
acid  in  the  blood  must  therefore  be  due  to  diminished  power  of  excretion  of  this  sub- 
stance by  the  kidneys.  This  view  is  difficult  to  reconcile  with  the  fact  that  if  uric 
acid  be  injected  subcutaneously  into  gouty  subjects  it  is  stated  to  be  excreted  in  the 
urine  exactly  in  the  same  way  and  as  rapidly  as  in  normal  persons.  It  has  been 
suggested  that  gout  consists  essentially  in  a  disturbance  in  the  various  fermentative 
mechanisms  which  are  responsible  for  the  changes  imdergone  by  the  purines,  so  that 
there  is  an  increased  amount  not  only  of  uric  acid  itself  but  of  various  intermediate 
products  in  its  formation  from  the  pm-ine  bases  of  the  food  and  of  the  tissues.  The 
deposit  of  the  uric  acid  in  the  joint  cartilages  characteristic  of  acute  gout  appears  to  be 
simply  a  crystallisation  of  lu'ate  of  soda  from  a  supersaturated  solution  of  this  substance 
in  the  blood.  The  whole  question  of  the  pathology  of  gout  and  of  the  disordered 
metabolism  which  may  precede  or  intervene  between  actual  acute  attacks  of  the  disease 
is  in  need  of  further  investigation.  Especially  is  it  important  to  determine  the  influence 
on  this  condition  not  only  of  the  nucleins  and  proteins  of  the  food,  but  of  the  other 
constituents,  such  as  carbohydrates  and  fats.  Speaking  broadly,  gout  is  a  disease 
of  the  well-to-do,  of  the  person  who,  while  pursuing  a  sedentary  or  no  occupation,  is 
not  limited  in  his  food-supply.  It  is  almost  unknown  in  the  labom'ing  class,  where 
hard  manual  work  is  combined  with  a  bare  sufficiency  of  food.  It  seems  therefore 
that  it  is  not  so  much  the  supply  of  purines  in  the  diet  which  must  be  controlled  as  the 
general  conditions  of  nutrition  which  determine  the  fermentative  changes  in  the  piu'ines, 
either  of  the  food  or  tissues,  under  normal  conditions  of  metabolism. 


SECTION  III 

THE   HISTORY   OF  FAT   IN  THE   BODY 

Fat  is  found  in  the  body  in  various  situations.  In  a  fat  animal  the  largest 
amount  occurs  in  the  panniculus  adiposus  in  the  subcutaneous  tissues. 
Large  quantities  are  also  found  surrounding  the  abdominal  organs  and 
between  the  layers  of  the  mesentery  and  great  omentum.  In  this  adipose 
tissue  the  fat  is  enclosed  within  and  distends  connective-tissue  cells,  the 
protoplasm  of  which  is  reduced  to  a  thin  pellicle  round  the  fat  globule. 
Fat  is  also  found  in  the  form  of  granules  in  more  highly  specialised  cells, 
such  as  the  secreting  cells  of  the  liver  or  the  muscle-cells.  The  condition 
of  these  cells  is  often  spoken  of  as  fatty  infiltration,  or  fatty  degeneration, 
according  to  the  circumstances  which  are  responsible  for  bringing  about 
the  deposition  of  fat.  We  shall  have  to  discuss  later  on  how  far  we  are 
justified  in  assuming  any  real  distinction  between  these  two  processes. 
From  the  physiological  standpoint  the  most  important  intracellular  depot 
of  fat  is  in  the  liver.  If  this  organ  be  deprived  of  glycogen  and  fat  by 
starvation,  a  fatty  meal  gives  rise  to  a  great  deposition  of  fat  in  its  cells. 
There  is  apparently  an  antagonism  between  the  processes  which  lead  on 
the  one  hand  to  the  deposition  of  glycogen  and  on  the  other  to  the  deposition 
of  fat.  Thus  an  excessive  carbohydrate  diet,  which  induces  great  deposition 
of  fat  in  the  subcutaneous  tissues,  only  causes  the  formation  of  glycogen 
in  the  liver.  The  glycogen  must  be  got  rid  of  before  it  is  possible  to  cause 
the  deposition  of  fat.  On  this  account,  the  normal  content  in  fat  of  the 
livers  of  dift'erent  animals  varies  with  their  ordinary  diet.  Fishes,  e.g.  the 
cod,  which  take  but  little  carbohydrate  in  their  food,  have  generally  a  very 
large  quantity  of  fat  in  their  livers.  Herbivorous  animals,  as  a  rule,  have 
practically  no  fat  in  the  liver. 

Fat  also  occurs  in  certain  secretions,  e.g.  the  milk  and  the  sebum,  its 
function  in  the  latter  case  being  mainly  protective. 

Besides  the  visible  deposit  of  fat  found  in  adipose  tissue  and  in  other 
situations  a  large  amount  of  fat  is  always  present  built  up  into  the  proto- 
plasm of  the  cells  in  such  a  condition  that  its  presence  cannot  be  detected 
by  histological  means.  The  presence  or  absence  of  visible  fatty  globules 
affords  very  little  clue  to  the  total  quantity  of  fat  in  the  cells.  Thus  in  one 
case  the  heart  muscle,  which  had  undergone  extreme  fatty  degeneration 
and  was  loaded  with  fat  globules,  contained  19  per  cent,  of  its  dried  weight 
of  fat.  A  heart  muscle  taken  from  a  normal  animal  at  the  same  time, 
presenting  no  visible  fat  globules,  contained  17  per  cent,  of  fat. 

783 


784  PHYSIOLOGY 

COMPOSITION  OF  FAT 

The  fats  occur  generally  in  the  form  of  triglycerides  of  various  fatty 
acids.  In  adipose  tissue  the  acids  are  chiefly  stearic,  palmitic,  and  oleic, 
the  consistency  of  the  fat  depending  on  the  relative  amount  present  of 
triolein,  with  its  low  melting-point.  In  certain  animals  the  glycerides  of 
more  unsaturated  fatty  acids  occur.  Thus  lard  contains  about  10  per 
cent,  of  fats  belonging  to  the  hnoleic  series.  The  fats  of  cows'  milk,  though 
consisting  chiefly  of  the  three  above  mentioned,  include  also  the  esters  of 
butyric  and  caproic  acids  in  fair  amounts,  and  traces  of  the  intermediate 
acids,  capryhc,  capric,  lauric,  and  myristic  acids. 

The  '  fat '  extracted  from  the  tissues  {e.g.  heart  muscle)  includes  a 
considerable  amount  of  '  phosphatides '  (lecithins,  &c.).  It  also  contains 
a  much  larger  proportion  of  unsaturated  fatty  acids,  of  the  linoleic  and  even 
lower  series,  so  that  its  '  iodine  value  '  is  generally  found  relatively  high 
(120  as  compared  with  40  to  60  in  adipose  tissue). 

FUNCTIONS  OF  FAT 

First  and  foremost  must  be  mentioned  the  significance  of  fat  as  a  reserve 
food  store.  The  power  of  the  organism  to  store  up  reserve  carbohydrate  is 
strictly  limited.  The  hver  of  man  can  probably  not  accommodate  more 
than  150  grm.  of  glycogen,  and  assuming  that  the  muscles  of  the  body  may 
contain  an  equal  amount,  300  grm.  represents  the  extreme  limit  of  storage 
of  carbohydrates  in  the  body.  On  the  other  hand,  in  most  animals  there 
is  practically  no  limit  to  the  amount  of  fat  which  can  be  laid  down,  and 
over-feeding,  whether  with  carbohydrates  or  fats,  leads  to  the  deposition 
of  fat.  This  fat  does  not  enter  into  the  normal  metabolism  of  the  body, 
but  is  available  for  use  whenever  the  needs  of  the  body  are  increased  above 
its  income. 

As  to  the  part  taken  by  fat,  especially  the  hidden  fat  of  the  working 
cells,  in  the  chemical  processes  which  determine  the  life  of  the  cell,  our 
knowledge  is  still  very  scanty.  Fats  enter  into  the  constitution  of  the 
complex  bodies  lecithin  and  myelin,  which  form  important  constituents  of 
the  limiting  membrane  of  every  hving  cell.  As  constituents  of  the  mem- 
brane itself,  fatty  substances  therefore  have  a  protective  action,  and  also 
regulate  the  passage  of  substances  into  the  cell  across  the  membranes. 

The  presence  of  lecithin  as  an  integral  constituent  of  all  protoplasm, 
and  of  the  first  products  of  disintegration  of  protoplasm,  suggests  that 
this  substance  may  play  a  part  in  the  normal  transformations  which  occur 
within  the  cell,  and  may  represent,  so  to  speak,  the  currency  into  which 
fat  is  transformed  in  order  to  participate  in  the  vital  processes,  and  that 
it  is  in  this  form  that  the  energy  of  fat  is  utilised  for  the  needs  of  the  cell. 

ORIGIN  OF  FAT  IN  THE  BODY 

Fat  formation  is  the  result  of  an  excess  of  income  over  expenditure. 
As  soon  as  the  latter  exceeds  the  former  the  fat  store  is  drawn  upon,  so 


THE  HISTORY  OF  FAT  IN  THE  BODY  785 

that  adipose  tissue  is  the  one  which  presents  the  greatest  loss  during  starva- 
tion. As  much  as  97  per  cent,  of  the  total  fat  of  the  body  may  disappear 
during  this  process.  We  have  therefore  to  consider  what  part  is  played 
by  each  class  of  food-stuffs  in  the  formation  of  fat.  Can  this  substance  be 
formed  from  all  three  classes  of  food-stuffs  ? 

FORMATION  FROM  THE  FAT  OF  THE  FOOD.  Experiment  has 
shown  that  the  composition  of  the  fat  of  any  animal  is  by  no  means  constant 
and  can  be  varied  within  ^vide  limits  by  alterations  in  the  nature  of  the 
fat  presented  in  the  food.  This  dependence  of  the  composition  of  the  fat 
on  the  fats  of  the  food  is  shown  strikingly  in  an  experiment  performed  by 
Lebedeff.  Two  dogs,  after  a  ;^reliminary  period  of  starvation,  were  fed, 
one  on  a  diet  containing  a  large  amount  of  linseed  oil,  and  the  other  on  a 
diet  containing  much  mutton  suet.  After  some  weeks,  when  the  animals 
had  put  on  a  large  amount  of  fat,  they  were  killed,  and  it  was  found  that 
whereas  the  fat  of  the  dog  which  had  been  fed  on  mutton  suet  was  solid 
at  50°  C,  that  of  the  dog  fed  on  oil  was  still  fluid  at  0°  C.  It  has  been 
shown  moreover  that  by  feeding  animals  with  fatty  acids  not  usually  found 
in  the  body  these  are  laid  down  in  the  adipose  tissue.  Thus  colza  oil 
contains  a  glyceride  of  erucic  acid,  and  an  animal,  as  Munk  has  shown, 
fed  on  colza  oil  lays  on  fat  in  which  erucic  acid  is  present.  The  same 
physiologist  has  observed  that  after  the  administration  of  various  fatty 
acids  to  a  man  with  a  chylous  fistula,  the  glycerides  of  the  corresponding 
fatty  acids  made  their  appearance  in  the  chyle,  whether  these  fatty  acids 
were  those  normal  to  man  or  consisted  of  substances,  such  as  erucic  acid, 
not  generally  found  in  human  fat.  One  must  conclude  therefore  that  the 
fats  taken  with  the  food,  if  not  immediately  required  for  the  energy  needs 
of  the  body,  are  laid  down  without  change  in  the  adipose  tissues,  as  well 
as  in  the  cells  of  the  body.  The  mechanisms  involved  in  the  translation  of 
fat  from  the  alimentary  canal  to  the  tissues  are  of  the  simplest  possible 
description  and  only  involve  changes  of  hydrolysis  and  dehydrolysis.  The 
fats  are  hydrolysed  in  the  gut  and  are  resynthetised  to  a  certain  extent 
in  their  passage  into  the  epithelium.  In  the  chyle  and  blood  they  probably 
wander  chiefly  as  neutral  fats,  to  be  rehydrolysed  for  their  passage  into 
the  cells  of  the  body,  which  they  may  enter  either  in  the  form  of  soaps  or 
possibly  as  fatty  acids  dissolved  in  some  of  the  constituents  of  protoplasm. 

FORMATION  OF  FAT  FROM  CARBOHYDRATES.  It  has  long  been 
the  experience  of  farmers  that  animals  might  be  fattened  on  a  diet  in  which 
carbohydrates  predominate.  The  chemical  difficulty  involved  in  the  trans- 
formation of  carboliydrates  into  fats  has  often  led  to  a  doubting  attitude 
on  the  part  of  chemists  towards  this  transformation.  Voit  put  forward 
the  view  that  when  fats  are  formed  in  the  body  as  a  result  of  an  excessive 
carbohydrate  diet,  they  are  formed,  not  directly  by  a  transformation  of 
carbohydrate,  but  from  the  proteins  of  the  food,  the  role  of  the  carbo- 
hydrates of  the  food  being  simply  to  protect  the  proteins  from  disintegration 
and  oxidation,  so  that  the  whole  of  their  carbon  can  be  utilised  for  the 
formation  of  fat. 


786  PHYSIOLOGY 

Definite  evidence  has,  however,  been  brought  forward,  especially  by 
Lawes  and  Gilbert,  for  the  transformation  of  carbohydrates  into  fats.  In 
these  experiments  two  young  pigs,  ten  weeks  old,  of  the  same  litter,  with 
approximately  equal  weights,  were  taken.  One  was  killed  and  the  fat 
and  total  nitrogen  in  the  body  estimated.  From  the  amount  of  nitrogen 
the  maximum  possible  quantity  of  proteins  present  was  calculated.  The 
second  was  fed  on  barley  for  four  months.  The  barley  was  measured  and 
analysed,  as  well  as  the  amount  of  undigested  fat  and  protein  that  passed 
through  the  animal.  At  the  end  of  the  four  months  the  second  animal 
was  killed  and  analysed.  It  was  found  that  the  animal  contained  1-56 
kilos  more  protein  and  8-6  kilos  more  fat.  It  had  taken  up  with  the  food 
7-49  kilos  more  protein  and  0-66  kilo  fat.  If  we  subtract  the  protein  added 
to  the  body  (1-56)  from  that  taken  up  with  the  food  (749)  there  is  a 
remainder  of  5-93  kilos  which  might  possibly  have  given  rise  to  fat.  But 
7-9  kilos  of  fat  had  been  added  in  the  body — a  far  larger  amount  than 
could  possibly  have  arisen  from  the  maximum  amount  of  protein  left  over 
for  the  purpose.  At  least  5  kilos  of  fat  in  this  experiment  must  have  been 
derived  from  the  direct  conversion  of  the  carbohydrates  of  the  food.  We 
must  conclude  that  fat  can  be  formed  directly  from  carbohydrates,  although 
how  and  where  this  conversion  takes  place  is  at  present  quite  unknown. 
The  fats  formed  on  a  carbohydrate  diet  are  deposited  chiefly  in  the  sub- 
cutaneous tissue.  For  the  reasons  already  given  the  Uver  is  found  free  from 
fat  under  these  conditions.  In  the  fat  formed  from  carbohydrate  the  two 
saturated  acids,  palmitic  and  stearic  acid,  predominate.  On  this  account 
the  fat  has  a  firm  consistency  and  a  high  melting-point.  The  fats  of  low 
melting-point,  such  as  olein,  are  absorbed  more  readily  from  the  intestine 
than  those  of  high  melting-point.  Where  the  fat  of  the  body  is  chiefly 
derived  from  the  fat  of  the  food  it  tends  to  be  of  the  more  fluid  acids  and 
contains  a  larger  percentage  of  olein. 

Although  it  is  impossible  to  trace  out  all  the  steps  in  the  process  of 
conversion  of  sugar  into  fatty  acid,  we  are  acquainted  with  certain  reactions 
which  may  throw  some  light  on  the  nature  of  the  changes  involved.  If 
we  compare  the  formula  of  dextrose  with  that  of  the  corresponding  fatty 
acid,  caproic  acid, 

CHg  CH2OH 

CH2  caoH 

CH2  OHOH 

CH2  CHOH 

CH2  CHOH 

COOH  CHO 

we  see  that  the  conversion  involves  a  considerable  loss  of  oxygen.     In 
order  to  convert  three  molecules  of  glucose,  CgHiaOe,  into  one  molecule 


THE  HISTORY  OF  FAT  IN  THE  BODY  787 

of  stearic  acid,  CigHgeOa,  it  is  necessary  to  split  off  16  atoms  of  oxygen. 
That  this  setting  free  of  oxygen  actually  occurs  in  the  transformation  of 
carbohydrate  into  fat  is  shown  by  the  study  of  the  respiratory  exchanges  of 
animals  which  are  rapidly  laying  on  a  store  of  fat  at  the  expense  of  a  carbo- 
hydrate food.  Thus  the  marmot,  towards  the  end  of  summer,  eats  large 
quantities  of  carbohydrate  food  and  very  rapidly  lays  on  a  thick  layer  of 
subcutaneous  fat  to  last  it  during  the  winter.  If  glucose  were  entirely 
oxidised  in  the  body  the  amount  of  oxygen  absorbed  would  be  exactly 
equal  to  the  amount  of  carbon  dioxide  evolved.     Thus 

CgHiaOe  +  GOo  =  6CO2  +  6H2O. 

In  this  case  the  respiratory  quotient  would  be 

6CO2  _  ^ 

If,  however,  oxygen  is  being  set  free  by  the  conversion  of  part  of  the 
carbohydrate  into  fat,  this  oxygen  will  be  available  for  the  oxidation  of 
other  portions  of  the  carbohydrate.  The  animal  Avill  not  need  to  take  in 
so  much  oxygen  from  outside  for  the  production  of  the  same  amount  of 
carbon  dioxide,  and  the  carbon  dioxide  output  of  the  animal  will  therefore 
be  greater  than  its  oxygen  intake.  Pembrey  has  shown  that  under  these 
conditions  the  respiratory  quotient  may  be  as  high  as  1-5.  We  caimot 
assume,  however,  that  the  process  of  conversion  of  glucose  into  fatty  acids 
takes  place  by  this  simple  process  of  deoxidation.  The  change  is  probably 
a  more  complex  one,  and  occurs  in  separate  stages.  Glucose  easily  breaks 
up  under  the  action  of  ferments  into  two  molecules  of  lactic  acid,  and 
lactic  acid  can  be  equally  easily  converted  into  aldehyde  and  formic  acid, 
thus  : 

CgHioOg  =  •2C3He03  lactic  acid,  and 

CH3" 

I       CH3   H 

CHOH  =1    +1 

I       CHO   COOH 

COOH 

Now  aldehydes  possess  a  marked  tendency  to  combine  with  other 
molecules  of  other  or  the  same  substance,  i.e.  to  undergo  polymerisation. 
Thus  from  two  molecules  of  aldehyde  we  get  one  molecule  of  aldol, 

CH3 

I 
CH3  CHOH 

2|  =         1 

CHO  CH2 

I 
CHO 

which  by  a  simple  transposition  of  oxygen  would  give  but^Tic  acid,  or  by 
oxidation  would  give  p-oxybutyric  acid,  a  substance  which  occurs  during 
various  abnormal  conditions  of  metabolism. 

The  fats  occurring  in  the  body,  e.g.  in  milk,  include  only  the  fatty  acids 


788  PHYSIOLOGY 

with,  an  even  number  of  carbon  atoms  {v.  p.  54).  We  may  probably  agsiim6 
from  this  fact  that  the  building  up,  as  well  as  the  breaking  down,  of  fatty 
acids  occurs  by  two  carbon  atoms  at  a  time.  Although  heating  aldehyde 
or  aldol  with  potash  or  any  other  polymerising  agent  gives  rise  to  a  mixture 
of  many  substances,  it  is  probable  that  under  the  catalytic  agencies  at  the 
disposal  of  the  li\^ng  cell  these  synthetic  changes  are  directed  entirely  in 
one  direction,  so  that  from  butyric  acid  we  shall  have  hexoic,  capryhc, 
capric  acid,  and  so  on.  The  process  would  seem  to  take  place  more  easily 
through  pyruvic  acid,  as  described  on  p.  121.  Why  the  process  comes  to 
an  end  with  the  formation  of  the  16  and  18  carbon  atoms  it  is  difficult  to 
see.*  Possibly  with  the  formation  of  acids  whose  melting-point  is  higher 
than  that  of  the  body  temperature,  a  certain  stability  is  imparted  to  them 
which  prevents  their  further  circulation  and  ready  synthesis  to  the  still 
higher  acids. 

With  regard  to  the  glycerine  which  is  a  necessary  constituent  of  the 
neutral  fats  laid  down  in  the  body,  there  is  no  difficulty  in  accounting  for 
its  formation  from  the  carbohydrates.  By  a  simple  splitting  of  glucose, 
we  may  obtain  two  molecules  of  glyceraldehyde, 

CHoOH 


CH2OH 
=  2  CHOH 
CHO 


CHOH 

I 
CHOH 

I 
CHOH 

I 
CHOH 

I 
CHO 

which  by  reduction  is  readily  converted  into  the  corresponding  alcohol 
glycerine,  CH2OH . CHOH .  CH^OH. 

We  may  conclude  then  that  fats  are  formed  by  the  body  with  ease 
from  carbohydrates,  and  that  in  all  probabihty  this  change  involves  a 
building  up  of  the  fatty  acid  from  the  lower  members  by  the  successive 
addition  of  a  group  containing  two  atoms  of  carbon.  The  whole  change, 
as  Leathes  has  shown  {v.  p.  121),  is  an  exothermic  one.  For  the  formation 
of  one  molecule  of  palmitic  acid,  four  molecules  of  glucose  would  be  required, 
and  12-5  per  cent,  of  the  total  energy  of  the  glucose  would  be  set  free  as 
heat. 

THE  FORMATION  OF  FAT  FROM  PROTEINS.  Among  the  decom- 
position products  of  proteins  the  amino-derivatives  of  the  fatty  acids  take 
a  prominent  part.  Of  these  some  may  be  converted  into  carbohydrate  in 
the  body,  while  others  such  as  leucine  and  tyrosine  may  give  rise  to  aceto- 
acetic  acid.  It  seems  therefore  that  these  latter  might  in  their  turn  be 
built  up  by  the  process  we  have  just  discussed  into  the  higher  members 

*  From  the  fats  extracted  from  the  kidney  Dunham  has  isolated  carnaubic  acid, 
CaiH^.Oo. 


THE  HISTORY  OF  FAT  IN  THE  BODY  789 

of  the  series.  For  many  years,  as  a  result  of  the  investigations  of  Voit, 
the  proteins  were  indeed  regarded  as  the  chief,  if  not  the  sole,  source  of 
the  fats  of  the  body,  and  it  needed  the  energetic  assaults  of  Pfliiger  on  this 
doctrine,  in  1891,  before  it  could  be  clearly  examined  by  physiologists. 

Let  us  see  what  are  the  grounds  for  assuming  a  formation  of  fat  from 
protein.  In  the  first  place,  there  is  a  well-known  experiment  by  Voit. 
A  dog  was  fed  with  large  quantities  of  lean  meat  for  a  considerable  time. 
Voit  found  that  the  whole  of  the  nitrogen  of  the  intake  was  excreted,  but 
that  a  certain  percentage  of  carbon  was  retained  in  the  body,  and  that 
the  percentage  of  this  carbon  was  greater  than  could  be  accounted  for  by 
the  deposition  of  glycogen  in  the  hver  and  muscles.  He  therefore  assumed 
that  it  must  have  been  laid  down  as  fat.  Pfliiger  showed  that  these  con- 
clusions were  not  justified  by  Voit's  results,  and  were  really  based  on  the 
fact  that  too  high  a  figure  had  been  assumed  for  the  carbon  of  the  meat. 
Whereas  Voit  found  that  the  animal  had  laid  on  56  grm.  of  fat  during 
one  day  of  the  experiment,  a  recalculation  of  the  same  results  by  Pfliiger 
shows  that  the  animal  could  not  have  put  on  more  than  3-9  grm.  of  fat, 
an  amomit  which  might  quite  well  be  accounted  for  by  the  fat  and  glycogen 
present  in  the  meat.  Pfliiger  has  shown  moreover  that  an  animal  may 
be  fed  for  weeks  on  the  leanest  meat  that  it  is  possible  to  procure,  in 
any  quantities,  without  putting  on  any  fat  at  all,  and,  as  we  have  seen,  in- 
creasing the  ration  of  protein  increases  simply  the  nitrogenous  and  general 
metabolism  of  the  body. 

Although  therefore  we  must  assume  that  the  healthy  body  does  not 
normally  form  fat  from  protein,  there  are  certain  pathological  conditions 
which  seem  at  first  to  tell  in  favour  of  such  a  conversion.  Thus  durins 
certain  diseases,  such  as  diphtheria,  pernicious  anaemia,  and  as  the  result 
of  poisoning  by  phosphorus,  the  majority  of  the  organs  of  the  body  imdergo 
acute  fatty  degeneration.  The  liver  may  be  enlarged  and  aU  its  cells  are 
studded  with  fat  granules  which  are  apparently  formed  by  a  change  in 
the  protoplasm  of  the  cells.  This  change  was  long  interpreted  as  due  to 
a  direct  conversion  of  protein  into  fat.  More  exact  analyses  have  shown 
that  during  fatty  degeneration  the  total  fat  in  the  body  is  not  increased. 
Thus  one  observer  took  124  pairs  of  frogs  and  poisoned  one  of  each  pair 
with  phosphorus.  The  animals  were  then  killed,  and  the  whole  of  them 
analysed.  The  difference  in  the  content  of  fat  between  the  poisoned  and 
unpoisoned  animals  fell  within  the  limits  of  experimental  error,  so  that 
there  had  been  no  increase  in  the  fat  of  the  body  as  the  result  of  the 
poisoning.  In  some  of  these  cases  the  liver  is  actually  enlarged,  but  this 
deposition  of  fat  in  the  cells  is  due  to  the  immigration  of  the  fat  from  other 
parts  of  the  body  and  not  to  conversion  of  the  protein  of  the  cells.  This 
is  shown  by  the  facts  that  the  composition  of  the  fat  in  the  degenerated 
liver  varies  according  to  the  composition  of  the  fat  in  the  rest  of  the  body, 
ai\d  that,  if  abnormal  fats  are  given  with  the  food,  such  as  erucic  acid  or 
iodine  fats,  these  are  found  in  the  fat  extracted  from  the  liver.  In  fatty 
Regeneration  two  processes  are  at  work  :    one  is  the  immigi-ation  of  fats 


790  PHYSIOLOGY 

from  other  parts  of  the  body  ;  the  second,  and  probably  the  more  important 
one,  is  a  change  in  the  relation  of  the  fat  to  the  protoplasm  of  the  cell. 

It  was  long  stated  that  the  fat  of  milk  was  not  increased  by  feeding  with 
fats,  but  only  by  feeding  with  proteins.  More  recent  researches  have  given 
contrary  results.  The  dependence  of  the  composition  of  milk  fat  on  the 
composition  of  the  fat  present  in  the  body  or  administered  in  the  food  is 
shown  by  the  fact  that  cows  fed  on  oilcake  may  produce  a  butter  which 
is  useless  for  commercial  purposes  owing  to  its  low  melting-point.  In  one 
experiment,  when  a  cow  was  fed  on  linseed  oil,  the  iodine  number  of  the 
milk  fat  rose  from  30,  its  normal  figure,  to  70-4.  After  the  introduction 
of  iodine  fat  subcutaneously,  iodine  fats  are  found  in  the  milk.  In  another 
experiment  a  bitch  which  had  been  fed  with  mutton  suet  and  had  deposited 
in  its  tissues  a  fat  of  high  melting-point  produced  a  milk  the  iodine  number 
of  which  was  the  same  as  that  of  the  mutton  suet.  In  this  case  the  fat 
of  the  milk  had  evidently  been  derived  from  the  tissues,  since  during  the 
lactation  the  animal  was  being  fed  on  meat  which  was  poor  in  fat.  The 
same  dependence  of  fatty  secretion  on  diet  has  been  found  in  geese,  where 
the  composition  of  the  oil  secretion  of  the  feather  glands  has  been  altered 
by  giving  abnormal  fats,  such  as  sesame  oil,  with  the  food. 

We  must  conclude  that  the  protein  of  the  food  does  not  give  rise  to 
fat  in  the  body.  A  nearer  consideration  of  the  composition  of  the  proteins, 
taken  in  connection  with  our  discussion  as  to  the  mechanism  by  means  of 
which  the  fat  is  built  up  in  the  body,  might  help  to  account  for  this  fact. 
The  fatty  acids  formed  by  the  disintegration  of  proteins  are  chiefly  the 
lower  acids  of  the  series,  such  as  acetic  and  propionic,  which  would  undergo 
rapid  oxidation  in  the  body.  Butyric  acid  has  not  yet  been  found  among 
the  products  of  disintegration  of  the  proteins,  and  the  6- carbon  acid, 
derived  from  leucine,  is  not  the  normal  acid,  but  is  a  branched  chain,  viz. 
isobutyl- acetic  acid. 

THE  UTILISATION  OF  FATS  IN  THE  BODY 
The  constant  presence  of  fat,  and  bodies  allied  to  fat,  in  protoplasm, 
from  whatever  source  obtained,  suggests  that  these  substances  can  enter 
directly  into  the  chemical  changes  on  which  the  life  of  the  cell  depends 
and  that  they  play  an  essential  part  in  vital  phenomena.  The  direct 
utiHsation  of  fat  for  the  needs  of  the  body  is  also  indicated  by  the  results 
of  experiments  on  man  and  the  lower  animals.  After  a  few  days'  starva- 
tion the  body  may  be  regarded  as  practically  free  from  stored  carbohydrate. 
The  sole  source  of  the  energy  which  is  evolved  under  these  circumstances 
must  be  fats  and  proteins,  and  it  is  possible  to  determine  by  an  estimation 
of  the  nitrogen  output  the  exact  fraction  of  the  total  energy  evolved  which 
is  to  be  ascribed  to  protein  metabohsm.  Thus  in  the  case  of  Cetti,  the 
professional  faster,  it  was  found  that  the  nitrogenous  metabolism  per  unit 
of  body  weight  remained  fairly  constant  between  the  fifth  and  tenth  days 
of  starvation,  and  corresponded  to  an  average  of  1  grm.  of  protein  per 
kilo  body  weight  daily,     In  order  to  convert  this  amount  of  protein  into 


THE  HISTORY  OF  FAT  IN  THE  BODY 


791 


urea,  carbonic  acid,  sulphuric  acid,  and  water,  nearly  2  grm.  of  oxygen 
would  be  required  in  the  twenty-four  hours,  i.e.  about  1  c.c.  per  minute. 
Cetti's  total  oxygen  consumption  was  at  the  rate  of  5  c.c.  per  kilo  per 
minute,  so  that  four-fifths  of  the  oxygen  absorbed  was  required  for  the 
oxidation  of  non- nitrogenous  substances,  and  these,  as  we  have  seen, 
could  only  have  been  fats.  In  animals  with  a  large  store  of  fat  the  pro- 
portion of  the  energy  obtained  at  the  cost  of  the  fats  may  be  still  greater. 
In  dogs  Rubner  and  Voit  reckoned  that  only  10  to  16  per  cent,  of  the  total 
energy  was  derived  from  proteins,  the  rest,  i.e.  8i  to  90  per  cent.,  being 
obtained  from  the  oxidation  of  fats. 

The  oxidation  of  .fats  supphes  energy  not  only  for  the  production  of 
heat  but  also  for  the  performance  of  mechanical  work,  and  it  seems  probable 
that  the  utihsation  of  the  fat  occurs  in  the  muscular  tissues  themselves. 
Fat  is  found  as  a  normal  constituent  of  all  muscle  fibres,  and  the  amount 
of  this  substance  is  greater  in  proportion  to  the  activity  of  the  muscles 
concerned.  Thus  the  ever-active  heart  muscle,  and  the  red  muscles  of 
the  diaphragm,  contain  larger  amounts  of  fat  than  the  pale  voluntary 
muscles  which  only  have  to  undertake  short  periods  of  activity.  In  the 
human  heart  muscle  15  per  cent,  of  the  sohds  are  soluble  in  ether,  and 
more  than  one-half  of  the  ether  extract  is  composed  of  fat,  and  is  suffi- 
cient to  supply  the  energy  of  the  contracting  heart  for  six  or  seven  hours' 
work. 

The  degree  to  which  the  muscles  during  contraction  call  upon  each 
class  of  food-stuffs  may  be  judged  from  the  respiratory  quotient.  If  the 
body  has -previously  supplied  the  greater  part  of  its  needs  at  the  expense 
of  fats,  it  will  continue  to  do  so  during  muscular  work.  This  is  well  shown 
in  the  following  Table,  in  which  the  oxygen  consumption  and  respiratory 
quotient  are  compared  in' a  man  resting  and  working  on  three  different 
diets,  one  principally  fat,  one  principally  carbohydrate,  and  the  other 
principally  protein  : 


Diet 
principally 

Resting 

Working 

m.  kg.  of 
work  done 

Per  m.  kg.  of  work 

c.c.  oxy- 
gen used 
per  min. 

Resp. 
quo- 
tient 

c.c.  oxygen 

used  per 

min. 

Resp. 
quo- 
tient 

c.c.  oxy- 
gen used 

Cal. 

Fat        . 

Carbohydrate 

Protein 

319 

277 
306 

0-72 

0-90 
0-80 

1029 
1029 
1127 

0-72 
0-90 
0-80 

354 
346 
345 

2-01 
2-17 
2-38 

9-39 
10-41 
11-35 

We  may  conclude  then  that  the  tissues  of  the  body  are  able  to  obtain 
their  energy  by  the  direct  utilisation  of  the  fats  which  they  contain.  The 
changes  in  the  fat  molecules  which  are  involved  in  the  utihsation  of  their 
energy  are  still  to  be  determined.  The  energy  of  fat  is  only  available  on 
its  oxidation.  The  transformation  of  fats  into  fatty  acids  or  glycerine, 
or  the  synthesis  of  fats  from  aldehydes  or  from  carbohydrates,  which  we 


792  PHYSIOLOGY 

have  discussed  in  the  previous  section,  do  not  involve  any  large  changes 
of  energy.  Weight  for  weight,  butyric  acid  with  its  4  carbon  atoms  has 
practically  the  same  heat- value  as  stearic  acid  with  its  18  carbon  atoms, 
or  stearine  T\ith  its  57  carbon  atoms.  We  have  therefore  to  determine 
what  changes  the  great  fat  molecule  undergoes  before  it  is  brought  into  a 
condition  in  which  it  may  undergo  oxidation  and  set  free  the  energy  required 
for  the  purposes  of  the  body.  The  general  tendency  of  metabohc  research 
of  recent  years  is  to  show  that  the  hving  cell  is  in  a  position  to  effect  all 
changes  which  do  not  involve  a  large  evolution  or  absorption  of  energy  in 
either  direction.  In  the  plant  cell,  at  any  rate,  the  fatty  acids  may  be 
converted  into  amino-acids,  or  the  latter  may  be  deaminised,  as  occurs 
in  the  liver,  into  fatty  or  oxyacids.  Dextrose  may  pass  into  maltose 
and  starch,  or  starch  may  be  converted  into  maltose  or  dextrose.  If 
therefore  fats  are  constantly  being  made  from  carbohydrates,  or  from 
the  lower  molecules  such  as  aldehyde,  by  a  process  of  repeated  addition 
of  a  group  containing  two  carbon  atoms,  it  is  probable  that  the  same  change 
wiU  go  on  in  a  reverse  direction  when  fats  are  broken  down  previous  to 
oxidation. 

In  the  germination  of  oily  seeds  the  utiHsation  of  the  fat  is  preceded 
by  the  spHtting  of  the  higher  fatty  acids  into  acids  of  lower  molecular 
weight.  Although  we  cannot  trace  out  in  the  animal  body  the  stages  in 
the  breakdown  of  a  large  fatty  acid,  such  as  stearic  acid,  we  can,  by  a  certain 
artifice  much  used  in  metabohc  experimentation,  bring  forward  evidence 
in  favour  of  the  view  that  the  breakdo'wn,  hke  the  building  up  of  fats, 
occurs  by  two  carbon  atoms  at  a  time.  When,  in  the  process  of  breaking 
down,  a  fat  finally  arrives  at  the  four-  or  two-carbon  stage,  it  is  quickly 
oxidised  and  is  therefore  not  traceable  in  the  excretions  or  in  the  fluids  of 
the  body.  This  end  stage  may,  however,  be  preserved  from  oxidation 
by  hanging  it,  so  to  speak,  on  to  an  aromatic  ring.  If  acetic  acid  or  ethyl 
alcohol  be  administered  in  small  quantities,  it  is  entirely  oxidised.  If, 
hoAvever,  these  bodies  be  attached  to  a  benzene  ring  and  be  administered 
as  a  phenacetic  acid  or  phenylethyl  alcohol,  they  are  excreted  in  the  oxidised 
form  of  phenaceturic  acid,  which  is  simply  a  combination  of  phenacetic 
acid  with  glycine.  In  the  same  way  benzoic  acid  and  benzyl  alcohol  are 
•excreted  in  the  form  of  hippuric  acid,  thus  : 

CgHs .  COOH  +  NHg .  CHg .  COOH  =  C6H5 .  CO .  NH .  CHg .  COOH  +  H2O 
Benzoic  acid  Glycine  Hippuric  acid 

Phenacetic  acid,  CeHg.CHgCOOH,  is  excreted  as  Cgllj.CHa.- 
CO.NH.CH2COOH.  In  each  case  the  fatty  side-chain  is  protected  from 
further  oxidation  by  its  attachment  to  the  benzene  ring  and  by  the  tacking 
on  of  the  glycine  molecule. 

With  phenylpropionic  acid  two  carbon  atoms  of  the  side-chain  are 
oxidised,  and  the  remaining  benzoic  acid  excreted  as  hippuric  acid.  Phenyl- 
butyric  acid  undergoes  a  similar  change  ;  two  carbon  atoms  are  oxidised 
away,  leaving  phenylacetic  acid,  which  is  excreted  as  phenylaceiuric  acid. 


THE  HISTORY  OF  FAT  IN  THE  BODY  793 

If  phenyl  valerianic  acid  be  given,  four  carbon  atoms  are  oxidised  away 
and  benzoic  acid  is  left,  and  appears  in  the  urine  as  hippuric  acid.  In 
each  case  the  oxidation  of  the  side-chain  occurs  by  two  carbon  atoms  at 
a  time,  and  it  seems  probable  that  a  similar  change  will  occur  in  the  ordinary 
fatty  acid,  the  last  stages,  in  the  absence  of  any  protective  ring  compound, 
being  oxidised  like  the  earlier  groups  and  therefore  not  detectable  in  the 
excretions. 

Evidence  in  the  same  direction  is  afforded  by  certain  cases  in  which 
the  oxidative  power  of  the  body  for  fats  is  inadequate,  either  by  reason  of 
morbid  changes  in  the  oxidative  powers  of  the  body,  or  as  the  result  of 
what  we  may  call  an  overstrain  of  the  fat-oxidising  powers.  Such  a  con- 
dition is  found  in  the  acetonuria  of  acute  acidosis,  such  as  occurs  in  the 
end  stages  of  diabetes.  The  oxybutyric  and  diacetic  acids  occurring  in 
the  urine  in  this  condition  were  formerly  thought  to  be  derived  from  the 
carbohydrates  of  the  food,  or  from  sugar  abnormally  produced  in  the 
body.  The  condition  of  acidosis,  however,  is  often  brought  on  directly 
as  the  result  of  putting  the  patient  on  a  strict  anti-diabetic  diet,  i.e.  one 
consisting  chiefly  or  exclusively  of  fats  and  proteins,  and  may  be  produced 
in  a  healthy  man  by  simple  starvation,  when  the  body  has  only  at  its 
disposal  its  stored-up  fats  and  proteins.  It  occurs  in  a  marked  degi-ee 
on  the  administration  of  a  diet  consisting  almost  entirely  of  fats.  Thus  in 
one  experiment  a  healthy  man  took  as  his  sole  diet  for  five  days  a  daily 
ration  of  250  grm.  of  butter,  200  grm.  of  oil.  and  a  little  wine.  The  result 
was  an  intense  acidosis,  such  as  is  only  found  in  the  severest  cases  of 
diabetes,  diacetic  acid,  oxybutyric  acid,  and  acetone  being  found  in  the 
urine  in  large  quantities.  On  the  last  day  of  the  experiment  these  acids 
caused  so  much  of  the  nitrogen  in  the  urine  to  appear  as  ammonia  that  of 
the  5-8  grm.  total  nitrogen  excreted  only  2-7  grm.  were  in  the  form  of  urea, 
while  as  much  as  2-1  grm.  were  present  as  ammonia. 

If,  during  a  period  of  starvation  in  man,  a  day  is  interpolated  on  which 
100  grm.  of  protein  are  taken,  the  amount  of  acetone  excreted  falls  below 
that  obtained  on  the  other  days  when  the  individual  is  living  chiefly  at 
the  cost  of  his  own  fat.  These  facts  indicate  that  the  chief  source  of  the 
p-oxybutyric  acid  and  the  diacetic  acid  is  the  fats  of  the  food  or  of  the 
body.  The  condition  of  acidosis  is  more  easily  brought  about  bv  ingestion 
of  butyric  acid  than  of  the  higher  acids,  such  as  palmitic  or  stearic,  sug- 
gesting that  whatever  fatty  acid  is  given  it  is  finally  reduced  to  butp-ic 
acid  before  its  oxidation,  and  that  in  the  condition  of  acidosis  it  is  merelv 
the  last  stages  of  this  oxidation  which  are  at  fault.  We  are  thus  justified 
in  concluding  that  the  oxidative  breakdo^vn  of  fats  occurs  always  by  an 
oxidation  in  the  p  position. 

We  take,  for  instance,  the  6-carbon  stage  : 

CH3 .  CH., .  CHo .  CH., .  CFo .  COOK 
the  first  change  which  probably  occurs  is  the  oxidation  : 
CH9.CHg.CHg.CHOH.CHg.COOH 


794  PHYSIOLOGY 

A  further  change  is  the  complete  oxidation  of  the  last  two  groups  and  the 
production  of  butyric  acid  : 

CH3.CH2.CH2.COOH 

This  then  undergoes  again  oxidation  in  the  p  position,  with  the  production 
of  p-oxy butyric  acid  : 

CH3.CHOH.CH2.COOH 

and  then  again  is  converted  to  diacetic  acid, 

CH3.CO.CH2.COOH 

In  the  normal  individual  this  last  stage  undergoes  complete  oxidation, 
both  oxybutyric  acid  and  diacetic  acid  given  to  a  healthy  person  being 
completely  destroyed  in  the  body.  It  is  only  under  the  abnormal  conditions 
which  we  have  mentioned  above  that  these  last  stages  fail  of  complete 
oxidation,  and  are  excreted  unchanged  in  the  urine. 

THE  QUESTION  OF  THE  FORMATION  OF  SUGAR  FROM  FAT 

The  ease  with  which  the  animal  body  performs  the  difficult  chemical 
operation  of  transforming  carbohydrate  into  fat  suggests  that  under 
appropriate  conditions  it  might  effect  the  reverse  change.  Is  there  any 
evidence  that  in  the  animal  body  sugar  may  be  derived  from  fat  ?  Such 
a  conversion  is  of  normal  occurrence  during  the  germination  of  fatty  seeds, 
starch  sugar  and  cellulose  being  formed  at  the  expense  of  the  stored-up 
fats  of  the  seeds.  If  such  seeds  be  allowed  to  germinate  over  mercury  in 
a  confined  volume  of  oxygen,  they  are  found,  like  seeds  containing  chiefly 
carbohydrate  reserves,  to  absorb  oxygen  and  to  give  off  carbon  dioxide. 
Whereas,  however,  in  the  latter  case  the  amount  of  carbon  dioxide  evolved 
is  almost  equal  to  the  oxygen  absorbed,  in  the  case  of  the  fatty  seeds  much 
less  carbon  dioxide  is  given  out  than  would  correspond  to  the  volume  of 
oxygen  absorbed,  so  that  the  total  volume  of  gas  above  the  seeds  diminishes. 

The  same  change  in  the  relation  of  oxygen  intake  to  carbon  dioxide 
output  is  found  under  certain  conditions  in  animals.  During  hibernation, 
as  Pembrey  has  shown,  the  marmot  has  a  very  low  respiratory  quotient, 
which  may  be  not  greater  than  0-3  or  0-4.  This  means  that  the  animal 
takes  in  more  oxygen  than  the  carbon  dioxide  which  it  gives  out,  and  this 
intake  of  oxygen  can  be  so  marked  as  to  cause  an  appreciable  increase  in 
the  weight  of  the  animal,  which  under  such  circumstances  is  literally  living 
on  air.  This  retention  of  oxygen  can  only  be  explained  by  assuming  that 
there  is  a  conversion  of  substances  containing  a  small  amount  of  oxygen 
into  substances  containing  a  larger  amount  of  oxygen  going  on  in  the  body, 
such  a  conversion  as  that  of  fats  into  carbohydrates.  Just  as  the  high 
respiratory  quotient  obtained  from  a  marmot  during  the  period  of  putting 
on  fat  was  shown  to  be  associated  with  a  conversion  of  carbohydrate  into 
fat,  so  does  the  abnormally  low  quotient  obtained  during  hibernation 
indicate  the  reverse  change  of  fat  into  carbohydrate. 

The  same  conversion  has  been  alleged  to  take  place  in  certain  cases  of 


THE  HISTORY  OF  FAT  IN  THE  BODY  795 

diabetes.  In  many  cases  when  the  diabetic  animal  is  Hving  on  a  purely 
protein  diet,  a  uniform  ratio  has  been  found  to  exist  between  the  glucose 
or  dextrose  and  the  nitrogen  excreted. 

—  equals  generally  2'8. 

In  certain  other  cases  a  constant  D  :  N  ratio  of  3-65  has  been  found.  The 
former  represents  a  conversion  of  45  per  cent.,  the  latter  of  58  per  cent., 
of  protein  into  sugar.  In  a  few  cases,  however,  even  during  complete 
starvation,  the  ratio  D  :  N  has  been  found  to  be  much  greater  than  that 
given  above  and  to  amount  to  as  much  as  10  or  12.  These  animals  are 
stated  to  be  practically  free  from  carbohydrates,  so  that  the  sugar  excreted 
in  the  urine  can  only  come  from  the  breakdown  of  proteins  or  fats.  It  is 
impossible  by  any  means  whatever  to  break  up  a  protein  molecule  so  as  to 
get  from  it  ten  times  as  much  dextrose  as  corresponds  to  the  nitrogen,  and 
Pflliger  concludes  that  in  cases  where  such  a  high  D  :  N  ratio  exists  the 
dextrose  must  have  been  derived  by  a  conversion  of  the  fats  of  the  body. 
This  conclusion  is  by  no  means  generally  accepted.  If  correct,  it  would 
bear  out  the  general  statement  made  above,  namely,  that  in  the  living 
body  practically  all  the  chemical  changes  are  reversible,  and  that  the  living 
cell  can  so  regulate  the  conditions  of  the  reaction  that  the  reversible  reaction 
becomes  practically  complete  in  either  direction,  the  direction  being  deter- 
mined by  the  needs  of  the  body  at  the  time. 

Accepting  this  generahsation,  the  chemical  mechanism  by  which  fats 
are  converted  into  carbohydrates  must  be  the  reverse  of  that  by  which 
carbohydrates  are  changed  into  fats.  The  2-carbon  group  spHt  oS  from 
the  large  fatty  molecules  are  probably  utilised  for  the  building  up  of  the 
sugar  molecule.  We  know  that  such  a  synthesis  can  take  place  from  such 
simple  groups  as  formic,  glycolhc,  or  glyceric  aldehyde.  Though  it  is 
impossible  to  deny  to  any  cell  of  the  body  the  power  of  effecting  the  con- 
version of  fats  into  carbohydrates,  or  carbohydrates  into  fats,  the  chief 
centre  for  such  conversions  is  probably  the  chemical  factory  of  the  body, 
namely,  the  liver.  It  is  significant  that  in  the  course  of  fatal  diabetes, 
in  which  the  fat  disappears  entirely  from  the  body,  and  there  is  wasting 
of  practically  all  the  tissues,  the  liver  is  the  only  organ  which  retains  its 
weight  unchanged.  During  this  disease  there  has  been  an  enormous 
amount  of  work  done  in  the  conversion  of  proteins  and  possibly  of  fats 
into  carbohydrates  which  could  not  be  utilised  by  the  body,  and  the  large 
size  of  the  hver  at  death  suggests  that  the  work  of  transformation  has  been 
performed  by  this  organ. 


SECTION  IV 
THE  METABOLISM  OF  CARBOHYDRATES 

All  the  carboliydrates  whicli  are  taken  in  with  the  food  are  ultimately 
transformed  in  the  alimentary  tract,  or  in  its  walls,  into  the  three  mono- 
saccharides, glucose,  fructose,  and  galactose.  These  three,  together  with 
mannose,  are  the  only  sugars  which  are  directly  fermentable  and  directly 
assimilable  by  higher  animals.  A  consideration  of  their  structural  formulae 
shows  that  they  are  fairly  easily  interconvertible,  galactose  presenting  the 
greatest  divergence  from  the  general  type.  This  conversion  actually  takes 
place  in  watery  solution.  If  a  solution  of  any  one  be  left  for  some  months, 
it  Mill  be  found  to  contain  all  four  at  the  end. 

Since  these  monosaccharides,  for  the  greater  part  glucose,  must  enter 
the  blood  in  large  quantities  during  the  absorption  of  a  heavy  carbohydrate 
meal,  one  would  expect  to  iind  a  greater  proportion  in  the  blood  during 
such  a  meal  than  during  a  period  of  starvation.  The  amount  of  reducing 
sugar  in  the  blood,  however,  is  practically  constant,  and  varies  between 
0-1  and  0-15  per  cent. 

Searching  for  the  origin  of  this  constant  proportion  of  reducing  sugar, 
Claude  Bernard  found  that  the  blood  of  the  hepatic  vein  in  a  fasting  animal 
contained  more  sugar  than  the  blood  taken  at  the  same  time  from  the  portal 
vein.  Although  the  reliabihty  of  this  experimental  result  has  been  put  in 
doubt  by  more  recent  investigators,  it  was  important  in  that  it  attracted 
Bernard's  attention  to  the  liver.  If  the  liver  be  taken  from  an  animal  which 
has  been  dead  for  some  time,  and  extracted  with  water,  the  extract  is  found 
to  contain  a  large  quantity  of  reducing  sugar  (glucose).  If,  however,  it  be 
removed  immediately  the  animal  is  dead,  its  vessels  washed  out  with  ice-cold 
saline  fluid,  and  be  then  cut  up  and  thrown  into  boihng  water,  ground  and 
extracted,  the  extract,  after  separation  of  the  coagulable  proteins,  contains 
hardly  a  trace  of  sugar,  and  no  more  than  is  present  in  the  blood.  The 
fluid  is,  however,  opalescent ;  and  Bernard  found  that  this  opalescence  was 
due  to  the  presence  of  a  substance  at  that  time  new  to  science,  belonging  to 
the  class  of  polysaccharides.  This  substance  he  called  glycogen,  i.e.  the 
sugar-former. 

After  a  carbohydrate  meal,  glycogen  may  be  present  in  very  large 
amounts  in  the  liver,  up  to  12  per  cent,  of  the  weight  of  the  fresh  liver. 
From  its  solution  in  water  it  can  be  thrown  down  by  the  addition  of  alcohol 
to  60  per  cent     When  collected  and  dried,  it  forms  a  snow-white  powder, 

796 


THE  METABOLISM  OF  CARBOHYDRATES  797 

tasteless  and  odourless,  with  a  formula  identical  with  that  of  starch,  viz. 
CgHinOj.  Like  starch,  it  is  hydrolysed  by  the  action  of  acids  and  super- 
heated water,  or  of  amylolytic  ferments,  into  dextrins,  maltose,  and  finally 
glucose.  It  gives  with  iodine  a  mahogany-red  colour,  which  disappears  on 
boiling,  but  returns  again  on  cooling. 

It  is  not  possible  to  extract  the  whole  of  the  glycogen  from  a  tissue  by  merely  boil- 
ing it  with  water.  Kiilz  introduced  on  this  account  the  method  of  dissolving 
the  tissues  in  caustic  alkali,  then  throwing  down  the  protein  with  phospliotungstic 
acid,  and  in  the  filtrate  i^rocipitating  the  glycogen  with  alcohol.  This  method  has 
been  modified  by  Pfliiger  as  follows  :  100  grm.  of  the  tissue  (liver  or  muscle)  are  heated 
with  100  c.c.  caustic  potash  containing  60  to  70  per  cent.  KHO  for  twenty-four  hom-s 
in  the  water  bath.  The  solution  is  then  cooled,  diluted  with  200  c.c.  of  water,  and 
treated  with  800  c.c.  alcohol  of  96  per  cent.  The  precipitate  of  glycogen  is  filtered  ofE 
and  washed  several  times  with  66  per  cent,  alcohol.  The  precipitate  of  glycogen  is 
now  washed  with  a  little  water  into  a  small  beaker,  neutralised  carefully  with  acetic 
acid,  and  then  introduced  into  a  100  c.c.  flask.  To  the  solution  5  c.c.  of  hydi'ochloric 
acid  of  1*19  sp.  gr.  are  added,  and  the  mixture  is  made  up  to  85  c.c.  The  flask  is  then 
heated  in  the  water  bath  for  thi-ee  hours.  By  this  means  the  whole  of  the  glycogen 
is  converted  into  glucose,  which  can  be  estimated  by  Fehling's  method  or  by  Allihn's 
method.  Li  practice  it  is  more  accm-ate  to  estimate  the  glycogen  in  the  form  of  sugar 
than  to  weigh  it  directly.  If  large  quantities  of  glycogen  are  expected  in  the  tissue, 
the  inversion  of  the  glycogen  must  be  carried  out  in  a  larger  beaker,  and  only  an 
aliquot  portion  taken  for  titration. 

The  large  amount  of  sugar  foimd  in  the  liver  which  has  been  left  in  the 
body  is  due  to  the  conversion  of  glycogen  into  glucose.  This  conversion  has 
been  variously  ascribed  to  the  activity  of  the  surviving  hver- cells,  or  to  the 
action  of  an  amylase  ferment  present  in  the  liver-cells.  That  it  is  really  a 
ferment  action  is  proved  by  the  fact  that  the  liver  may  be  dehydrated  with 
alcohol,  dried  and  powdered,  and  kept  for  months  in  this  condition  without 
any  alteration  occurring  in  the  glycogen.  If,  however,  the  coagulated  liver 
be  mixed  with  water  and  allowed  to  remain  at  the  temperature  of  the  body 
for  some  hours,  the  glycogen  is  found  to  disappear  and  give  place  to  glucose. 

FORMATION  OF  GLYCOGEN 

Glycogen  is  most  readily  formed  from  the  carbohydrates  of  the  food. 
In  order  to  obtain  a  large  amount  from  the  liver,  the  animal  is  fed  twelve  to 
twenty-four  hours  previously  on  a  meal  which  is  rich  in  carbohydrates. 
Not  all  carbohydrates  will  give  rise  to  the  formation  of  glycogen.  Only 
those  which  we  have  mentioned  as  directly  assimilable,  i.e.  which  will  give 
rise  in  the  alimentary  tract  to  mannose,  glucose,  fructose,  or  galactose,  will 
cause  an  increased  formation  of  glycogen.  The  conversion  involves  a  direct 
polymerisation  of  the  glucose,  produced  either  directly  from  the  foods  or  by 
a  molecular  rearrangement  taking  place  in  one  of  the  other  three  of  these 
monosaccharides. 

Glycogen  can  also  be  formed  from  the  proteins  of  the  food,  or  from  the 
products  of  their  disintegration,  the  amino-acids.  By  means  which  we 
shall  consider  shortly,  it  is  possible  to  free  the  liver  of  animals  entirely 
from  glycogen  :  if  such  animals  be  fed  on  a  diet  of  washed  fibrin  or  of  pure 


798  PHYSIOLOGY 

caseinogen,  or  even  on  the  ultimate  products  of  pancreatic  digestion  of 
proteins  (containing  therefore  only  amino-acids),  and  be  killed  shortly  after- 
wards, the  liver  is  found  to  contain  glycogen.  It  does  not  seem  to  be  possible 
for  the  hver  to  manufacture  glycogen  out  of  fats.  At  any  rate,  that  is  the 
interpretation  which  is  generally  placed  on  experiments  on  feeding  with 
fats.  In  these  experiments  it  is  found  that  if  fats  be  administered  to  an 
animal  after  the  hver  has  been  freed  from  glycogen,  although  the  liver  may 
store  up  fats  it  does  not  store  up  any  glycogen. 

If  an  animal  be  starved,  the  glycogen  gradually  disappears  from  the 
Uver,  although  even  at  the  end  of  ten  or  twelve  days'  complete  deprivation 
of  food  small  traces  of  glycogen  may  still  be  found  in  this  organ.  If  starva- 
tion be  combined  with  hard  work ;  if,  for  instance,  a  dog  be  made  to  drag 
about  a  milk-cart  on  the  second  day  of  the  starvation  period,  its  liver 
becomes  quite  free  from  glycogen.  The  same  disappearance  of  glycogen 
may  be  produced  by  any  means  which  evoke  an  increased  muscular  activity, 
e.g.  poisoning  with  strychnine.  Of  the  various  reserve  materials  which  are 
available  the  carbohydrate  is  the  first  to  be  called  upon  to  meet  the  increased 
needs  of  the  tissues  during  functional  activity,  such  as  muscular  work  or 
increased  heat  production.  Thus  the  glycogen  rapidly  disappears  from 
the  Hver  of  a  rabbit  which  has  been  immersed  in  a  cold  bath. 

The  glycogen  of  the  hver  represents  a  reserve  material  analogous  to  the 
reserve  carbohydrates  stored  up  as  starch  in  different  parts  of  plants. 
When  the  blood  is  loaded  with  carbohydrates,  a  considerable  proportion  is 
laid  down  as  the  inert  polysaccharide  glycogen.  As  soon  as  the  supply  of 
sugar  to  the  blood  is  withdrawn,  the  tissues  continue  to  use  the  sugar  of  the 
blood,  which  is  made  up  at  the  expense  of  the  glycogen  in  the  hver.  In  every 
liver- cell  therefore  a  twofold  process  is  always  going  on,  namely,  a  building 
up  of  glycogen  by  the  activity  of  the  hver-cells,  and  a  breaking  down  of 
glycogen  under  the  action  of  the  ferment  formed  in  the  liver-cells.  Which  of 
these  two  processes  preponderates  depends,  in  the  normal  animal,  on  the 
percentage  amount  of  sugar  in  the  blood  which  is  circulating  through  the 
organ. 

On  account  of  the  importance  of  glycogen  as  a  reserve  material  it  is 
produced  and  stored  up  in  almost  all  growing  tissues,  to  be  utihsed  in  their 
subsequent  development.  Thus  it  is  found  in  large  quantities  in  the  placenta 
during  a  certain  period,  in  foetal  muscles,  and  in  various  other  situations.  It 
is  found  in  yeast,  in  oysters,  and  in  the  muscles  of  the  body  generally.  In 
foetal  muscles  it  may  amount  to  as  much  as  40  per  cent,  of  the  total  dried 
sohds.  The  glycogen  of  the  adult  muscle  is  apparently  utihsed  during 
muscular  work,  and  diminishes  in  amount  with  activity  of  the  muscle.  In 
adult  muscles  it  never  reaches  anything  like  the  percentage  which  is  found  in 
the  hver.  The  average  amounts  found  by  Schondorf  in  the  different  tissues 
were  as  follows  : 


THE  METABOLISM  OF  CARBOHYDRATES 


709 


Maximum  per  cent. 

Minimum  percent. 

of  fresh  tissue 

of  fresh  tissue 

Liver      .... 

18-69 

7-300 

Muscle   . 

3-72 

0-720 

Heart     . 

1-32 

0-104 

Bone 

1-90 

0-197 

Intestines 

1-84 

0-026 

Skin       . 

1-68 

0-090 

Blood     . 

0-0066 

0-0016 

THE  UTILISATION  OF  SUGAR  IN  THE  BODY 
Arterial  blood  is  always  found  to  contain  between  0-12  and  0-15  per 
cent,  of  sugar  in  the  form  of  glucose.  The  same  amount  is  fovmd  whether 
the  blood  be  taken  from  an  animal  after  a  heavy  carbohydrate  meal  or 
from  one  in  a  condition  of  complete  starvation.  The  constancy  of  the 
sugar  content  of  the  blood  suggests  that  this  substance  is  a  necessary  con- 
stituent of  the  circulating  fluid,  necessary,  that  is  to  say,  for  the  nutrition  of 
the  tissues.  That  it  is  being  used  up  in  all  the  processes  of  the  body  is 
shown  by  the  immediate  alteration  in  the  respiratory  quotient  which  occurs 
when  the  food  is  changed  from  a  mixed  diet  to  one  consisting  mainly  of 
carbohydrate.  An  important  factor  in  the  maintenance  of  a  constant  sugar 
content  in  the  blood  is  the  reconversion  of  the  stored-up  glycogen  of  the 
Hver  into  sugar.  The  glycogen  is  not,  however,  the  sole  source  of  the  sjgar, 
since  in  complete  starvation  the  sugar  content  of  the  blood  remains  constant 
even  after  the  last  traces  of  glycogen  have  disappeared  from  the  Hver.  If  the 
liver  be  cut  out  of  the  body  or  removed  from  the  circulation,  during  the 
few  hours  that  the  animal  survives  there  is  a  steady  diminution  in  the  blood- 
sugar,  pointing  to  the  hver  being  the  chief,  if  not  the  sole,  source  of  the  blood 
sugar.  In  some  animals,  e.g.  the  carnivora,  it  would  seem  that  the  liver 
can  continue  to  supply  sugar  to  the  blood  on  a  diet  which  includes  only 
proteins  and  fats,  and  we  have  already  seen  that  in  such  animals  glycogen 
itseK  can  be  stored  up  at  the  expense  of  protein.  It  is  doubtful  whether  a 
perfectly  normal  existence  is  possible  in  man  in  the  total  absence  of  carbo- 
hydrates from  the  food,  though  there  is  no  doubt  that  in  the  northern  nations, 
e.g.  the  Eskimos,  the  amount  of  carbohydrate  consumed  is  very  smaU  in 
comparison  with  the  fats  and  proteins.  During  muscular  exercise  the 
increased  output  of  energy  is  associated  ■svith  a  corresponding  increase  in  the 
absorption  of  oxygen  and  in  the  output  of  carbon  dioxide,  pointing  to  a 
consumption  of  carbohydrate  and  fat  in  the  contracting  muscles.  We  might 
therefore  assume  that  sugar  is  being  normally  released  by  the  hver  into  the 
blood-stream  so  as  to  maintain  the  proportion  of  this  substance  in  the  blood 
at  a  certain  level,  and  that  the  sugar  is  as  constantly  being  taken  up  and  oxi- 
dised in  the  muscles,  where  it  serves  as  a  source  of  energy.  According  to 
Chauveau  and  Kaufmann  the  venous  blood  flowing  from  a  contracting 
muscle  contains  less  sugar  than  the  arterial  blood  flowing  to  the  muscle.     A 


800  PHYSIOLOGY 

similar  consumption  of  glucose  occurs  in  the  isolated  contracting  mammalian 
heart  when  fed  with  Einger's  fluid  containing  a  small  trace  of  glucose.  A 
heart,  fed  with  blood  and  performing  a  normal  amount  of  work,  may  use 
about  4  mg.  sugar  per  gramme  of  heart  muscle  per  hour.  That  the  question 
of  utilisation  of  sugar  by  the  tissues  is  highly  complex  is  shown  by  a  study 
of  the  conditions  under  which  sugar  may  appear  in  the  urine.  We  learn 
thereby  to  appreciate  to  some  extent  the  significance  of  carbohydrates  both 
as  sources  of  energy  and  as  foods  for  the  tissues,  though  we  are  still  a  long  way 
from  unravelling  all  the  changes  which  the  sugar  must  undergo  in  the  cell 
before  it  appears  once  again  in  the  oxidised  products,  carbon  dioxide  and 
water. 

GLYCOSURIA 

Normal  urine  always  contains  a  small  proportion  of  sugar,  about  1  part 
per  1000,  i.e.  about  the  same  as  the  blood  itself.  For  the  detection  of  these 
small  traces  of  sugar  in  the  urine  special  methods  are  necessary.  The  term 
glycosuria  is  not  employed  unless  sugar  appears  in  quantities  large  enough 
to  give  a  reaction  wdth  Fehling's  solution  or  with  the  phenylhydrazine  test. 
Such  a  condition  may  easily  be  brought  about  by  the  injection  of  sugar 
subcutaneously  or  intravenously.  It  is  then  found  that  any  trace  of  the  di- 
saccharides,  cane  sugar  or  lactose,  introduced  in  the  circulation,  is  excreted 
in  the  urine.  A  rather  larger  quantity  of  maltose  may  be  injected  slowly 
without  appearing  in  the  urine,  since  the  blood-serum  contains  a  ferment 
maltase,  which  converts  the  maltose  into  glucose.  Glucose,  fructose,  man- 
nose,  or  galactose,  if  introduced  slowly  into  the  circulation,  are  stored  up 
as  glycogen  in  the  liver.  If,  however,  the  percentage  of  sugar  in  the  blood 
rises  above  2  parts  per  1000,  the  sugar  (generally  glucose)  appears  in  the  urine. 
When  this  condition  of  hyperglycsemia  (excess  of  sugar  in  the  blood)  is  set  up, 
the  concentration  of  the  sugar  in  the  urine  no  longer  corresponds  to  that  in 
the  blood.  If  the  blood  contains,  e.g.  4  parts  per  1000,  the  urine  may  contain 
from  2  to  7  per  cent,  of  sugar.  Up  to  a  certain  point,  then,  blood-sugar  is 
kept  back  by  the  kidneys  as  a  necessary  food  material  for  the  tissues.  Any 
excess  above  the  normal  apparently  acts  as  a  foreign  substance  and  is 
excreted  by  the  kidneys  in  a  concentration  much  greater  than  that  in  which 
it  exists  in  the  blood- serum. 

(1)  ALIMENTARY  GLYCOSURIA.  A  state  of  hyperglyca^mia  may  be 
induced  by  the  administration  of  abnormally  large  quantities  of  glucose 
by  the  alimentary  canal.  The  amount  has  to  exceed  in  a  healthy  individual 
100  grm.  in  order  that  it  shall  appear  in  the  urine.  In  certain  individuals  the 
power  of  assimilating  glucose  may  be  deficient  so  that  an  alimentary  glyco- 
suria may  be  caused  by  any  over-indulgence  in  carbohydrate  food.  In  the 
healthy  person  it  is  hardly  possible  to  produce  glycosuria  by  the  administra- 
tion of  starchy  foods,  since  the  liver  can  store  up  the  excess  of  glucose  as  fast 
as  it  is  produced  from  the  starch  by  digestion  and  absorbed  into  the  blood 
stream. 

(2)  DIABETIC  PUNCTURE.  It  was  shown  by  Claude  Bernard  that 
puncture  of  the  floor  of  the  fourth  ventricle  in  rabbits  is  often  followed 


THE  METABOLISM  OF  CARBOHYDRATES  801 

immediately  by  an  excessive  secretion  of  urine  and  the,  appearance  of  sugar 
in  this  fluid.  The  glycosuria  may  last  from  twenty-four  to  thirty  hours. 
If  at  the  end  of  this  time  the  animal  be  killed,  the  liver  is  found  to  be  free 
from  glycogen.  A  sample  of  blood  taken  during  the  height  of  glycosuria  may 
contain  from  3  to  4  parts  of  sugar  per  1000.  In  order  that  the  experiment 
may  succeed  it  is  important  that  the  animal  be  previously  well  fed.  If  the 
puncture  or  '  piqure '  be  carried  out  on  an  animal  that  has  been  starved  or 
whose  Uver  has  been  freed  by  any  means  from  glycogen,  no  glycosuria 
is  produced.  It  is  evident  that  the  effect  of  the  puncture  has  been  to  cause 
a  rapid  conversion  of  the  glycogen  previously  stored  up  in  the  liver  into 
glucose.  The  glucose  so  formed  escapes  into  the  blood,  raising  the  sugar 
content  of  this  fluid  above  the  normal,  and  the  excess  is  immediately  excreted 
by  the  kidneys  together  with  an  increased  amount  of  water.  A  similar 
temporary  hyperglycaemia  and  glycosuria  may  be  brought  about  by  fright, 
strugghng  or  the  administration  of  ansesthetics  ;  but  the  effect  is  absent, 
if  both  splanchnic  nerves  have  been  previously  divided  above  the  supra- 
renals.  It  has  been  shown  (Elliott,  Cannon)  that  all  these  conditions  are 
associated  with  an  increased  discharge  of  adrenahn  from  the  medulla  of 
the  suprarenals  into  the  circulation.  Since  the  injection  of  adrenaline  itself 
causes  a  condition  of  diabetes  similar  in  all  its  limitations  and  aspects  to 
'  puncture  diabetes,'  it  is  now  generally  believed  that  the  two  conditions  are 
identical,  and  that  the  diabetic  puncture  acts  through  the  splanchnic  nerves 
on  the  suprarenals,  setting  free  adrenahn,  which  passing  to  the  liver  causes 
a  rapid  '  mobilisation '  of  the  stored-up  glycogen,  and  a  consequent  hyper- 
glycaemia  and  glycosuria,  lasting  as  long  as  the  glycogen  store  holds  out. 
!■  ;  (3)  PHLORIDZIN  DIABETES.  Phloridzin  is  a  glucoside  extracted  from 
the  root  cortex  of  the  apple-tree.  It  may  be  decomposed  into  a  sugar  and 
phloretin.  When  phloridzin  or  phloretin  is  administered  by  the  mouth  or 
subcutaneously  it  gives  rise  to  glycosuria,  unaccompanied,  at  first  at  any  rate, 
by  any  other  symptom.  The  urine  may  contain  from  5  to  15  per  cent,  of 
glucose.  The  glycosuria  induced  in  this  way  differs  from  the  forms  already 
described  in  the  fact  that  it  is  not  due  to  hyperglycsemia.  Analysis  of  the 
blood  shows  that  the  sugar  is  shghtly  diminished  rather  than  increased.  The 
excretion  of  glucose  seems  to  be  due  to  a  specific  effect  of  the  drug  upon  the 
kidneys.  If  a  cannula  be  placed  in  the  two  ureters  so  as  to  collect  the  urine 
from  each  kidney  separately  and  a  small  dose  of  phloridzin  be  then  injected 
by  a  hypodermic  syringe  into  the  left  renal  artery,  the  urine  flowing  from 
the  left  ureter  will  in  two  minutes  be  found  to  contain  sugar,  while  the 
urine  from  the  right  kidney  will  not  contain  any  sugar  for  another  five  or  ten 
minutes.  The  effect  therefore  is  rapidly  to  drain  off  sugar  from  the  blood. 
In  order  to  maintain  the  sugar  content  of  the  blood  at  its  normal  height  the 
liver  must  rapidly  manufacture  fresh  sugar  to  take  the  place  of  that  lost  by 
the  kidneys.  In  the  first  instance  the  liver  will  utilise  its  stored-up  glycogen 
for  this  purpose.  If  a  dose  of  phloridzin  be  given  to  each  of  tw(;  animals  and 
one  animal  killed  as  soon  as  the  excretion  of  sugar  is  coming  to  an  end,  the 
liver  W'ill  be  found  free  from  glycogen.     If  now  a  second  dose  of  phloridzin 

20 


802 


PHYSIOLOGY 


be  given  to  the  other,  which  may  be  regaided  as  glycogen-free,  glycosuria  is 

produced  as  before,  and  the  excretion  of  sugar  can  be  continued  indefinitely 

by  repeated  administration  of  the  drug.     So  long  as  suiiicient  food  is  given, 

including  carbohydrates,  the  loss  of  sugar  does  not  entail  any  increase  in  the 

destruction  of  the  tissues ;    but  if  the  drug  be  administered  to  starving 

animals  the  waste  of  sugar  has  to  be  made  good  at  the  expense  of  material 

other  than  carbohydrate.     The  source  of  the  sugar  excreted  under  these 

circumstances  is  the  protein  of  the  tissues.     The  nitrogen  excreted  in  the 

urine  rises  in  amount  in  proportion  to  the  quantity  of  sugar  excreted,  and 

there  is  a  constant  ratio  between  the  amount  of  nitrogen  and  the  amount 

of  sugar  excreted  in  the  urine.     In  different  experiments  this  ratio  D  :  N 

varies  from  2-8  :  1  to  3-6  :  1.     If  meat  be  administered  to  such  starving 

animals  with  glycosuria,  the  D  :  N  ratio  does  not  alter ;    the  amount  of 

nitrogen  in  the  urine  increases,  but  the  sugar  increases  in  the  same  proportion. 

The  sugar  production  is  therefore  proportional  to  the  protein  metabohsm  and 

must  be  derived  from  protein.     The  source  of  the  sugar  is  the  amino-acids 

of  which  the  protein  is  composed.     It  has  been  shown  by  Lusk,  Embden  and 

Dakin  that  the  following  amino-acids  yield  large  amounts  of  glucose  when 

administered  to  a  phloridzinised  animal :   glycine,  alanine,  serine,  cystine, 

aspartic  acid,   glutamic  acid,   ornithine,  proMne  and  arginine.    We  must 

assume  that  these  amino-acids  produced  in  digestion  or  by  the  autolysis 

of  the  tissues  undergo  deamination  and  that  the  sugar  is  formed  by  a  process 

of  s}Tithesis  from  the  oxyacids  thereby  produced.     On  the  other  hand 

leucine,  tyrosine  and  phenylalanine  give  no  increase  in  the  output  of  sugar. 

It  is  however  just  these  amino-acids  which  seem  to  follow  the  line  of  fat 

metabohsm,  since  they  are  converted  into  aceto-acetic  acid  when  perfused 

through  a  dog's  Hver — and  the  administration  of  fats  to  phloridzinised  dogs 

is  also  without  effect  on  the  sugar  excretion.     The  drain  of  sugar  from  the 

organism  determined  by  the  action    of    phloridzin  on  the  kidneys  thus 

necessitates  a  continued  breakdown  of  the  nitrogenous  tissues  of  the  body 

in  the  effort  to  maintain  a  normal  supply  of  sugar  to  the  tissues,  and  unless 

excessive  feeding  be  employed  the  animal  must  waste.     The  great  increase 

in  the  nitrogenous  output  resulting  from  the  condition  of  phloridzin  diabetes 

is  shown  in  the  following  Table  (Lusk)  : 


Goat 

Dog 

D 

N 

D:N 

D 

N 

D:N 

Fasting    . 
Fasting    . 

Fasting  and  diabetic  . 
Fasting  and  diabetic . 
Fasting  and  diabetic . 
Fasting  and  diabetic . 

20-33 
26-08 
23-39 
1901 

3-72 
3-71 
4-90 

8-83 
8-06 
6-84 

4-15 
2-95 
2-90 

2-78 

63-55 
65-30 
65-84 
64-60 

4-04 
4-17 
12-66 
18-76 
18-57 
17-29 

5-02* 
3-38 
3-54 
3-74 

*  The  high  D  :  X  ratio  on  the  first  day  is  evidently  due  to  the  conversion  of  the 
glycogen  still  present  in  the  body. 


THE  METABOLISM  OF  CARBOHYDRATES 


803 


The  constant  drain  of  sugar  will  in  time  involve  a  relative  carbohydrate 
starvation  of  the  tissues,  which  will  make  good  their  energy  requirements  as 
much  as  possible  at  the  expense  of  protein  and  fat.  The  administration  of 
meat  will  diminish  the  fat  metabolism  to  a  certain  extent,  but  since  it  does 
not  alter  the  D  :  N  ratio  it  would  appear  that  the  latter  does  not  depend  in 
any  way  on  the  quantity  of  fat  undergoing  oxidation.  This  is  shown  in  the 
following  respiration  experiment  (Mandel  and  Lusk)  on  a  dog  with  phloridzin 
glycosuria,  in  which  the  metabolism  dming  starvation  and  after  ingestion  of 
meat  was  determined  : 


rJ:X 

Calories  from 
proti'iii 

Calorics  from 
lat 

Calorics 
total 

Fasting 

300  grm.  meat 

3-69 
3-55 

80-2 
161-9 

274-4 
261-7 

354-6 
423-6 

The  enormous  waste  of  energy  involved  in  such  a  constant  loss  of  sugar 
will  be  apparent  if  we  consider  that  a  D  :  N  ration  of  3-65  means  that  52-5 
per  cent,  of  the  energy  in  the  protein  taken  as  food  or  set  free  from  the  tissues 
is  lost  to  the  organism  in  the  form  of  glucose.  According  to  Rubner  28-5  of 
the  energy  of  meat  protein  is  not  utilised  in  the  body,  but  is  liberated  simply 
as  heat.  This  stimulating  effect  of  protein  on  metabolism  or  on  the  processes 
of  oxidation  in  the  body  is  described  by  Rubner  as  the  '  specific  d^aiamic 
action  '  of  proteins.  If  we  accept  this  view  and  add  this  28-5  per  cent,  lost 
as  heat  to  the  52-5  per  cent,  lost  as  sugar  there  would  remain  a  balance  of 
only  19  per  cent,  actually  available  for  the  vital  activities  of  the  tissues. 
It  is  not  to  be  wondered  at  that  the  nitrogenous  metaboHsm  may  be 
increased  three-  to  five-fold  as  a  result  of  the  artificial  induction  of  the 
diabetic  condition. 

The  carbohydrate  starvation  has  other  deleterious  effects,  since  we  have 
evidence  that  a  certain  amount  of  carbohydrate  food  is  a  necessary  con- 
dition for  both  fat  and  protein  metabohsm.  The  necessity  of  carbohydrate 
for  the  assimilation  of  protein  is  brought  out  in  an  experiment  by  Cathcart. 
It  has  long  been  known  that  carbohydrate  administration  has  a  sparing  effect 
on  protein  metabolism.  If  an  animal  or  man  be  starved,  the  nitrogenous 
output  sinks  to  a  certain  level  and  there  remains  practically  stationary.  If 
now  pure  carbohydrate  food  be  administered  sufficient  to  meet  the  energy 
requirements  of  the  animal  or  man  (about  35  calories  per  kilo),  there  is  at 
once  a  rapid  drop  in  the  output  of  nitrogen  and  therefore  in  the  protein 
waste  of  the  tissues.  Fat  has  a  much  slighter  or  no  sparing  effect  on  the 
nitrogenous  metabohsm.  Indeed  in  certain  experiments  by  Cathcart  the 
administration  of  fat  caused  an  actual  rise  in  the  nitrogenous  output. 

The  importance  of  carbohydrates  is  borne  out  by  the  results  of  feeding 
animals  with  proteins  which  have  been  digested  ^vith  pancreatic  juice  imtil 
the  biuret  reaction  has  disappeared.  After  Loewi  had  sho^^^l  that  it  was 
possible  to  maintain  nitrogenous  equilibrium  in  dogs  with  such  a  digest. 


804  PHYSIOLOGY 

Lesser  was  unable  to  confirm  his  results  ;  but  it  has  been  pointed  out  that  the 
essential  difference  between  the  two  observers  was  that  Loewi  gave  an 
abundant  supply  of  carbohydrates  with  the  digest,  while  Lesser  omitted 
carbohydrates  altogether  and  administered  fats  and  protein  digest  alone. 

The  evidence  that  the  carbohydrates  play  a  necessary  part  in  the  meta- 
bolic history  of  fats  has  already  been  mentioned  {v.  p.  793).  We  have  seen 
that  in  the  absence  of  carbohydrates  the  last  stages  in  the  oxidation  of  fats 
make  default  so  that  the  partially  oxidised  fatty  acids,  oxybutyric  acid  and 
aceto-acetic  acid,  accumulate  in  large  quantities  and  are  excreted  as  such  or 
as  acetone  in  the  urine.  Not  only  does  this  involve  a  loss  of  energy  to  the 
body,  but  these  organic  acids  require  other  bases  for  their  neutralisation. 
Up  to  a  certain  point  they  will  be  excreted  in  the  urine  in  combination  with 
the  fixed  alkaHes.  When  these  are  no  longer  present  in  sufficient  quantity 
they  will  be  excreted  in  combination  with  ammonia,  so  that  the  ammonia  of 
the  urine  is  largely  increased.  If  the  condition  of  carbohydrate  starvation 
be  continued,  this  mechanism  of  neutrahsation  is  insufficient  and  the  pheno- 
mena of  acidosis,  dyspnoea  and  coma,  ensue,  resulting  in  the  death  of  the 
animal. 

Another  effect  of  continued  administration  of  phloridzin  is  fat  infiltration 
of  the  Uver.  This  is  merely  a  result  of  the  carbohydrate  starvation.  A 
similar  condition  of  fat  infiltration  can  be  brought  about  by  feeding  with  a 
pure  protein  plus  fat  diet.  The  liver  seems  to  be  able  to  act  as  a  storehouse 
either  of  fat  or  of  carbohydrate,  so  that  there  is  an  inverse  ratio  between 
the  amormt  of  glycogen  and  the  amount  of  fat  stored  up  in  the  Hver  at 
any  given  time.  It  has  been  shown  that  the  fat  in  the  liver  under  these 
circumstances  is  simply  fat  which  has  been  transferred  to  this  organ  from 
the  ordinary  fat  depots,  subcutaneous  tissues,  &c.,  of  the  body. 

(4)  PANCREATIC  DIABETES.  Von  Mering  and  Minkowski  found  that 
total  excision  of  the  pancreas  gives  rise  to  a  severe  and  rapidly  fatal  diabetes, 
which  presents  many  similarities  to  the  severer  cases  of  diabetes  in  man. 
Owing  to  the  fact  that  the  tissues  of  a  diabetic  are  extremely  prone  to  in- 
fection, it  is  often  difficult  after  total  excision  of  the  pancreas,  when  diabetes 
has  been  set  up,  to  procure  healing  of  the  wounds  without  suppuration. 
The  operation  is  therefore  usually  carried  out  in  two  stages.  In  the  first 
stage  one  small  portion  of  the  tail  of  the  pancreas  is  transplanted  under  the 
skin  of  the  abdomen,  while  the  rest  of  the  gland  is  excised.  Such  animals 
do  not  get  diabetes  and  therefore  recover  quickly  from  the  operation.  When 
the  wounds  are  quite  healed  the  transplanted  portion  is  removed  through  a 
simple  skin  incision.  The  second  operation  is  followed  in  a  few  hours  by  the 
appearance  of  a  large  amount  of  sugar,  5  to  10  per  cent,  in  the  urine.  The 
glycosuria  persists,  the  animal  rapidly  wastes,  and  finally  dies  at  the  end 
of  two  to  three  weeks  from  diabetic  coma.  From  the  nature  of  the  operation 
it  is  evident  that  the  condition  of  diabetes  observed  under  these  circumstances 
has  nothing  to  do  with  the  presence  or  absence  of  the  pancreatic  secretion 
from  the  intestine,  since  this  secretion  is  cut  off  at  the  first  operation  and 
diabetes  does  not  make  its  appearance  until  the  second  small  portion  of  the 


THE  METABOLISM  OF  CARBOHYDRATES  805 

gland  is  removed.  Moreover  ligature  of  the  ducts  of  the  pancreas  or  obstruc- 
tion of  the  ducts  by  the  injection  of  melted  paraffin  does  not  give  rise  to 
diabetes.  The  excretion  of  sugar  by  the  kidneys  is  due  to  an  increase  in  the 
sugar  content  of  the  blood.  The  blood-sugar  may  amount  to  between  4  and 
5  parts  per  1000.  This  state  of  hyperglycaemia  and  the  excretion  of  sugar 
in  the  urine  persist  even  when  the  animal  is  completely  starved  or  is  fed  on  a 
pure  protein  or  protein  plus  fat  diet.  Moreover,  as  in  phloridzin  glycosuria, 
we  find  a  constant  ratio  between  the  sugar  and  the  urinary  nitrogen,  the  D  :  N 
ratio  being  usually  about  2-8.  The  administration  of  protein  food  to  an 
animal  previously  starved  increases  the  output  of  nitrogen,  but  increases 
at  the  same  time  the  output  of  glucose.  No  similar  increase  in  the  glucose 
excretion  is  observed  as  a  result  of  the  administration  of  fat.  We  must 
conclude  therefore  that  in  the  absence  of  carbohydrate  from  the  diet  the 
excess  of  sugar  in  the  blood  as  well  as  that  escaping  by  the  urine  is 
derived  from  the  breakdown  of  the  proteins  of  the  tissues.  On  the  other 
hand,  the  power  of  the  animal  to  assimilate  or  utilise  carbohydrate  is 
diminished  and  sometimes  entirely  abohshed,  so  that  glucose  administered 
to  a  starving  animal  with  pancreatic  diabetes  may  appear  quantitatively 
in  the  urine.  The  amount  taken  by  the  alimentary  canal  is  simply  added 
to  the  amount  which  would  have  been  excreted  if  no  food  had  been  given. 
In  most  cases,  at  any  rate  during  the  first  week  after  total  extirpation,  there 
is  apparently  still  some  power  of  carbohydrate  assimilation,  since  adminis- 
tration of  glucose  causes  a  transitory  rise  in  the  respiratory  quotient  (Moor- 
house).  Glycogen  disappears  entirely  from  the  liver ;  but  the  muscles, 
especially  the  heart,  may  contain  a  normal  or  an  increased  amount  of 
glycogen.  There  is  a  rapid  wasting  of  all  the  tissues  of  the  body,  including 
the  fats  and  proteins,  and  finally  the  animal  is  destroyed  by  the  accumulation 
of  the  products  of  imperfect  oxidation  of  the  fatty  acids. 

It  is  still  very  difficult  to  say  definitely  why  removal  of  the  pancreas 
brings  about  this  condition  or  what  disturbance  of  metabolism  is  primarily 
responsible  for  it.  Two  views  have  been  put  forward.  According  to  one, 
the  primary  disturbance  is  the  diminished  or  absent  power  of  utilisation 
of  sugar  by  the  tissues  ;  according  to  the  second,  an  increased  production 
of  sugar  by  the  liver.  There  is  no  doubt  that  in  the  diabetic  animal  the 
power  of  utilising  carbohydrates  is  deficient.  This  is  shown  by  the  low 
respiratory  quotient  and  by  the  fact  that  administration  of  glucose  to 
the  animal  causes  an  almost  corresponding  increase  in  the  amount  of 
glucose  excreted  in  the  urine.  But  the  loss  of  power  of  utilisation  is  not 
absolute,  at  any  rate  in  the  first  week  of  the  disorder.  Administration  of 
glucose  causes  a  slight  and  temporary  rise  in  the  respiratory  quotient, 
and  if  20  gms.  of  glucose  be  administered,  it  is  often  possible  to  recover 
only  about  15  to  18  gms.  from  the  urine.  Moreover  the  increased  amount 
of  glycogen  in  the  heart  muscle  of  diabetic  dogs  points  to  a  persistent 
power  of  assimilation  of  sugar  by  this  organ.  The  heart  from  a  diabetic 
animal,  if  fed  with  its  own  blood,  can  be  shown  to  use  up  not  only  the 
sugar  circulating  in  the  blood  but  also  its  store  of  glycogen,  and  this  utilisa- 


806  PHYSIOLOGY 

tion  is  especially  marked  if  the  heart  be  made  to  work  excessively  by 
raising  the  arterial  resistance  and  administering  adrenahn ;  but  taken  as 
a  whole  the  power  of  utihsing  glucose  is  very  inferior  to  that  possessed 
by  normal  animals.  One  of  the  most  striking  features  of  the  condition 
caused  by  total  extirpation  of  the  pancreas  is  the  rapid  diminution  of  the 
fat  depots  of  the  body,  attended  by  a  marked  condition  of  lipaemia  and 
accumulation  of  fat  in  the  Hver.  The  blood  is  so  full  of  fat  globules  that 
it  has  been  compared  in  appearance  to  strawberries  and  cream.  One  of 
the  first  effects  of  extirpation  of  the  pancreas  is  therefore  a  rapid  fat 
mobihsation,  and  the  respiratory  quotient  agrees  with  that  obtained  when 
the  metabolic  needs  of  the  body  are  being  mainly  satisfied  at  the  expense 
of  the  fat.  The  sugar  of  the  urine,  after  the  depletion  of  the  glycogen 
store  of  the  Uver,  is  derived  from  the  protein,  and  the  protein  tissues  of 
the  body  therefore  diminish  as  rapidly  as  the  fat  stores.  On  the  theory 
of  deficient  utihsation,  it  is  thought  that  these  tissues  suffer  from  carbo- 
hydrate starvation,  even  though  they  are  bathed  in  a  medium  containing 
an  increased  amount  of  sugar,  and  that  the  liver  in  response  to  some  call 
from  the  tissues  turns  first  its  glycogen  and  later  on  the  proteins  of  the 
body  into  sugar  to  supply  this  lack — all  to  no  purpose  however,  since  the 
tissues  are  unable  to  avail  themselves  of  the  sugar  or  ferment. 

According  to  the  second  view,  the  primary  disorder  affects  only  the 
Hver.  This  organ  is  freed  from  some  restraining  influence  on  its  power  of 
manufacturing  sugar  from  glycogen  and  from  protein,  so  that  the  blood  is 
flooded  with  sugar,  which  is  therefore  excreted  in  the  urine.  Any  deficient 
utihsation  of  the  sugar  would  be  regarded  as  secondary  to  a  poisoning  of 
the  tissues  by  this  overloading  of  their  nutrient  fluids  with  sugar.  It  is 
certain  that  the  sugar  production  in  diabetes  is  excessive,  as  is  shown  by 
the  rapid  wasting  of  the  protein  tissues  to  give  rise  to  the  sugar,  and  that 
this  over-production  takes  place  in  the  hver  is  shown  by  the  fact  that 
extirpation  of  the  liver  in  the  diabetic  animal  causes  a  rapid  disappearance 
of  the  sugar  from  the  blood. 

According  to  the  Vienna  school  (Eudinger,  Falta,  and  others),  a  close 
interaction  exists  between  the  thyroid,  the  suprarenals,  the  pancreas,  and 
the  liver,  the  thyroid  to  a  slight  extent,  the  pancreas  still  more,  inhibiting 
the  glycogenic  functions  of  the  liver,  while  the  suprarenals  through  their 
excretion  of  adrenalin  stimulate  this  function.  Glycsemia  and  glycosuria 
caused  by  extirpation  of  the  pancreas  would  therefore  be  ascribed  to  an 
unchecked  activity  of  the  suprarenals.  An  important  difference  however 
seems  to  exist  between  the  two  conditions.  Adrenalin  glycosuria  comes 
to  an  end  when  the  glycogen  store  of  the  liver  is  exhausted,  whereas  pan- 
creatic diabetes  continues  until  the  death  of  the  animal,  long  after  all 
traces  of  glycogen  have  disappeared  from  the  liver.  We  do  not  yet  know 
how  the  pancreas  affects  sugar  production  or  utilisation  in  the  normal 
animal.  It  is  generally  assumed  that  it  secretes  into  the  blood  stream  a 
hormone  which  may,  according  to  the  view  of  the  nature  of  diabetes  which 
we  adopt,  pass  to  the  tissues  and  enable  them  to  utilise  sugar,  or  pass  to 


THE  METABOLISM  OF  CARBOHYDRATES  807^ 

the  liver  and  inhibit  the  sugar  production  in  this  organ.  A  very  small 
portion  of  the  pancreas  is  suificient  for  this  purpose,  but  we  have  been 
unable  to  imitate  the  action  of  the  pancreas  still  in  vascular  connection 
with  the  body  by  injection  or  administration  of  extracts  of  this  organ. 
Even  connection  of  a  healthy  animal  with  a  diabetic  animal  by  means 
of  its  blood-vessels,  so  as  to  allow  the  healthy  blood,  presumably  provided 
with  the  products  of  secretion  of  the  pancreas,  to  circulate  through  the 
diabetic  animal,  does  not  abolish  the  condition  of  hyperglycsemia  in  the 
latter,  though  connection  of  the  portal  vein  of  the  healthy  animal  with  that 

A  B 


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Fig.  356.  (A)  and  (B)  show  an  islet  with  the  surrounding  tissue  in  a  resting  gland  (A) 
and  after  exhaustion  with  .secretin  (B).  In  (A)  the  secreting  acini  are  charged  with 
symogen  granules.  In  (  B)  these  have  entirely  disappeared.  On  the  other  hand  no 
change  is  noticeable  in  the  cells  of  the  islet.  In  the  latter  the  granular  cells  are  the 
h  cells,  and  the  clear  hyaline  cells  are  the  a  cells,  (m)  showing  what  are  called 
Minkowski  granules.  The  granulation  of  this  cell  is  regarded  by  Bensley  as  due  to 
postmortem  changes. 

of  the  diabetic  animal  has,  according  to  Hedon,  had  the  effect  of  stopping 
the  condition  of  glycosuria.     Further  work  is  required  on  this  point. 

We  thus  see  that  the  pancreas  has  a  two-fold  function,  namely,  the 
secretion  of  a  digestive  juice  into  the  intestine  and  the  exercise  by  some 
means  or  other  of  an  influence  on  general  metabolism,  the  absence  of 
which  is  followed  by  the  supervention  of  diabetes.  Corresponding  with 
this  two-fold  fimction,  two  kinds  of  structures  are  present  in  the  gland, 
the  secreting  acini  and  the  islets  of  Langerhans.  These  latter,  though 
arising  in  connection  with  the  ducts,  are  solid  masses  of  cells  and  have  no 
communication  with  the  lumen  of  tlie  ducts.  According  to  Bensley  and  Lane 
the  islet  cells  may  be  divided  into  two  varieties  which  have  been  given  the 
name  of  A  and  B  cells,  according  as  their  granules  are  fi.xed  respectively 
by  alcoholic  or  watery  solutions.  It  has  been  shown  both  by  Bensley  and 
by  Homans  that  these  cells  undergo  no  alterations  when  the  gland  is  excited 
to  secrete  by  the  injection  of  secretin.     On  the  other  hand,  if  four-fifths 


808  PHYSIOLOGY 

of  the  pancreas  be  removed,  the  remaining  part  may  gradually  become 
inadequate  to  prevent  diabetes,  and  Homans  has  shown  that  when  under 
these  circumstances  diabetes  supervenes,  the  granules  disappear  from  the 
B  cells.  Changes  have  also  been  found  in  the  islets  of  Langerhans  in  fatal 
cases  of  diabetes  in  man.  It  seems  therefore  probable  that  what  we  may 
term,  for  lack  of  a  better  word,  the  antidiabetic  functions  of  the  pancreas, 
are  associated  with  and  dependent  on  the  integrity  of  the  islets  of  Langerhans. 
(5)  DIABETES  IN  MAN.  In  its  severer  forms  the  diabetes  of  man 
resembles  very  closely  that  produced  in  the  dog  by  total  extirpation  of 
the  pancreas.  The  output  of  urine  is  largely  increased  and  the  frequency 
of  micturition  is  often  the  first  symptom  noticed.  On  examination  the 
urine,  though  hght  in  colour,  is  of  a  high  specific  gravity,  1030  to  1035, 
and  may  contain  from  5  to  10  per  cent,  of  sugar.  The  appetite  is  largely 
increased,  but  in  spite  of  the  large  amount  of  food  taken  the  body  wastes. 
The  excessive  quantity  of  fluid  lost  by  the  body  gives  rise  to  a  constant 
thirst.  The  patient  may  die  after  some  months  or  years  in  a  condition 
of  diabetic  coma.  Warning  of  the  onset  of  this  condition  is  given  by  the 
rise  of  ammonia  in  the  urine  and  by  the  appearance  of  oxybutyric  and 
diacetic  acids.  The  breath  may  smell  of  acetone,  and  this  substance  may 
also  be  present  in  the  urine.  On  the  other  hand,  the  diabetic  state  is 
attended  by  diminished  resistance  of  the  tissues  to  infection.  A  pimple 
may  become  a  carbuncle ;  a  slight  sore  on  the  foot  may  give  rise  to  a 
rapidly  spreading  gangrene  of  the  lower  extremity ;  tubercular  infection 
of  the  lungs  spreads  rapidly  to  the  whole  organ  so  as  to  stimulate  pneu- 
monia. The  patient  may  thus  die  of  some  such  intercurrent  infection 
before  the  onset  of  coma.  In  a  few  cases  the  pancreas  is  found  to  be 
atrophied  or  diseased,  but  in  the  large  majority  no  marked  pathological 
change  is  to  be  observed  in  this  organ.  Yet  the  condition  is  essentially 
similar  to  that  which  occurs  in  pancreatic  diabetes.  The  radical  defect 
is  the  inability,  relative  or  complete,  of  the  organism  to  assimilate  carbo- 
hydrate. We  may  find  all  grades  between  such  cases  and  those  in  which 
there  is  still  a  considerable  power  of  assimilation.  In  order  to  determine 
the  grade  of  the  disorder  it  is  usual  to  give  a  test  diet  with  a  certain  pro- 
portion of  carbohydrate,  e.g.  100  grm.  of  bread  with  meat,  bacon,  eggs, 
butter,  green  vegetables,  cheese,  lettuce,  coffee  and  wine.  If  the  urine 
remains  free  from  sugar  on  this  diet,  the  diabetes  is  mild  in  character. 
More  bread  may  then  be  added  to  the  diet  from  time  to  time  until  sugar 
appears  in  the  urine  and  the  limit  of  tolerance  for  carbohydrate  has  been 
reached.  In  many  cases  the  sugar  will  disappear  from  the  urine  on  the 
administration  of  a  diet  consisting  entirely  of  proteins  and  fats.  When 
this  has  been  effected  carbohydrates  may  be  added  in  small  proportions 
to  the  diet  until  the  limit  is  found  at  which  the  assimilatory  powers  of  the 
patient  are  reached.  It  seems  that  administration  of  any  carbohydrate 
in  excess  of  this  limit  is  of  disadvantage  to  the  patient  and  hastens  the 
progress  of  his  disorder.  When  the  power  of  assimilating  carbohydrates 
is  entirely  abolished  the  prognosis  is  almost  absolutely  fatal.     This  point 


THE  METABOLISM  OF  CARBOHYDRATES  809 

may  be  determined  in  two  ways.  In  the  first  place,  a  patient  with  no 
power  of  carbohydrate  assimilation  will  continue  to  excrete  sugar  in  the 
urine  on  a  pure  protein  fat  diet,  and  the  D  :  N  ratio  will  be  2-8  or  higher. 
Information  may  also  be  obtained  from  a  study  of  his  respiratory  quotient. 
The  production  of  dextrose  from  protein  involves  the  absorption  of  oxygen. 
Oxygen  ^^^ll  therefore  be  taken  in  which  will  not  reappear  as  carbon  dioxide 
in  the  expired  air.  In  severe  cases  of  diabetes  therefore  the  respiratory 
quotient  will  faU  below  that  representing  fat  metaboHsm,  i.e.  below  0-7. 
In  most  cases  of  diabetes,  where  there  is  still  some  power  of  assimilating 
carbohydrate  and  of  storing  up  glycogen,  the  respiratory  quotient  wiU  be 
found  approximately  normal.  A  very  low  respiratory  quotient  is  a  sign 
of  the  severity  of  the  disorder. 

This  study  of  the  conditions  of  carbohydrate  metabohsm  shows  how  aU 
three  classes  of  food-stuffs  co-operate  in  the  maintenance  of  the  chemical 
processes  which  lie  at  the  root  of  the  existence  and  the  activities  of  Kving 
organisms.  We  see  how  fallacious  were  the  ideas  that  the  proteins  alone 
were  necessary  for  life  and  that  protoplasm  w^as  simply  living  protein. 
Protoplasm,  i.e.  the  material  substrate  of  life,  must  be  regarded  as  a  complex 
in  which  proteins,  fats,  carbohydrates,  nucleins,  salts,  and  water  all  play 
a  part  and  of  which  each  is  an  essential  constituent.  In  the  higher  animals 
proteins  are  necessary  to  furnish  the  proteins  of  the  tissues,  and  the  food 
must  contain  just  those  amino-acids  which  are  requisite  for  the  building 
up  of  the  proteins  characteristic  of  each  separate  tissue.  Moreover  certain 
groups  of  the  protein  molecule  appear  to  be  destined  to  serve  as  mother- 
substances  of  hormones  and  other  chemical  compounds  which  play  a 
dynamic  rather  than  static  part  in  the  phenomena  of  life,  and  supply 
conditions  of  activity  rather  than  material  for  the  production  of  energy. 
The  carbohydrates  not  only  act  as  sources  of  energy,  but  are  necessary  to 
the  building  up  of  the  proteins  into  the  protoplasmic  complex.  Without 
them  moreover  this  complex  cannot  properly  utiUse  the  fat  contained  in 
itself  or  supphed  in  its  food.  On  the  other  hand,  the  carbohydrates  by 
themselves  are  not  available  as  food,  but  require  some  connecting  hnk, 
which  may  be  protein  or  nitrogenous  in  character,  to  enable  their  associa- 
tion with  the  active  part  of  the  protoplasm  and  their  utihsation  by  oxidation. 
At  the  same  time  there  is  a  certain  possibility  of  interconversion  between 
these  different  substances ;  sugar  may  be  formed  from  proteins,  fats  from 
carbohydrates.  On  the  other  hand,  the  formation  of  fats  from  proteins  is 
apparently  impossible  in  the  cells  of  the  higher  animals,  and  the  evidence 
for  the  formation  of  sugar  from  fat  is  Umited  to  the  study  of  the  respiratory 
quotient  in  hibernating  animals.  With  the  exception  of  a  few  cases  quoted 
by  Pfliiger  and  von  Noorden,  no  support  for  such  a  conversion  is  obtained 
from  the  conditions  observed  in  the  glycosuria  caused  by  the  administration 
of  phloridzin  or  by  extirpation  of  the  pancreas. 


26* 


CHAPTER  XII 

THE    BLOOD 

In  the  unicellular  animals  and  in  the  lowest  metazoa  the  cells  are  bathed 
by  the  medium  in  which  the  organisms  live,  and  are  therefore  exposed  to 
all  the  changes  in  the  composition  of  this  fluid  which  may  be  brought 
about  by  cosmic  events.  With  the  evolution  of  a  body  cavity  filled  with 
fluid  the  tissue- cells  are  set  free  from  the  necessity  of  adapting  their  meta- 
bohsm  to  wide  ranges  of  chemical  composition,  being  bathed  by  an  internal 
medium  which  is  maintained  practically  constant  in  its  characters  for  any 
given  tj^pe.  With  increasing  differentiation  the  fluid  of  the  coelom,  which 
may  be  called  blood,  becomes  enclosed  in  branching  systems  of  tubes, 
and  its  circulation  is  provided  for  by  the  development  of  contractile 
chambers  at  some  point  or  points  of  the  tubes.  In  all  the  higher  animals, 
the  blood,  the  common  medium  and  means  of  exchange  for  all  parts  of  the 
body,  circulates  through  a  closed  system  of  tubes,  a  constant  flow  being 
kept  up  by  the  action  of  the  heart.  It  is  separated  from  the  tissue  elements 
themselves  by  the  walls  of  the  blood-vessels.  The  free  interchange  of 
material  between  blood  and  tissues  is  facilitated  by  the  tenuity  of  the 
vascular  wall.  The  interstices  of  the  tissues  contain  a  fluid,  the  '  tissue 
fluid,'  any  excess  of  which  is  drained  off  by  special  channels  known  as 
lymphatics  and  carried  back  to  the  blood.  Interchange  between  the 
blood  and  the  tissue-cells  can  be  effected  partly  by  diffusion,  partly  by 
a  direct  exudation  or  filtration  of  the  fluid  parts  of  the  blood  with  certain 
of  its  constituents  through  the  capillary  walls.  Since  the  function  of  the 
blood  is  to  act  as  the  common  nutritive  medium  of  all  parts  of  the  body, 
it  has  to  convey  food  materials  from  the  digestive  organs  and  oxygen  from 
the  lungs  to  the  tissues,  From  these  it  receives  in  exchange  their  waste 
products,  namely,  carbon  dioxide  and  the  results  of  nitrogenous  metabolism, 
and  carries  them  away  to  the  excretory  organs,  such  as  the  lungs  and 
kidneys,  by  which  they  are  ehminated.  It  is  evident  that  the  composition 
of  the  blood  must  vary  from  time  to  time  and  place  to  place  according 
to  the  condition  of  activity  and  the  function  of  the  organ  which  it  is 
traversing.  The  organs  of  the  body  are  adjusted  to  respond  to  very 
minute  changes  in  the  composition  of  the  circulating  fluid,  and  add 
to  or  subtract  from  its  constituents  according  as  these  are  present  in 
deficiency  or  excess.  The  changes  are  therefore  kept  within  infinitesimal 
limits  ;   in  most  cases  they  are  within  the  limits  of  errors  of  analysis, 

810 


THE  BLOOD  811 

and  we  may  therefore  treat  the  blood  as  a  fluid  of  approximately  constant 
composition  and  qualities. 

Blood  obtained  from  a  mammal  is  an  opaque  fluid  varying  in  tint 
according  to  the  vessel  from  which  it  is  derived,  being  scarlet  when  taken 
from  an  artery,  purplish  in  colour  when  taken  from  a  vein,  the  difference 
being  determined  by  the  degree  of  oxygenation  of  the  blood.  On  shaking 
venous  blood  with  air  it  takes  up  oxygen  and  acquires  the  scarlet  colour 
characteristic  of  arterial  blood.  If  examined  in  a  thin  layer  under  the 
microscope  its  opacity  is  seen  to  be  due  to  the  fact  that  it  is  not  homo- 
geneous, but  consists  of  a  number  of 
corpuscles  of  different  kinds  sus- 
pended in  a  light  yellow  transparent 
fluid.  In  order  to  make  out  the 
characters  of  these  corpuscles  the 
blood  should  be  diluted  with  some 
'  normal '  fluid,  such  as  0-9  per  cent. 
sodium  chloride.  It  is  then  seen  to 
contain  two  classes  of  corpuscles. 
Much  the  most  numerous  are  the 

(J  1       J      m,  Tis         ■         Fig.   357.  "^[[Non-micleated  red  blood-discs 

red    corpuscles.      These    difEer    m         of  1,^^^^  blood.    On  the  right  of  the 

appearance    according    as    the    blood  figure   the  corpuscles  are  seen  on  edge. 

.         ,       .         ,     »  l  J.  (SW.VLE  ViNCEST.) 

IS  derived  from  a  mammal  or  from 

one  of  the  lower  orders  of  vertebrates.  In  all  the  latter  it  is  a  nucleated 
cell.  In  the  frog,  for  instance,  it  is  an  oval  bi-convex  disc  containing  an 
oval  nucleus  in  the  centre.  In  man  and  other  mammals  the  red  corpuscle 
is  a  bi-concave  circular  disc  (Fig.  357),  varying  in  size  in  different  species. 
The  average  sizes  of  the  corpuscles  in  man  are  given  in  the  follo^^^ng  Table  : 

Diameter    ......       7-1  to  7-8  /m 

Thickness  (at  periphery)       .         .         .       2-5  fi 
Thickness  (at  centre)   .         .         .         .       1  -0  to  2  -0  /x 

In  the  blood  of  man  there  is  an  average  of  five  million  red  blood-discs 
in  every  cubic  millimetre  of  blood. 

The  other  kind  of  formed  element,  the  white  corpuscle,  or  leucocyte, 
is  present  in  much  smaller  numbers  than  the  red  corpuscle,  there  being  in 
human  blood  an  average  of  one  leucocyte  to  every  500  red  corpuscles.  These 
leucocytes  are  colourless  cells,  somewhat  larger  than  the  red  blood-discs  of 
man,  presenting  one  or  more  nuclei  and  a  granular  or  hyaline  protoplasm. 
When  examined  on  the  warm  stage  they  are  seen  to  be  amoeboid,  and 
many  of  them,  like  the  amoeba,  have  the  power  of  ingesting  granules  of 
carmine,  food,  or  dead  bacteria  with  which  they  may  come  in  contact. 

In  addition  to  these  two  classes,  a  third  body  is  generally  described 
under  the  name  of  '  blood-platelets  '  or  hsematoblasts.  These  are  especially 
well  seen  when  the  blood  has  been  received  directly  into  an  excess  of  osmic 
acid.  It  is  still  doubtful  whether  they  are  pre-existent  in  the  circulating 
blood  or  are  formed  in  the  plasma  by  a  process  of  precipitation. 


812  PHYSIOLOGY 

Unless  special  precautions  are  taken,  the  examination  of  blood  obtained 
from  a  blood-vessel  is  interfered  with  by  the  process  of  clotting,  which 
ensues  shortly  after  the  blood  has  left  the  blood-vessels.  If  blood  be 
received  into  a  beaker  it  is  at  first  perfectly  fluid,  so  that  it  can  be  poured 
from  one  vessel  to  another.  After  a  space  of  time  varying  from  three  to 
eight  minutes  it  begins  to  be  viscous,  and  if  poured  out  of  the  beaker  leaves 
an  adherent  layer  on  the  sides  of  the  vessel.  A  minute  later  the  whole 
mass  of  the  blood  becomes  sohd  and  the  beaker  can  be  inverted  without 
spiUing  its  contents.  If  a  section  be  made  of  this  blood-clot  it  is  found 
to  owe  its  soHdity  to  a  network  of  fine  threads  of  a  protein  substance  named 


Fig.  358.  Network  of  fibrin,  after  washing  away  the  corpuscles  from  a  filiu  of 
blood  that  has  been  allowed  to  clot ;  many  of  the  filaments  radiate  from  little 
clumps  of  blood-platelets.     (Schafee.) 

fibrin,  which  have  formed  throughout  the  plasma  and  enclose  the  corpuscles 
in  their  meshes  (Fig.  358).  On  leaving  the  clot  for  some  hours,  drops  of 
yellow  fluid  appear  on  its  surface  and  run  together.  The  whole  clot 
contracts,  and  finally  there  is  a  reduced  clot  floating  or  suspended  in  a 
yellowish  fluid  known  as  serum.  If  after  the  blood  has  left  the  vessels 
it  be  whipped  with  a  bunch  of  twigs,  or  stirred  with  a  glass  rod,  the  fila- 
ments of  fibrin  as  they  are  formed  are  deposited  on  the  twigs.  After  three 
or  four  minutes  the  twigs  can  be  withdrawn  and  the  spongy  fibrin  collected. 
The  blood  which  is  left  consists  only  of  the  corpuscles,  plus  serum,  and 
wiU  not  clot,  since  its  fibrin  has  been  removed.  It  is  known  as  defibrinated 
blood.  Since  the  corpuscles  are  apparently  unchanged  in  the  meshes  of 
the  clot  and  clotting  can  be  produced  in  blood-plasma  entirely  separated 
from  corpuscles,  we  must  look  upon  the  process  of  coagulation  as  deter- 
mined in  the  main  by  changes  in  the  blood-plasma.  We  can  regard  the 
blood  therefore  as  a  tissue  consisting  of  a  fluid  matrix,  which  is  extremely 
unstable  and  undergoes  change  when  it  leaves  the  vessels,  and  as  having. 
embedded  in  its  matrix,  formed  elements  or  cells  of  various  kinds. 


SECTION  I 

THE  WHITE   BLOOD-CORPUSCLES 

Amoeboid  cells  are  a  constant  constituent  of  the  coelomic  fluid  in  all 
classes  of  animals.  Even  in  the  lower  metazoa,  where  there  is  not  yet  a 
body  cavity,  wandering  mesoderm  cells  are  present  which  apparently 
discharge  functions  analogous  in  all  respects  to  those  of  the  white  blood- 
corpuscles  of  mammals.  On  carefully  examining  a  specimen  of  human 
blood,  either  fresh  or  in  the  form  of  a  thin  stained  film,  several  varieties 
of  these  cells  are  seen  to  be  present.  In  a  fresh  specimen  we  can  distingmsh 
the  following  varieties  : 

(a)  A  cell  with  a  lobed  nucleus  and  finely  granular  protoplasm  ; 


Fig.  359.     Various  forms  of  leucocytes. 
a,  eosinophile  corpuscle  ;  h,  ordinary  polynuclear  leucocyte  ('  ncutrophile  ') ; 
c,  hyaline  corpuscle  ;  d,  lymphocyte. 

(6)  A  small  cell  consisting  almost  entirely  of  a  nucleus  surrounded  by 
a  thin  layer  of  protoplasm  ; 

(c)  A  cell  with  a  single  nucleus  and  clear  hyahne  protoplasm  ; 

((Z)  A  cell  with  a  lobed  or  reniform  nucleus,  the  cytoplasm  being  beset 
with  large  coarsely  refracting  granules. 

These  four  types  are  known  as  the  finely  granular  or  polymorpho- 
nuclear cell,  the  lymphocyte,  the  hyaline  corpuscle,  and  the  coarsely 
granular  corpuscle. 

The  dift'ereutiation  of  the  various  types  of  leucocytes  is  more  easily 
made  if  recourse  be  had  to  staining  with  mixtures  of  aniline  dyes.  This 
method  was  introduced  by  Ehrhch,  who  classified  leucocytes  according  to 
the  staining  characters  of  their  granules,  dividing  the  latter  into  : 

(a)  Those  staining  with  acid  dyes,  such  as  eosin — acidophile  or  eosino- 
phile granulation  ; 

(6)  Those  staining  with  basic  dyes — basophile  ; 

813 


814  PHYSIOLOGY 

(c)  Those  staining  only  with  a  mixture  of  the  acid  and  basic  dyes  and 
therefore  spoken  of  as  neiitrophile. 

An  acid  dye  is  generally  a  salt  in  which  the  colouring-matter  plays  the  part  of  an 
acid  radical.  Thus  eosin  is  the  sodium  salt  of  the  coloured  acid  tetrabrom-fluorescein. 
Basic  dyes  possess  basic  colour  radicals.  An  example  of  this  class,  methylene  blue, 
is  the  chloride  of  the  coloiu'ed  base  tetramethyldiphenthiazine.  Neutral  dyes,  accord- 
ing to  Ehrlich,  are  those  in  which  a  colour  base  is  combined  with  a  colovu?  acid,  such  as 
the  eosinate  of  methylene  blue,  or  the  picrate  of  rosaniline. 

In  preparations  stained  with  mixtures  of  these  dyes  we  may  distinguish 
the  following  types  : 

(1)  The  polymorphonuclear  cells.  These  preesnt  a  lobed  nucleus,  and 
their  protoplasm  contains  abundant  fine  neutrophile  granules.  They  form 
about  70  per  cent,  of  the  total  leucocytes.  If  the  specimen  be  overstained 
with  eosin  the  granules  may  take  on  a  red  stain. 

(la)  A  few  cells  are  sometimes  seen  with  a  horseshoe  or  hour-glass 
nucleus  and  presenting  a  few  neutrophile  granules.  These  are  spoken  of 
as  transitional  cells,  and  have  been  supposed  to  represent  an  intermediate 
stage  between  large  mononuclear  or  hyaline  cells  and  the  polymorpho- 
nuclear leucocyte.  They  do  not  form  more  than  1  per  cent,  of  the  leuco- 
cytes. 

(2)  The  lymphocytes  are  small  cells  with  a  round  nucleus  surrounded 
by  a  thin  layer  of  hyahne  protoplasm  which  is  free  from  granules.  These 
form  23  per  cent,  of  the  leucocytes. 

(3)  Large  mononuclear  or  hyahne  corpuscles.  These  cells  are  two  or 
three  times  the  size  of  a  red  corpuscle,  and  possess  a  large  oval  nucleus 
which  stains  feebly  with  basic  dyes.  In  normal  blood  not  more  than  2  per 
cent,  of  the  leucocytes  are  of  this  type. 

(4)  In  every  well-stained  blood-fihn  the  eosinophile  corpuscle  is  very 
evident,  although  not  forming  more  than  3  per  cent,  of  the  white  corpuscles. 
The  nucleus  is  generally  single,  but  is  often  crescent-shaped  or  reniform. 
The  protoplasm  is  crammed  with  large  discrete  highly  refractive  granules 
which  stain  deeply  with  eosin  and  give  micro- chemical  reactions  for  iron 
as  well  as  phosphorus.  The  granules,  which  in  man,  dog,  and  rabbit  are 
spherical,  are  cuboidal  in  the  horse,  and  in  birds  have  the  shape  of  short 
rods. 

(5)  A  cell  which  is  found  with  difficulty,  but  is  apparently  a  normal 
constituent  of  human  blood,  is  the  basophile  leucocyte.  This,  which  is 
somewhat  smaller  than  the  polymorphonuclear  cell,  has  a  lobed  or  tri-lobed 
nucleus  and  presents  a  number  of  granules  in  its  protoplasm  which  stain 
deeply  with  basic  dyes.  It  is  sometimes  spoken  of  as  a  '  Mast '  cell,  the 
German  term  for  the  cell  being  used  without  translation.  It  does  not 
form  more  than  0-5  per  cent,  of  the  total  leucocytes  of  the  blood.  The 
granules  are  practically  invisible  in  fresh  specimens,  in  this  respect  pre- 
senting a  contrast  with  the  eosinophile  granules.  The  leucocytes  as  a 
whole  undergo  variations  in  number  according  to  the  physiological  state 
of  the  animal  and  are  increased  during  digestion,  specially  of  a  protein 


THE  WHITE  BLOOD-CORPUSCLES  815 

meal.     They  vary  from  one  in  300  to  one  in  600  red  corpuscles,  or,  taken 
as  a  whole,  from  18,000  to  9000  per  cubic  millimetre  of  blood. 

FORMATION  OF  THE  LEUCOCYTES 
In  classifying  the  white  corpuscles  of  the  blood  it  is  essential  to  know 
whether  the  different  varieties  we  have  described  represent  phases  in  one 
and  the  same  corpuscle  or  a  number  of  different  cells  of  separate  origin. 
The  question  as  to  the  specificity  of  each  kind  of  leucocyte  cannot  be 
regarded  as  settled.  According  to  some  observers,  Gulland  and  others, 
all  the  leucocytes  are  derived  from  one  kind  of  cell,  namely,  the  lymphocyte. 
Ehrlich  and  his  school,  on  the  other  hand,  regard  each  type  as  forming  a 
tissue  sui  generis,  originating  in  separate  localities  and  from  distinct  kinds  of 
cells.  Since  division  of  the  leucocytes  in  the  blood  itself  appears  to  be  an 
occurrence  of  the  utmost  rarity,  we  must  locate  the  original  seat  of  forma- 
tion of  these  cells  in  two  tissues.  Lymphocytes  are  derived  from  the 
adenoid  tissue  forming  the  lymphatic  glands  and  the  lymph  nodules  sur- 
rounding so  many  of  the  mucous  cavities.  These  lymphatic  nodules 
present  towards  their  centre  a  clearer  zone,  consisting  of  cells  rather  larger 
than  those  of  the  periphery  and  known  as  the  '  germ  centre.'  The  nuclei 
in  these  cells  present  a  well-marked  reticular  arrangement,  and  nuclear 
figures  are  often  to  be  seen.  By  the  division  of  these  cells  lymphocytes 
are  formed,  pushing  towards  the  periphery  of  the  nodule,  where  they  make 
their  way  into  the  lymph-sinus  and  are  carried  slowly  by  the  Ijmaph  into 
the  blood.  Some  of  these  lymphocytes  may  possibly  pass  directly  through 
the  capillary  wall  into  the  blood-stream. 

The  other  tissue  concerned  in  the  formation  of  leucocytes  is  the  bone- 
marrow.  This  is  the  chief  blood-forming  tissue  of  the  body,  since  it  is  re- 
sponsible also  for  the  production  of  all  red  blood- corpuscles  which  are  formed 
during  adult  life.  In  the  red  marrow  are  seen  a  number  of  cells  known 
as  myelocytes.  These  contain  a  single  rounded  nucleus  and  a  well-marked 
protoplasm  which  may  be  non-granular  or  may  contain  granules,  generally 
eosinophile  in  character,  but  sometimes  basophile.  It  is  stated  that  all 
intermediate  stages  are  to  be  found  in  the  bone-marrow  between  these 
'  myelocytes  '  and  the  polymorphonuclear  leucocyte  as  well  as  the  eosino- 
phile leucocyte.  It  is  certain  that  in  the  disease  leukaemia,  which  is 
associated  with  an  increased  number  of  leucocytes  in  the  blood,  there  may 
be  an  increase  either  of  eosinophile  cells  or  of  the  neutrophile  cells,  and 
either  condition  is  associated  with  changes  in  the  red  bone-marrow.  We 
may  therefore  provisionally  arrange  the  leucocytes  of  the  blood  according 
to  their  origin  as  follows  : 

(1)  Small  lymphocyte  derived  from  lymphoid  tissue. 

(2)  Large  mononuclear  or  hyaline  corpuscle  :  doubtful  whether  derived 
by  a  growth  of  (1)  or  from  a  myelocyte. 

(3)  Polymorphonuclear  leucocyte  formed  in  bone-marrow. 

(4)  Eosinophile  cell  derived  from  similar  cells  in  the  bone-marrow. 
This  origin  of  the  eosinophile  corpuscle  is  rendered  more  probable  by  the 


816  PHYSIOLOGY 

fact  that  the  shape  of  the  granule,  which  differs  from  one  species  to  another, 
is  the  same  whether  the  cell  be  derived  from  the  blood  or  the  bone-marrow. 
The  intermediate  or  transitional  ceU  may  be  derived  either  from  the 
lymphocyte  or  from  a  myelocyte.  In  many  cases  of  leuksemia  the  myelocyte 
passes  into  the  blood  in  large  numbers  without  undergoing  the  changes 
necessary  to  convert  it  into  the  typical  blood-cell.  We  find  then  mono- 
nuclear cells  which  are  either  free  from  granules  or  contain  eosinophile  or 
basophile  granules. 

FUNCTIONS  OF  THE  LEUCOCYTES 

PHAGOCYTOSIS.  We  have  seen  that  the  leucocytes  from  whatever 
animal  they  be  taken  present  two  phenomena,  viz.  that  of  amoeboid  move- 
ment and  that  of  ingesting  foreign  particles  which  may  be  presented  to 
them.  On  account  of  this  power  of  eating  up  foreign  particles  they  are 
frequently  spoken  of  as  '  phagocytes,'  in  this  respect  resembhng  unicellular 
organisms  and  the  undifierentiated  cells  of  many  kinds  of  tissue.  All  the 
phenomena  connected  with  the  process  of  inflammation  in  higher  animals 
are  directed  to  the  assemblage  of  leucocytes  at  the  spot  which  is  the  seat 
of  injury  or  of  infection,  so  that  they  may  devour  and  remove  either  the 
injured  tissue  or  the  invading  micro-organisms.  This  process  plays  there- 
fore an  important  part  in  determining  the  immunity  of  any  animal  against 
infection  ;  though  in  the  higher  animals  it  is  assisted  by  a  number  of  other 
mechanisms  directed  towards  the  same  end,  which  we  shall  have  to  discuss 
in  a  subsequent  chapter.  The  use  of  phagoc3rtosis  is  not,  however,  confined 
to  the  protection  of  the  organism  against  infection.  Wherever  any  efiete 
or  dead  tissue  has  to  be  cleared  away,  whether  as  the  result  of  injury  or 
in  the  course  of  metamorphosis  of  organs,  the  leucocytes  play  an  important 
part.  Thus  in  the  great  rearrangement  of  tissues  which  occurs  in  the 
larval  state  of  insects,  the  removal  of  the  muscle  fibres  which  are  no  longer 
required  is  effected  by  the  accumulation  of  phagocytes  around  them.  The 
phagocytes  may  send  processes  into  the  muscle  substance,  which  dissolve 
this  tissue  and  then  take  it  up.  The  absorption  of  the  tail  of  the  tadpole 
is  effected  in  the  same  way  by  means  of  phagocytes.  In  mammals,  including 
man,  the  moulding  of  the  long  bone  which  occurs  in  the  process  of  growth 
is  effected  by  continual  and  coincident  processes  of  absorption  and  new 
formation  of  bone.  The  absorption  is  carried  out  by  means  of  special 
phagocytes  formed  by  the  aggregation  of  a  number  of  leucocytes,  the 
well-known  '  giant  cells '  or  myeloplaxes  which  form  so  prominent  a 
constituent  of  bone-marrow. 

The  blood-corpuscles  represent  the  wandering  phagocytes  of  the  body. 
There  are  fixed  phagocytes  of  which  the  myeloplaxes  just  mentioned  may 
be  regarded  as  a  type.  Other  members  of  this  class  are  the  endothelial 
cells  (Kupfer's  '  Sternzellen ')  which  line  the  capillaries  of  the  liver.  If  a 
suspension  of  carmine  or  of  micro-organisms  be  injected  into  the  blood- 
stream these  endothelial  cells  are  found  a  little  later  to  have  taken  up 
large  numbers  of  the  foreign  bodies.     Under  normal  circumstances  these 


THE  WHITE  BLOOD-CORPUSCLES  817 

cells  as  well  as  some  similar  cells  in  the  spleen  take  up'efEete  red  blood- 
corpuscles  and  destroy  them.  During  the  process  of  degeneration  of  a 
peripheral  nerve  brought  about  by  its  separation  from  the  ganghon- cells 
of  which  its  fibres  are  the  processes,  a  marked  proliferation  of  the  nerve- 
nuclei  takes  place.  These  become  surrounded  with  protoplasm  and  act 
the  part  of  phagocytes,  loading  themselves  with  the  fat  globules  set  free 
by  the  degeneration  of  the  myelin  sheath.  To  the  same  class  of  fixed 
phagocytes  ma}^  possibly  be  ascribed  certain  of  the  plasma-cells  of  the 
connective  tissues. 

That  the  polymorphonuclear  leucocytes  are  endowed  with  these 
phagocytic  properties  is  universally  acknowledged,  but  some  doubt  still 
exists  as  to  how  far  the  other  types  of  leucocytes  which  we  have  described 
can  function  as  phagocytes.  It  is  probable  that  the  lymphocytes,  and 
certainly  the  large  mononuclear  or  hyaline  corpuscles,  are  endowed  with 
these  properties.  The  granular  corpuscles,  namely,  eosinophile  and  baso- 
phile,  are  thought  by  some  to  function  as  unicellular  glands  and  to  react 
to  infection,  not  by  englobing  the  micro-organisms,  but  by  discharging 
substances  stored  up  in  their  granules  which  have  a  poisonous  effect  on 
the  micro-organisms,  and  so  prepare  them  for  subsequent  ingestion  by  the 
polymorphonuclear  leucocytes. 

The  other  functions  which  have  been  ascribed  to  leucocytes  are  un- 
important as  compared  with  their  role  as  phagocytes,  and  are  all  of  them 
questionable.  Thus  some  authors  ascribe  to  leucocytes  an  important 
part  in  the  taking  up  of  fat  from  the  intestine  and  its  carriage  into  the 
lymphatic  system.  In  the  coagulation  of  the  blood  the  leucocytes  have 
been  supposed  to  act  by  the  discharge  of  substances  which  may  act  as 
precursors  of  the  fibrin  ferment.  In  the  invertebrata  the  wandering 
mesoderm  cells  not  only  remove  the  injured  tissue  but  apparently  give 
rise  to  new  connective  tissues.  The  same  function  was  formerly  assigned 
to  the  leucocytes  of  mammals  by  Ziegler,  and  Metchnikoff  still  beheves 
that  after  the  removal  of  any  injured  tissue  the  emigrated  leucocytes 
undergo  elongation  to  form  so-called  fibroblasts,  by  the  further  division 
of  which  are  produced  the  white  fibres  of  the  connective  tissues  as  well  as 
the  branched  connective-tissue  cells.  Most  authors  at  the  present  time 
have  come  to  the  conclusion  that  the  work  of  the  leucocytes  is  complete 
with  the  removal  of  dead  or  injured  tissue,  and  that  the  process  of  re- 
generation is  carried  out  by  the  plasma-cells  of  the  connective  tissue,  which 
enlarge,  undergo  division,  and  form  the  fibroblasts  of  the  developing  tissue. 
These  plasma-cells  can  change  their  position  and  act  as  phagocytes,  eating 
up  and  digesting  the  polymorphonuclear  leucocytes  which  have  prepared 
the  way  for  their  regenerative  activity.  Their  amoeboid  power  is  shown 
by  the  fact  that  if  two  sterile  cover-glasses  be  introduced  under  the  skin, 
new  connective  tissue  is  formed  between  the  cover-glasses,  and  this  method 
has  been  adopted  by  Ziegler  for  the  study  of  the  cellular  changes  involved 
in  the  new  regeneration  of  this  tissue. 


SECTION   II 
THE   RED    BLOOD-CORPUSCLES 

The  red  blood-corpuscles,  or  erythrocytes,  in  man  and  in  mammals  are 
nucleated  bi-concave  discs,  about  7  to  8^  (32^00  ^^•)  ^^^  diameter  and  about 
one-third  of  this  in  thickness.  The  colour  of  a  single  corpuscle  when  viewed 
under  the  microscope  is  yellow,  the  red  colour  being  only  apparent  when 
larger  numbers  are  seen  together.  The  red  corpuscles  form  about  50  per 
cent,  of  the  total  mass  of  the  blood,  there  being  about  5,000,000  red  corpuscles 
in  every  cubic  millimetre  of  blood.  They  are  soft,  flexible,  and  elastic,  so  that 
they  can  readily  squeeze  through  apertures  and  canals  narrower  than 
themselves  without  undergoing  permanent  distortion.  Each  red  corpuscle 
consists  of  a  framework  or  stroma,  composed  chiefly  of  protein  material, 
containing  in  its  meshes  or  in  a  state  of  loose  chemical  combination 
a  red  colouring-matter,  haemoglobin,  to  which  is  due  the  colour  of  the 
corpuscles  and  of  the  blood  itself. 

It  is  only  in  mammalia  that  the  red  corpuscles  are  of  the  character 
described.  In  the  camel  they  are  oval  in  shape,  but  otherwise  resemble  the 
corpuscles  of  other  mammals.  In  all  other  classes  of  vertebrata  the  red 
corpuscles  are  oval,  nucleated  cells.  The  hsemoglobin  is  diffused  through  the 
protoplasm  of  the  cell-body  and  does  not  extend  to  the  nucleus.  During  the 
early  part  of  foetal  life  the  corpuscles  of  mammals  are  also  nucleated,  but 
in  the  adult  condition  the  erythrocytes,  except  under  abnormal  conditions, 
lose  all  traces  of  the  nucleus  before  entering  the  blood  stream.  The  small 
size  and  great  number  of  the  red  corpuscles  determine  that  a  very  large  area  of 
surface  of  red  corpuscles  is  exposed  to  the  plasma.  The  volume  of  each  corpuscle 
has  been  estimated  as  -0000000722  mm.^,  and  its  surface  as  -000128  mm.  2,  so 
that  the  total  surface  of  red  corpuscles  in  the  blood  of  a  man  weighing  about 
70  kilos  (assuming  his  total  blood  as  ^^  of  the  body  weight)  would  be  about 
3000  sq.  metres,  or  1500  times  the  surface  of  the  body  itself.  This  great 
extent  of  surface  is  of  importance  in  facilitating  the  exchange  of  material, 
especially  oxygen,  between  the  corpuscle  itself  and  the  surrounding  plasma. 

On  treating  the  blood  with  weak  solutions  of  tannic  or  boracic  acid  a 
separation  occurs  between  the  hsemoglobin  and  the  stroma,  the  former 
appearing  as  a  small  ball  near  the  centre  of  a  colourless  disc  or  being  extruded 
so  as  to  lie  just  outside  the  stroma.  Briicke,  who  first  observed  this  appear- 
ance, gave  the  name  of  '  zooid  '  to  the  mass  of  hsemoglobin  and  of  '  oecoid ' 
to  the  stroma. 

818 


THE  EED  BLOOD-CORPUSCLES  819 

OSMOTIC  RELATIONSHIPS  OF  THE  RED  CORPUSCLE.  If  the  blood- 
plasma  be  concentrated  by  evaporation  or  by  the  addition  of  neutral  salts 
its  osmotic  pressure  rises  and  water  diffuses  from  the  corpuscles  into  the 
plasma  in  order  to  equahse  the  osmotic  pressure  within  and  without  the 
corpuscle.  The  latter  therefore  becomes  -^Tinkled  or  crenated.  On  the 
other  hand,  dilution  of  the  plasma  diminishes  its  osmotic  pressure  below 
that  of  the  corpuscle,  and  water  therefore  passes  into  the  latter,  which  swell 
up  and  become  spherical,  and  if  the  plasma  be  made  sufficiently  dilute  the 
corpuscles  burst  with  the  liberation  of  the  haemoglobin  they  contain.  The 
corpuscles  of  mammalian  blood  neither  gain  nor  lose  volume  in  a  solution 
containing  0-9  per  cent,  sodimn  chloride.  The  osmotic  pressure,  as  deter- 
mined by  the  freezing-point,  of  such  a  solution  is  identical  with  that  of  the 
blood.  For  frogs'  blood  such  a  solution  would  be  too  concentrated  and 
bring  about  crenation.  The  salt  solution  which  is  normal  for  frogs'  blood 
only  contains  0-65  per  cent,  sodium  chloride. 

Although  the  average  molecular  concentration  of  blood-plasma  in  mammals  is 
equivalent  to  tliat  of  a  0*9  per  cent,  sodium  chloride  solution,  it  may  vary  even  in  one 
animal  within  fairly  wide  limits,  as  is  shown  by  the  following  determinations  of  the 
freezing-point  of  blood-serum  taken  from  animals  under  various  circmnstances  : 

Man(heahhy) -0-56  to  -0-600 

Dog -0-55  to  -0-645 

Ox -0-55  to  -0-662 

Rabbit -0-55  to  -0-620 

The  behaviour  of  the  red  corpuscles  when  immersed  in  solutions  of  sodium 
chloride  of  different  concentrations  shows  that  its  limiting  membrane  or 
most  external  layer  is  impermeable  to  sodium  chloride.  If  this  salt  be  added 
to  defibrinated  blood  and  the  crenated  corpuscles  separated  by  the  centrifuge, 
practically  the  whole  of  the  added  sodium  chloride  remains  in  the  plasma 
or  serum.  The  red  corpuscle  is  impermeable  to  most  neutral  salts  as  well  as 
to  cane  sugar  and  glucose.  We  may  therefore  make  '  normal '  solutions 
with  sodium  chloride,  sodium  sulphate,  potassium  nitrate,  or  cane  sugar, 
taking  care  that  each  of  the  solutions  shall  be  isotonic  ^\'ith  a  0-9  percent, 
solution  of  sodium  chloride.  On  the  other  hand,  a  solution  of  urea  behaves 
towards  the  corpuscles  hke  distilled  water.  If  some  red  corpuscles  be  added 
to  a  1  per  cent,  solution  of  urea  in  normal  salt  solution,  they  neither  shrink 
nor  swell,  and  if  the  mixture  be  centrifuged  and  the  corpuscles  and  super- 
natant fluid  examined  separately,  the  percentage  of  urea  in  the  two  cases 
will  be  found  identical,  though  there  would  be  a  great  preponderance  of 
sodium  chloride  in  the  supernatant  fluid.  If  a  1  or  2  per  cent,  solution  of  urea 
in  water  be  added  to  defibrinated  blood,  the  corpuscles  will  swell  up  and 
burst  just  as  if  distilled  water  had  been  added.  There  are  a  large  number  of 
substances  to  which  the  corpuscles  are  permeable,  e.g.  alcohol,  chloroform, 
ether,  &c.  In  their  permeability  the  corpuscles  resemble  most  other  vege- 
table and  animal  cells  in  permitting  the  passage  of  all  those  substances  which 
are  soluble  in  fats  and  the  allied  substances,  cholesterin,  lecithin,  and 
protagon,  which  are  invariable  constituents  of  all  living  cells.     According 


820  PHYSIOLOGY 

to  Orerton  the  external  limiting  pellicle  of  tlie  red  corpuscles,  as  in  most 
living  cells,  is  formed  by  a  lecitliin-ch-olesterin  compound,  whose  solvent 
power  determines  the  permeabihtj  of  the  ceU  by  foreign  substances.  If 
therefore  we  wish  to  stain  the  Hving  ceU  we  must  choose  some  dyestuif,  such 
as  methylene  blue  or  neutral  red,  which  is  soluble  in  such  lipoid  bodies. 

CHEMISTRY  OF  THE  RED  BLOOD-CORPUSCLES 

The  red  corpuscles  consist  of  two  parts,  haemoglobin  and  stroma,  probably 
in  a  state  of  loose  chemical  combination.  By  various  means  it  is  possible  to 
destroy  this  combination  and  to  dissolve  out  the  haemoglobin,  leaving  the 
colourless  swoUen-up  stroma  floating  in  the  plasma.  At  the  same  time  the 
blood  becomes  darker  but  more  transparent,  and  is  spoken  of  as  '  laked  ' 
blood. 

It  has  been  thought  by  Schwann,  Schafer.  and  others  that  the  red  corpuscle  con- 
sists of  a  solution  of  haemoglobin  contained  within  an  envelope  which  contains  lecithin 
and  cholesterin  and  forms  the  stroma.  Though  the  haemoglobin  can  be  separated  from 
the  stroma  by  very  simple  means,  it  is  difficult  to  believe  that  it  is  in  watery  solution. 
Thus  the  blood-corpuscles  contain  a  greater  percentage  of  solids  than  any  soft  tissue 
of  the  body.  The  blood-corpuscles  contain  36-7  per  cent,  solids,  as  against  muscular 
tissue  with  25  per  cent,  or  nervous  with  22  per  cent,  solids.  Of  these  solids,  95  per 
cent,  consist  of  haemoglobin,  so  that  the  solution  would  have  to  contain  at  least  30  per 
cent,  haemoglobin.  No  solution  of  haemoglobin  of  this  strength  can  be  prepared.  In 
many  animals,  such  as  the  rat  and  guinea-pig,  it  is  sufficient  merely  to  '  lake  '  the 
blood,  i.e.  to  bring  the  haemoglobin  into  solution  in  the  surrounding  plasma  or  serum, 
in  order  to  make  the  haemoglobin  crystallise  out.  Some  form  of  combination  is  there- 
fore necessary  in  the  corpuscles  if  merely  to  keep  the  haemoglobin  from  separating  out 
in  a  crystalline  form. 

Blood  may  be  '  laked  '  by  any  of  the  following  means  : 
(a)  Addition  of  a  small  amount  of  ether. 
(6)  Free  dilution  with  water. 

(c)  Alternate  freezing  and  thawing  of  the  blood. 

(d)  Addition  of  bile-salts. 

(e)  The  action  of  foreign  blood-serum  or  of  various  haemolysins  whose 
nature  we  shall  have  to  discuss  later. 

From  such  laked  blood  we  may  prepare  either  haemoglobin  or  stroma. 

In  order  to  separate  the  stroma  from  the  haemoglobin,  blood  which  has  been  de- 
fibrinated  or  prevented  from  clotting  by  the  addition  of  a  little  sodium  oxalate  is 
centrifuged  matil  all  the  formed  elements  form  a  solid  cake  at  the  bottom  of  the  tube. 
The  tube  is  then  filled  up  with  normal  saline  fluid  and  again  centrifuged,  and  this 
process  repeated  twice  in  order  to  wash  away  adherent  plasma  or  serum.  After  the 
final  washing  two  volumes  of  distilled  water  saturated  with  ether  are  added  to  one 
volume  of  caked  corpuscles.  The  corpuscles  swell  up  and  their  haemoglobin  passes 
into  solution  into  the  surrounding  fluid.  The  blood  is  laked.  The  fluid  is  once  more 
centrifuged  in  order  to  throw  down  white  blood  corpuscles.  A  1  per  cent,  solution 
of  acid  sodixun  sulphate  is  now  added  drop  by  drop  until  the  solution  acquires  the 
opaque  appearance  presented  by  ordinary  blood.  The  action  of  this  salt,  as  of  dilute 
acids,  is  to  precipitate  the  swollen-up  stromata,  which  reacquire  the  power  of  reflecting 
light  from  their  surfaces  and  restore  the  opacity  to  the  blood.  On  centrifuging,  the 
stromata  are  thrown  down,  and  can  be  collected  and  washed  with  distilled  water  several 
times  on  the  centrifuge. 


THE  RED  BLOOD-CORPUSCLES 


821 


The  stroma  protein  only  forms  about  4  per  cent,  of  the  total  solids  of 
the  corpuscle.  It  is  insoluble  in  dilute  acids,  but  easily  soluble  in  dilute 
alkahes.  On  gastric  digestion  the  greater  part  dissolves,  leaving  a  residue 
which  is  rich  in  phosphorus,  and  has  been  called  nuclein.  Stroma  protein  is 
therefore  spoken  of  as  a  nucleo-protein.  Wooldridge,  who  devised  the  method 
given  above  for  the  preparation  of  pure  stromata,  regarded  the  protein  as  a 
compound  of  protein  and  lecithin.  The  substance  certainly  contains  a  large 
quantity  of  lecithin,  the  greater  part  of  which  is  present  in  the  precipitate 
obtained  on  gastric  digestion.  According  to  Wright  the  nuclein  residue 
yields  purine  bases  on  hydrolysis,  and  is  therefore  rightly  classed  with  the 
other  nucleins  from  tissue-cells  and  contained  in  nuclei. 

From  the  laked  solution  of  corpuscles  oxy haemoglobin  can  be  obtained  in  a  crystalline 
form  with  varying  readiness  according  to  the  animal  from  which  the  blood  is  derived. 
Thus  in  the  case  of  the  rat,  the  guinea-pig,  the  dog,  and  the  horse  it  is  sufficient  merely 
to  cool  the  laked  blood,  preferably  in  a  freezing  mixtme  to  about  —  10°  C.  in  order  to 
obtain  a  large  crop  of  hsemoglobin  crystals.  Crystallisation  is  facilitated  by  the  addi- 
tion of  25  per  cent,  of  absolute  alcohol  to  the  mixtme,  though  the  use  of  alcohol  certainly 
tends  to  interfere  with  the  subsequent  piu-ification  and  solubility  of  the  haemoglobin. 
Oxyheemoglobin  can  be  recrystallised  by  dissolving  it  in  weak  alkali  at  35°  C,  cooling 
the  solution  to  0°  C,  and  then  adding  cold  alcohol  to  25  per  cent,  and  allowing  the 
mixture  to  stand  for  some  days  at  a  temperatm'e  of  —  5°  to  —  10°  C.  In  the  case  of 
those  bloods  which  yield  oxyhaemoglobin  crystals  with  greater  difficulty,  it  is  better  to 
add  to  the  laked  blood  an  equal  volume  of  a  saturated  solution  of  ammonium  sulphate. 
The  precipitate  of  globulins  is  filtered  off  and  the  filtrate  allowed  to  stand  in  a  cool 
place.     Crystals  of  hagmoglobin  then  come  down  in  quantity. 


PROPERTIES  OF  HAEMOGLOBIN 

The  crystals  thus  obtained  are  as  a  rule  microscopic  in  size.  Most 
animals  yield  an  oxyhaemoglobin  which  crystallises  in  rhombic  prisms  or 
needles  belonging  to  the  rhombic  system. 
In  the  guinea-pig  the  crystals  are  tetrahe- 
dral  in  form,  while  the  oxyhsemoglobin  of 
the  squirrel  crystallises  normally  in  the 
form  of  six-sided  plates.  On  recrystalli- 
sation,  however,  a  squirrel's  haemoglobin 
can  be  obtained  as  a  mixture  of  rhombic 
prisms  with  rhombic  tetrahedra.  The 
water  of  crystallisation  of  oxyhsemoglobin 
varies  in  different  animals  between  3  and 
9  per  cent.  The  solubihty  of  the  crystals 
differs  according  to  the  animal  from  which 
they  have  been  derived,  and  is  in  direct  proportion  to  the  difficulty  with 
which  the  crystals  are  obtained.  They  are  more  soluble  in  highly  diluted 
solutions  of  ammonia  and  the  caustic  alkalies  and  their  carbonates  than  in 
water.  A  solution  of  haemoglobin  will  not  diffuse  through  parchment  paper  ; 
the  elementary  analysis  of  oxyhaemoglobin  crystals  gives  somewhat  varying 


Fig.  360.    Crystals  of  oxyhsemoglobin. 
1.  From  rat.     2.  From  guinea-pig. 
3.  From  squirrel. 


822 


PHYSIOLOGY 


results  according  to  the  animal  employed.     In  the  case  of  the  oxyhaemo- 
globin  of  the  dog  Jaquet  obtained  the  following  figures  : 


In  100  part 

3 

c 

.       53-91 

54-97 

H         .         .         . 

6-62 

7-22 

N          .         .         .         . 

15-98 

16-38 

Fe         .          .          .          . 

0-333       .. 

0-336 

S           .         .         .         . 

0-54 

0-568 

0          .         . 

.       22-62 

20-93 

Fe  per  cent. 

Authority 

0-336       . 

Jaquet. 

0-335       . 

Zinoffsky 

0-336       .  . 

Hiifner. 

0-336       . 

Jaquet. 

The  chief  differences  between  different  animals  appear  to  have  re- 
lation to  the  sulphur.  Haemoglobin  from  the  hen  contains  0-857  per  cent, 
sulphur.  All  specimens  are  alike  in  containing  a  constant  proportion  of 
iron,  as  is  shown  in  the  following  Table  : 

Oxyhsemoglobin  of 

Dog 

Horse  .  .  . 

Ox 

Hen 

On  the  assumption  that  each  molecule  of  oxyhsemoglobin  contains  one 
atom  of  iron,  its  molecular  weight  would  be  16,660,  and  this  result  is  borne 
out  by  the  volume  of  oxygen  or  carbonic  oxide  which  can  enter  into  combina- 
tion with  haemoglobin.  It  has  been  suggested  by  Bunge  that  the  enormous 
size  of  the  haemoglobin  molecule  finds  a  teleological  explanation ;  if  we 
consider  that  iron  is  eight  times  as  heaAr^^  as  water,  a  compound  which  would 
float  easily  along  with  the  blood- current  through  the  vessels  could  only  be 
secured  by  the  iron  being  taken  up  by  so  large  an  organic  molecule.  Oxy- 
haemoglobin  is  a  compound  in  definite  proportions  of  oxygen  and  haemo- 
globin or  reduced  haemoglobin.  It  can  be  easily  dissociated  and  is  split  up  by 
such  simple  means  as  exposure  to  a  vacuum.  If,  for  instance,  some  arterial 
blood  or  solution  of  oxyhaemoglobin  be  introduced  into  a  Torricellian 
vacuum,  the  fluid  is  seen  to  give  off  bubbles  of  gas,  and  the  colour  changes 
from  a  brilliant  scarlet  to  a  dull  bluish  red.  In  this  process  each  gramme  of 
oxyhaemoglobin  gives  off  1-34  c.c.  of  oxygen.  The  same  change  can  be 
effected  by  treating  a  solution  of  oxyhaemoglobin  with  reducing  agents  such 
as  an  alkaline  solution  of  ferrous  tartrate  (Stokes's  fluid)  or  ammonium 
sulphide  ;  in  the  latter  case  reduction  is  aided  by  gently  warming  the 
solution.  Another  reagent  of  value  for  effecting  the  reduction  of  oxyhaemo- 
globin is  a  solution  of  hydrazine.  The  oxygen  in  oxyhaemoglobin  can  be 
replaced  by  equivalent  quantities  of  other  gases.  Thus  if  carbon  monoxide 
gas  be  led  through  a  solution  of  oxyhaemoglobin,  oxygen  is  given  off  and  its 
place  is  taken  by  an  equal  volume  of  carbon  monoxide  with  the  formation  of 
a  more  stable  compound,  carbon  monoxide  haemoglobin.  This  body  is  only 
dissociated  with  extreme  slowness  and  is  unaffected  by  the  addition  of 
reducing  agents.  By  using  special  precautions  to  prevent  oxidation  of  the 
gas  the  carbon  monoxide  can  be  replaced  in  this  compound  by  nitric  oxide, 


THE  RED  BLOOD-CORPUSCLES 


823 


NO.  We  have  therefore  a  series  of  three  compounds  which  can  be  arranged 
in  order  of  stabihty,  thus  : 

NO-haemoglobin. 

CO-hsemoglobiu. 
Oa-hsemoglobin. 

The  poisonous  properties  of  carbon  monoxide  are  due  to  its  power  of  turning 
out  the  oxygen  from  the  oxyhsemoglobiu,  thus  depriving  the  tissues  of  the 
oxygen  which  is  normally  carried  to  them  by  the  red  corpuscles. 

Haemoglobin  and  its  derivatives  give  well-marked  absorption  spectra. 
Thus  dilute  solutions  of  oxyhaemoglobin  placed  in  front  of  the  sHt  of  a 
spectroscope  show  two  well-marked  absorption  bands  between  Fraunhofer's 


Fig.  361.     The  spectra  of  oxyhsemoglobin  in  different  grades  of  concentration, 

of    (reduced)  haemoglobin,  and  of  carbon  monoxide  haemoglobin.     (After 

Peeyer  and  Gamgee.) 

1  to  4.     Solution  of  oxyhaemoglobin  containing  (1)  less  than  -01  per  cent., 

(2)  "09  per  cent.,  (3)  -37  per  cent.,  (4)  -8  per  cent.,    (.5)  solution  of  (reduced) 

haemoglobin  containing  about   '2   per  cent.,   (G)  solution  of  carbon  monoxide 

haemoglobin.     In  each  of  the  six  cases  the  layer  brought  before  the  spectroscope 

was  1  cm.  in  thickness.     The  letters  (^4,  a.  Sec.)  indicate  Fraunhofer's  lines  and 

the  figures  wave-lengths  expressed  in  xWiTrnr  millemetre. 

lines  D  and  E.  The  centre  of  the  band  nearest  to  D  corresponds  to  X  579, 
and  is  often  spoken  of  as  the  band  a,  while  the  second  band,  the  one  next 
to  E,  which  can  be  called  the  band  [3,  is  broader,  has  less  sharply  defined 
edges,  and  its  centre  corresponds  approximately  to  X  544.  On  concentrating 
the  solution  or  using  thicker  layers  a  point  is  reached  at  which  the  two  bands 
fuse  into  one,  and  with  a  still  stronger  solution  it  will  be  found  that  the  whole 
of  the  spectrum  is  absorbed  with  the  exception  of  the  red  end. 

The  above  figure  shows  the  spectrum  of  oxyhaemoglobin  in  varying 
concentrations,  a  stratum  one  centimetre  thick  being  examined.  If  a 
reducing  agent  be  added  to  the  solution  of  oxyhaemoglobin  the  two  bands 
disappear  and  their  place  is  taken  by  a  more  diffuse  band  hnng  midway 
between  the  two  (Fig.  361,  5),  its  centre  corresponding  to  \  555.     This  is  the 


824  PHYSIOLOGY 

absorption  spectrum  of  haemoglobin  or  reduced  haemoglobin.  The  spectrum 
of  carboxyhaemoglobin  is  very  similar  to  that  of  oxyhaemoglobin,  the  bands, 
however,  being  shifted  shghtly  towards  the  red  end.  This  solution  is  of 
a  brighter  red  than  oxyhaemoglobin.  Its  tint  is  best  observed  on  diluting 
the  blood  to  a  large  extent,  when  oxyhaemoglobin  acquires  a  yellowish  tint, 
while  the  pink  colour  of  CO-haemoglobin  is  retained  so  long  as  any  colour  is 
visible.  The  fact  that  CO-haemoglobin  is  not  altered  by  reducing  agents 
can  be  shown  by  adding  ammonium  sulphide  to  CO-haemoglobin  and  examin- 
ing with  the  spectroscope,  when  no  change  is  observed. 

All  these  derivatives  of  haemoglobin,  besides  their  absorption  bands  in  the  visible 
spectrum,  have  characteristic  absorption  of  light  in  the  ultra-violet  spectrum,  as  has 
been  shown  by  Gamgee.  In  the  case  of  oxyhaemoglobin  this  absorption  causes  a  band 
(Soret's  band)  which  occupies  the  greater  part  of  the  spectral  region  between  Fraun- 
hofer's  lines  G  and  H.  In  reduced  haemoglobin  this  band  is  displaced  towards  the 
visible  part  of  the  spectrum. 

Another  compound  of  haemoglobin  with  oxygen  is  methcBmoglohin.  This 
substance,  although  not  of  normal  occurrence  in  the  body,  is  found  in  urine 
and  in  blood  whenever  there  is  a  sudden  breaking  down  of  red  blood- 
corpuscles  with  the  setting  free  of  haemoglobin  in  the  blood-plasma.  It  may 
be  prepared  by  the  addition  of  a  ferricyanide,  permanganate,  or  nitrite,  or 
other  oxidising  or  reducing  agents  to  the  laked  blood  or  to  solutions  of  oxy- 
haemoglobin. It  is  a  chocolate-brown  substance,  crystalHsable,  and  gives 
a  distinct  absorption  band  in  the  red  between  Fraunhofer's  lines  C  and  D.  It 
is  unaltered  by  exposure  to  a  vacuum.  On  treatment  with  reducing  agents, 
however,  such  as  Stokes's  fluid,  the  methaemoglobin  is  converted  into 
haemoglobin,  from  which  by  shaking  with  air  oxyhaemoglobin  can  be  re- 
formed. The  fact  that  methaemoglobin  cannot  be  reduced  by  exposure 
to  a  vacuum  indicates  that  it  is  a  compound  of  oxygen  with  haemoglobin  in 
which  the  oxygen  is  in  a  different  state  of  combination.  According  to  Buck- 
master  methaemoglobin  only  contains  half  the  oxygen  contained  by  oxyhae- 
moglobin, so  that  the  composition  of  the  two  bodies  might  be  represented. 

Hb^    I  (oxyhaemoglobin)  and  Hb  =  0  (methaemoglobin). 

The  change  from  oxyhaemoglobin  to  methaemoglobin  is  not  affected,  however, 
by  a  simple  shifting  of  the  oxygen  groups,  but  must  be  assumed  to  involve 
two  distinct  events.  The  whole  of  the  oxygen  in  loose  combinatioii  with 
haemoglobin  is  given  off,  and  the  oxygen  in  the  methaemoglobin  molecule  is 
derived  from  the  oxidising  agent  added,  so  that  ferricyanide  of  potash,  for 
instance,  is  converted  into  ferro-cyanide.*  Since  the  whole  of  the  oxygen 
in  the  oxyhaemoglobin  is  given  off  on  the  addition  of  potassium  ferricyanide, 
we  may  use  this  fact  in  order  to  determine  the  total  amount  of  oxygen  in 
combination  in  the  blood  {v.  p.  859). 

*  When  the  change  is  effected  by  reducing  agents  we  must  assume  that  the  oxygen 
of  the  water  or  air  is  the  source  of  that  required  for  the  oxidation  of  the  reduced  haemo- 
globin to  methaemoglobin. 


THE  RED  BLOOD-CORPUSCLES  825 

DERIVATIVES  OF  HEMOGLOBIN.  Haemoglobin  is  a  compound  of 
an  iron-containing  coloured  group  (the  prosthetic  group)  with  a  protein, 
which  probably  varies  somewhat  in  different  animals.  The  prosthetic  group 
is  identical  in  every  case  where  it  has  been  examined.  A  separation  of  the 
prosthetic  group  from  the  protein  moiety  can  be  effected  with  extreme  ease, 
and  occurs  whenever  the  haemoglobin  is  treated  with  weak  acids,  with 
alkaUes,  or  is  heated  above  70°  C.     The  protein  group  is  known  as  globin. 

In  order  to  separate  globin,  oxyhsemoglobin  crystals  are  dissolved  in  water  and 
treated  with  small  quantities  of  very  dilute  hydrochloric  acid.  A  precipitate  of  pig- 
ment forms,  which,  if  the  haemoglobin  used  be  free  from  inorganic  salt,  rapidly  dissolves 
in  excess  of  the  acid.  Alcohol  and  ether  are  then  added  in  such  relative  quantities 
that  the  ether  separates  rapidly  from  the  aqueous  solution.  The  colouring-matter 
(hsematin)  dissolves  in  the  ether,  whilst  the  protein  (globin)  remains  in  solution 
in  the  water.       The  solutions  are  separated  by  a 

separating  funnel  and  ammonia  added  carefully  to  ^         ^''JT- 

the  aqueous  solution.       This   throws  down  a  pre-  /  ^    j^  ^Jk  -^■»?' 

cipitate  of  the  protein,  which  is  soluble  in    acids  ^^^    r^  -^a       ^ 

and  alkalies  and  coagulable  on  heating  ;  the  coagu-         s,  ^   /         ^  '-/'     jW^   '  \ 
lum,  however,  is  soluble  in  acids.     It  is  precipitated       A        -v-^*~  \  *      ^    '^^    :^ 
bj^  ammonia  in  the  presence  of  ammonium  chloride.        a      't      ^^      *     N         VT    \  K 
It  contains   as   much  as  16-89  per  cent,   nitrogen,      j>&     k     /      ;S    "^^       '  ^""^ 
and    yields   a    considerable   amount    of    the    basic  'jS  ^  A       !)      ^  *  ^ 

derivatives  on  hydrolysis.     It  is  therefore  classified      /  '     _,        \.if  -^f    , 

with  the  histones.  ^TiC'^^   ''      ^=^        ■i'-fi       W- 

Haemoglobin  yields  about  94  per  cent,  of         '-'v-<^jx.    '"    ^^      ^  ^  "^ 

globin  and  about  4-5  per  cent,  of  the  chromo-  ^       ^ f  >-\       '^ 

genie  group,  haematin.      In  order  to  obtain         -r.     o^o     u   "^        .*■  ^ 
o  &     _r'  ....  Fig.  362.     Hsemin  crystals. 

hcematin  in  a  pure  condition  it  is  usual  to 

start  with  the  crystalline  derivative  of  haemoglobin  known  as  hmmin. 
When  some  dried  blood  is  heated  with  a  crystal  of  common  salt  and 
placed  in  acetic  acid  on  a  slide,  a  residue  is  obtained  in  which  a  nmnber 
of  reddish-brown  needles  are  embedded  known  as  Teichmaim's  crystals  or 
haemin  crystals  (Fig.  362).  The  preparation  of  these  crystals  is  often  used 
as  a  convenient  test  for  the  identification  of  blood. 

In  order  to  obtain  them  in  large  quantities  the  following  method,  devised  by 
Chalfejew,  is  employed.  One  volume  of  defibrinated  blood  is  added  to  four  volumes  of 
glacial  acetic  acid  previously  heated  to  80°  C.  As  soon  as  the  temperature  has  fallen  to 
60°  C.  the  liquid  is  again  warmed,  and  then  allowed  to  cool.  Crystals  are  formed 
which  are  allowed  to  stand  for  twelve  hours  and  are  then  separated  and  washed  by 
decantation,  first  with  distilled  water  and  then  with  graduated  strengths  of  alcohol. 
In  order  to  purify  these  crystals  the  crude  material  is  shaken  for  fifteen  minutes  with  a 
mixture  of  chloroform  and  pyridine.  The  solution  is  filtered  and  then  thrown  into 
glacial  acetic  acid  previously  saturated  with  sodium  chloride  and  heated  to  105°  C. 
A  few  drops  of  concentrated  hydrochloric  acid  are  then  added  and  the  mixtm'e  allowed 
to  stand  for  twenty-four  hours.  The  crystals  which  separate  out  are  filtered  off, 
washed  Avith  dilute  acetic  acid,  and  then  ch'ied. 

Haemin  crystals  have  been  regarded  as  hydrochloride  of  hannatin. 
Elementary  analysis  shows  that  they  have  the  following  formula  (Will- 
statter)  :   C33H3204N4Cl.Fe.     By  dissolving  haemin  in  alkahes  and  throxN-ing 


826 


PHYSIOLOGY 


the  solution  into  an  excess  of  acid  a  precipitate  is  obtained  which  is  hsematin. 
Hsematin  forms  a  powder  of  bluish-black  colour  and  metallic  lustre.  It  is  in- 
soluble in  water,  alcohol,  or  ether,  but  is  shghtly  soluble  in  glacial  acetic  acid 
and  in  absolute  alcohol.  It  is  easily  soluble  in  concentrated  sulphuric  acid, 
but  undergoes  decomposition,  losing  its  atom  of  iron  and  being  transformed 
into  hwmatoporphyrin,  which  forms  a  deep  purple  solution.  The  formula 
of  hsematin  has  not  yet  been  ascertained  with  certainty.     It  is  probably 


£C 


Fig.  363.     Absorption  spectra  of  haemoglobin  and  its  derivatives. 

1.  Oxybsemoglobin.  2.  Reduced  hsemoglobin.  3.  Methsemoglobin. 
4.  Alkaline  methsemoglobin.  5.  Acid  hsematin  in  ether.  6.  Alkaline 
hsematin  in  rectified  spirit.  7.  Reduced  hsematin.  8.  Acid  hsematopor- 
phyrin.     9.  Alkaline  hsematoporphyrin.     (From  MacMunn.) 

C33H3204N4Fe.OH.  Its  compounds  with  acids  and  alkahes  are  spoken  of  as 
acid  and  alkaline  hsematin,  and  each  gives  a  characteristic  absorption  spec- 
trum (Fig.  363).  The  alkaline  solutions  exhibit  one  indistinct  absorption 
band  between  C  and  D,  the  acid  solutions  an  absorption  band  also  between  C 
and  D  but  nearer  to  C,  and  resembling  somewhat  the  band  presented  by  methse- 
moglobin. According  to  Hoppe-Seyler  and  Gamgee  perfectly  pure  solutions 
of  hsematin  in  alkalies  are  quite  unaffected  by  reducing  agents  ;  in  the  pres- 
ence of  certain  foreign  matters,  however,  alkaline  hsematin,  when  treated 
with  reducing  agents,  exhibits  a  spectrum  known  as  that  of  reduced  alkaline 
hsematin,  which  is  identical  with  that  of  hsemochromogen.     The   same 


THE  RED  BLOOD-CORPUSCLES  827 

change  is  further  observed  when  alkahne  ha3matin  made  by  the  action  of 
alkalies  on  ordinary  blood  is  treated  with  reducing  agents  such  as  ammonium 
sulphide.  Since  this  substance  haemochromogen  is  responsible  for  the 
respiratory  functions  of  the  haemoglobin,  i.e.  the  power  of  its  molecule 
to  form  unstable  compounds  with  oxygen,  its  preparation  merits  fuller 
consideration. 

Hcemochromogen  is  prepared  by  the  action  of  caustic  alkalies  on 
haemoglobin  in  the  absence  of  oxygen.  For  this  purpose  a  test-tube  con- 
taining a  solution  of  sodium  or  potassium  hydrate  is  placed  in  a  bottle  with 
two  necks  containing  a  solution  of  haemoglobin,  care  being  taken  not  to 
spill  any  of  the  alkaline  solution.  Hydrogen  is  then  passed  through  the 
larger  bottle  until  the  haemoglobin  is  entirely  reduced  and  all  the  air  is 
replaced  by  hydrogen.  The  bottle  is  then  inverted  so  as  to  mix  its  contents 
with  the  caustic  alkali,  when  haemochromogen  is  formed  and  can  be  recog- 
nised by  its  characteristic  colour  and  spectrum.  The  haemochromogen  in 
solution  has  a^  cherry- red  colour,  and  when  sufficiently  diluted  shows  two 
well-marked  absorption  bands  identical  with  those  given  by  reduced  alkahne 
haematin  (Fig.  363,  7).  Of  the  two  absorption  bands  which  are  situated 
between  D  and  E,  that  nearest  to  D  has  very  sharply  defined  borders  ;  the 
position  of  the  two  absorption  bands  may  be  given  in  terms  of  their  wave- 
lengths as  follows  :  \  567  to  547  and  X  532  to  518.  The  band  nearest  D  is 
given  by  haemochromogen  solutions  diluted  so  that  there  is  only  one  part 
of  the  pigment  in  25,0(X)  parts  of  water,  so  that  the  formation  of  reduced 
alkahne  haematin  is  an  even  more  delicate  test  for  blood  than  the  spectrum 
of  oxyhaemoglobin  itself.  When  CO-haemoglobin  is  treated  in  the  same  way 
with  alkali  in  the  absence  of  oxygen,  a  body  CO-haemochromogen  is  formed 
which  contains  exactly  the  same  volume  of  CO  in  combination  as  the  original 
CO-haemoglobin.  This  fact,  combined  with  the  possibility  of  reducing 
ordinary  alkahne  haematin  by  the  action  of  ammonium  sulphide  or  Stokes's 
fluid,  indicates  that  the  group  of  atoms  which  in  haemoglobin  is  responsible 
for  taking  up  oxygen  or  carbon  monoxide  gas  passes  unchanged  into  the 
haemochromogen  molecule.  Haemochromogen  therefore  represents  an  iron- 
containing  coloured  radical  which  can  combine  with  protein  bodies  to 
form  haemoglobin,  and  is  responsible  for  the  oxygen-combining  powers  of  the 
latter.  We  may  assume  therefore  that  oxyhaemoglobin  and  CO-haemoglobin 
contain  oxyhaemochromogen  and  CO-haemochromogen  respectively. 

HcBmato'por'phjrin.  If  haemoglobin,  haematin,  or  haemin  be  mixed  with 
concentrated  sulphuric  acid,  it  dissolves  forming  a  purple-red  solution. 
On  pouring  this  solution  into  a  large  quantity  of  water,  haematoporphp'in 
is  thrown  down  in  the  form  of  a  brown  precipitate.  In  order  to  prepare 
haematoporphyrin,  pure  crystallised  haemin  is  added  to  a  saturated  solution 
of  hydrobromic  acid  in  glacial  acetic  acid.  The  whole  is  allowed  to  stand 
for  three  or  four  days  and  then  thrown  into  distilled  water.  The  resulting 
mixture  is  filtered  and  the  haematoporphyrin  thrown  down  by  careful 
neutralisation  of  the  hydrobromic  acid  with  caustic  soda.  Haemato- 
porphyrin is  easily  soluble  in  alkalies  and  somewhat  less  readily  so  \n  acids. 


828  PHYSIOLOGY 

forming  alkaline  and  acid  haematoporphyrin  respectively.  The  formula  of 
hsematoporphyrin  has  been  given  by  Nencki  and  Sieber  as  CigHisNaOg, 
and  is  according  to  them  isomeric  with  the  chief  bile-pigment,  bihrubin. 
According  to  Willstatter  its  formula  is  C33H38lSr406.  An  alcohohc  solution 
of  hsematoporphyrin  acidulated  with  hydrochloric  acid  shows  two  absorption 
bands  :  one,  the  fainter,  between  C  and  D,  and  the  other,  broader  and 
more  defined,  midway  between  D  and  E.  Solutions  of  alkaline  hsemato- 
porphyrin  show  four  absorption  bands  :  a  weak  band  between  C  and  D, 
another  between  D  and  E,  a  more  strongly  marked  band  nearer  to  E,  and 
a  fourth  band,  darkest  of  all,  between  h  and  F,  It  wall  be  observed  that 
in  the  formation  of  haematoporphyrin  from  hsematin  the  iron  of  the  latter 
has  been  spht  ofi  by  the  action  of  the  strong  acid.  Laidlaw  has  found 
that  the  sphtting  off  of  iron  occurs  much  more  readily  in  the  absence  of 
oxygen.  If  reduced  haemoglobin  be  taken,  or  defibrinated  blood  which 
has  been  allowed  to  stand  rmtil  it  is  thoroughly  reduced,  it  is  sufficient  to 
add  15  per  cent,  hydrochloric  acid  in  order  not  only  to  convert  the  greater 
part  of  the  haemoglobin  to  haematin  but  to  split  off  the  iron  of  the  latter 
and  form  haematoporphyrin.  Haemotoporphyrin  occurs  in  minute  quantities 
in  normal  urine  and  in  larger  quantities  in  certain  toxic  conditions,  especially 
in  poisoning  by  sulphonal,  when  the  urine  may  have  a  bright  purple  colour. 
It  is  important  to  remember  that  although  urine  is  acid  from  the  presence 
of  acid  sodium  phosphate,  urinary  haematoporphyrin  is  always  alkahne 
haematoporphyrin  and  gives  the  spectrum  of  this  body. 

CHEMICAL  RELATIONSHIPS  OF  H^MATIN.  Hsematin,  or  hsemochromogen, 
is  widely  diffused  through  the  animal  kingdom,  occurring  in  the  form  of  haemoglobin 
in  a  large  number  of  the  invertebrata,  as  well  as  in  all  the  vertebrata  except,  perhaps, 
Amphioxus.  Since  the  respiratory  function  of  haemoglobin  depends  on  the  power  of 
its  iron-containing  radical  to  combine  with  a  molecule  of  oxygen,  forming  an  easily 
dissociable  compound,  it  becomes  of  interest  to  try  whether  by  a  study  of  its  disinte- 
gration products  we  can  throw  any  light  on  its  chemical  relationships  and  on  the  con- 
ditions of  its  formation  in  the  living  organism.  When  hsematin  is  oxidised  with  sodium 
bichromate  and  acetic  acid  two  new  acids  are  formed,  called  the  haematinic  acids. 
One  of  these  has  the  formula  CgHgO^N,  and  the  other  CgHgOj.  The  first  acid  is  con- 
verted into  the  second  by  the  action  of  alkalies.  The  relationship  of  the  two  haematinic 
acids  can  be  represented  by  the  following  formulae  : — 

CO  /^% 

C5H7/         >0  C5H7        NH 


-CO/ 


\rn/ 


CO- 

COOH  COOH 

If,  on  the  other  hand,  haemin  or  haematoporphyi'in  be  reduced  by  the  action  of  hydriodic 
acid  dissolved  in  acetic  acid  with  the  addition  of  phosphonium  iodide,  and  the  product 
be  distilled  with  steam,  the  distillate  contains  a  niixtmre  of  substituted  pyrroles  formerly 
known  as  hsemopyrroes.  The  mixtm-e  readily  oxidises  to  a  red  substance  on  exposure 
to  the  air.  If  ammonia  be  added  to  the  colom'ed  solution  the  colour  changes  to  yellow, 
which,  on  the  addition  of  an  aipmoniacal  solution  of  zinc  chloride,  changes  to  pink 
with  a  green  fluorescences.  These  reactions  are  also  given  by  urobilin,  one  of  the 
ui'inary  pigments  and  the  chief  pigment  of  the  faeces,  as  well  as  by  hydi'obilirubin,  a 
substance  obtained  by  the  action  of  tin  and  sulphuric  acid  on  an  alcoholic  solution  of 
hsematin. 


THE  RED  BLOOD-CORPUSCLES 


829 


The  hsemopyrroles,  according  to  Willstatter  are  three  in  number  and    have  the 
following  formula  : — 


Cryptopyrrole 

CH3,  jC2Hg 

NH 


Phyllopyrrole 
CHs         ^C2H5 

'cHa 


ca 


NH 


Isohaemopyrrole 

CH3,  ^^C2H6 

CH3V  yTL 

NH 


The  same  substances  can  be  obtained  from  the  chlorophyll  of  plants.  On  treatment 
with  acid  chlorophyll  loses  magnesium,  and  is  converted  into  phacophytin.  From 
this  three  COOH  groups  can  be  sjDlit  off  leaving  a  substance  setioporphjTin. 

It  is  interesting  that  hsematoporphyrin  can  be  readily  converted  into  the  same 
substance.  On  treatment  with  pyiidin  and  alcoholic  potash  it  is  converted  into 
haemoporphyrin,  and  this  heated  with  soda  lime  gives  setioporphyrin  (C31H36X4), 
Thus  the  same  group  forms  the  basis  both  of  the  substance  which  is  responsible  in  the 
plant  for  the  assimilation  of  carbon  from  carbon  dioxide,  and  of  the  pigment  which 
in  the  animal  is  the  carrier  of  oxj^gen  between  the  tissues  and  the  surrounding  medium. 
According  to  Willstatter,  setioporphyrin  and  hfematoporphyrin  are  both  built  up  of 
four  substituted  pyrrole  rings. 

Thus  hiBmatopoi"j)hyi'in  has  the  following  structmal  formula  : — ■ 


CH3.C- 

OH.C2H4.C- 

COOH.CaH^Ct 


CHs.a 


-CH 

)n 

-C 

=c 

\xH 
=C.CH3 


C- 
N< 
C- 

c= 


-C.CH=CH.OH 


-CH 


^C.CsH^.COOH 


HX 


\ 
CH3.C= 


-C.CH3 


and  the  same  worker  suggests  the  following  foiuiula  for  hannin  : — 

CH3C  —  CH  CH  -C.CH3 


COOH.C2H4.C 


CH,.0 


C.C2H4.COOH 


THE  SYNTHESIS  OF  THE  BLOOD-PIGMENTS.  Chemists  have  not 
yet  succeeded  in  the  artificial  formation  of  h^matoporphp'in.  Given 
hsematoporphyrin,  however,  evidence  has  been  brought  forward  both  by 
Menzies  and  Laidlaw  of  the  possibiUty  of  forming  artificially  both  ha?matin 
and  haemoglobin,  or  some  substance  indistinguishable  from  the  latter. 


830  PHYSIOLOGY 

Reduced  haemoglobin  is  a  compound  of  haemochromogen  and  a  protein, 
globin.  The  spMtting  off  of  the  prosthetic  chromatogenic  group — ^hsemo- 
chromogen — can  be  effected  either  by  acid  or  alkali.  When  the  latter  is 
employed  we  obtain  a  red  solution  which  is  fairly  stable,  and  can  be  con- 
verted by  shaking  up  with  air  into  ordinary  alkahne  hsematin.  With  acids 
the  decomposition  is  easily  carried  further.  Even  with  2  per  cent,  hydro- 
chloric acid  a  certain  amount  of  haematoporphyrin  is  formed,  and  if  the 
strength  of  the  acid  be  increased  to  15  per  cent,  the  whole  of  the  iron  is 
spht  off  and  the  haemochromogen  is  converted  entirely  into  haemato- 
porphyrin. 

If  oxyhaemoglobin  be  treated  in  the  same  way  it  yields  acid  or  alkaline 
haematin  directly,  so  that  haematin  must  be  regarded  as  an  oxyhaemo- 
chromogen.  The  distinction  drawn  by  Hoppe-Seyler  between  haemo- 
chromogen  and  reduced  alkaline  haematin  had  its  chief  ground  in  the  fact 
that  pure  haematin  is  not  reduced  to  haemochromogen  by  the  action  of 
such  reducing  agents  as  ammonium  sulphide.  The  conversion  can,  how- 
ever, be  easily  effected  by  using  a  strong  reducing  agent,  such  as  hydrazine 
hydrate.  Whether  the  haematin  contains  the  whole  of  the  oxygen  of  the 
oxyhaemoglobin  is  doubtful.  According  to  Ham  and  Balean,  when 
oxyhaemoglobin  is  converted  by  means  of  acids  into  acid  haematin,  exactly 
half  of  the  oxygen  of  the  oxyhaemoglobin  is  given  off,  so  that  haematin 
would  only  contain  one-half  of  the  oxygen  of  the  oxyhaemoglobin.  There 
is  a  marked  difference  between  the  stabihty  of  haematin  and  haemochromogen. 
In  the  oxidised  form  of  haematin  the  iron  is  firmly  bound  and  can  only  be 
spUt  off  by  using  strong  sulphuric  acid,  concentrated  hydrochloric  acid 
being  insufficient  for  the  purpose. 

It  has  been  shown  by  Laidlaw  that  the  change  in  the  reverse  direction, 
i.e.  the  combination  of  iron  with  haematoporphyrin  to  form  haemochromogen, 
may  be  effected  with  equal  ease.  One  gramme  haematoporphyrin  prepared 
by  Nencki's  method  is  dissolved  in  dilute  ammonia  and  warmed  in  a  flask 
on  the  water-bath.  Some  Stokes's  fluid,  prepared  from  about  2  grm. 
ferrous  sulphate,  and  a  few  drops  of  a  50  per  cent,  hydrazine  hydrate 
solution  are  added.  At  the  end  of  one  or  two  hours  the  solution  is  seen 
to  be  of  a  bright  red  colour  when  examined  in  thin  layers,  and  on  dilution 
shows  the  typical  absorption  spectrum  of  haemochromogen,  which  changes 
to  that  of  alkaline  haematin  on  shaking  with  air.  Strong  potash  is  added, 
and  the  ammonia  is  boiled  off  in  an  evaporating  dish  with  free  exposure 
to  the  air.  The  hydrazine  is  decomposed,  and  a  solution  of  haematin 
remains,  and  can  be  precipitated  by  acidification  with  hydrochloric  acid. 
The  pigment  obtained  in  this  way  agrees  in  every  respect  with  that  prepared 
from  oxyhaemoglobin.  Analysis  of  the  product  gave  9-58  per  cent,  of  iron, 
which  agrees  with  Nencki's  formula  for  haematin,  CggHgoN^OgPe. 

A  pigment  occurring  in  the  wing  feathers  of  certain  birds,  called  turacin,  was  shown 
by  Church  to  contain  copper,  and  to  yield,  on  treatment  with  strong  sulphui'ic  acid, 
a  substance  indistinguishable  from  haematoporphyrin.  Laidlaw  has  succeeded  in 
synthetising  this  pigment  by  treating  ordinary  hsematoporphjrrin  obtained  from  blood 


THE  RED  BLOOD-CORPUSCLES  831 

with  ammoniacal  copper  solution,  showing  that  it  is  a  compound  corresponding  to 
hsematin,  in  which  the  place  of  iron  is  taken  bj^  copper. 

It  was  stated  some  years  ago  by  Menzies  that  a  solution  of  impure 
hsemochromogen,  prepared  by  the  action  of  ammonium  sulphide  on  alkaUne 
hsematin  obtained  in  the  ordinary  way  from  blood,  on  standing  for  some 
days  was  reconverted  into  reduced  haemoglobin.  Ham  and  Balean  have 
confirmed  this  observation,  and  have  shown  in  addition  that  haemo- 
chromogen,  prepared  by  the  action  of  ammonium  sulphide  on  an  alkaUne 
solution  of  pure  hsemin,  though  perfectly  stable  by  itself,  was  rapidly 
reconverted  into  haemoglobin  if  a  solution  of  globin  were  added  to  the 
mixture.  The  same  change  took  place  if  egg-white  were  used  instead  of 
globin.  The  haemoglobin  thus  formed  was  changed  into  oxyhaemoglobin 
on  shaking  with  air.  xA.lthough  in  these  experiments  the  oxyhaemoglobin 
was  not  separated  in  the  crystalline  form,  its  colour  and  spectral  characters 
are  so  very  distinctive  that  we  are  justified  in  concluding  not  only  that  it 
is  possible  to  effect  a  recombination  of  the  haemochromogen  and  globin, 
but  also  that  other  proteins  can  take  the  place  of  globin  in  the  haemoglobin 
molecule. 

THE  LIFE-HISTORY  OF  THE  RED  BLOOD-CORPUSCLES 

The  growth  of  the  embryo  as  well  as  of  the  young  animal  must  be 
attended  with  a  continual  increase  in  the  number  of  red  blood-corpuscles 
present  in  the  body.  In  the  developing  embryo  the  first  formation  of  red 
corpuscles  occurs  in  the  vascular  area.  In  the  chick,  about  the  twentieth 
hour  of  incubation,  the  area  opaca,  which  surrounds  the  blastoderm,  and 
will  later  become  the  area  vascidosa,  presents  on  examination  under  the 
low  power  a  network  of  anastomising  strands  more  opaque  than  the  rest 
of  the  area.  On  section  these  strands  are  seen  to  be  made  up  of  cellular 
masses,  the  ordinary  mesenchyma,  mth  branched  cells  and  amoeboid 
corpuscles  lying  between.  The  cells  in  these  cords  are  continually  multi- 
plying by  indirect  di^^sion.  Those  on  the  outer  side  of  the  cord  become 
the  endothelimn  of  dilated  blood-vessels,  while  those  in  the  interior  acquire 
a  yellowish  colour  from  the  laying  down  of  haemoglobin  in  their  cytoplasm. 
The  cords  become  canalised,  and,  as  soon  as  a  connection  is  estabhshed 
with  the  vascular  system  of  the  embryo,  the  newly  formed  blood- corpuscles 
move  slowly  on  into  the  general  circulation.  The  red  corpuscles  in  the 
bird  are  true  erythrocytes,  i.e.  are  nucleated  cells.  The  leucoc}i;es  seem 
to  arise  by  the  immigration  of  wandering  cells  from  the  surrounding 
mesenchyma.  Other  places  in  the  foetus  Avhere  a  similar  growth  of  corpuscles 
proceeds  throughout  foetal  Hfe  are  the  liver  and  the  spleen,  and  later  on 
the  bone-marrow. 

In  the  mammal  the  nucleated  erythrocytes,  though  forming  the  majority 
of  the  red  corpuscles  in  early  foetal  life,  become  fewer  and  fewer  in  number 
as  gestation  advances,  so  that  at  birth  practically  the  whole  of  the  cor- 
puscles are  of  the  non-nucleated  type.  These,  however,  can  be  shown  to 
be  derived  from  nucleated  rod  corpuscles  by  a  process  either  of  extrusion 


832 


PHYSIOLOGY 


or  of  degeneration  and  solution  of  the  nucleus  (Fig.  364).  The  formation 
of  red  corpuscles  does  not  cease  with  the  end  of  foetal  life  or  even  with  the 
attainment  of  full  stature  by  the  animal.  We  have  definite  proof  that  a 
continual  formation  of  red  corpuscles  can  proceed  and  is  proceeding 
throughout  the  whole  of  adult  hfe.  In  an  adult  the  total  volume  of  blood 
and  the  total  number  of  corpuscles  remain  approximately  constant.  By 
bleeding  an  animal  we  can  diminish  the  total  amount  of  corpuscles.     The 


/ 
eiv 


-_.  :         .  .  -     .  J 

Fig.  364.     Part  of  a  blood-vessel  from  the  yolk-sack  of  the  rabbit  embryo,  showing 
the  changes  which  occur  in  the  formation  of  erythrocytes.     (From  Schafer 
after  Maximow.  ) 
a,  megaloblasts  ;    h,  normoblasts  changing  into  erythroblasts  ;    c,  erythroblasts, 
in  which  the  nuclei  are  disappearing  ;  d,  an  erythrocyte  fully  formed,  but  not  yet  disc- 
shaped ;  tn,  phagocytic  endothelial  cells  ;  I,  lymphocytes  ;  Ic,  a  divided  lymphocyte  ; 
n,  erythroblasts,  shrunken  with  atrophic  nucleus. 

first  effect  of  such  a  bleeding  is  that  the  fluid  parts  of  the  blood  are  made 
up,  so  that  the  volume  of  the  blood  is  restored  to  normal  and  the  blood 
therefore  becomes  relatively  poor  in  corpuscles.  In  a  few  weeks,  however, 
the  corpuscular  content  of  the  blood  is  found  to  be  once  more  normal, 
showing  that  the  loss  of  corpuscles  has  been  followed  by  a  compensatory 
regeneration.  The  fact  that  the  pigments  constantly  leaving  the  body 
with  the  urine  and  fseces,  namely,  urochrome  and  urobilin  or  stercobihn, 
are  derived  by  means  of  the  liver  from  haemoglobin,  shows  that  a  constant 
destruction  of  red  corpuscles  must  be  proceeding.  Since  the  number  of 
corpuscles  remains    unaltered,   this  loss   of  haemoglobin  must  be  made 


THE  RED  BLOOD-CORPUSCLES 


833 


good  by  a  continual  regeneration  of  fresh  haemoglobin  and  new  red  cor- 
puscles. The  seat  of  the  formation  of  red  corpuscles  in  the  higher  verte- 
brates is  the  bone-marrow.  Here  we  have  a  structure  protected  from 
pressure  where  the  capillaries  and  veins  are  dilated  and  thin-walled,  and 
allow  a  slow  passage  of  blood  and  the  entry  of  newly  formed  corpuscles 
through  the  imperfect  walls  into  the  blood-stream  (Fig.  365).  That  the 
marrow  is  the  tissue  involved  in  the  process  is  shown  by  the  fact  that  it  is 
the  only  tissue  of  the  body  which  undergoes  an  alteration  in  appearance 
when  blood  formation  is  stimulated  by  such  means  as  repeated  bleeding 
(or  destruction  of  corpuscles  by  the  injection  of  toxic  agents.     Under  such 


fi^. 


'Mra.'i^Hm' 


. <i 


Fig.  365.     Section  of  rod  marrow  of  mammal.     (Bohm  and  Davidoff,) 

a,  e,  crythroblasts  ;  h,  recticulum  ;  c,  myeloplax  ;  d,  g,  marrow  cells  ; 

/,  a  marrow  cell  dividing  ;  h,  a  space  which  was  occuiiied  by  fat, 

conditions  the  red  marrow,  which  in  adult  mammals  is  present  only  in  the 
epiphyses,  is  found  to  have  increased  in  extent  and  in  many  cases  to  occupy 
the  greater  part  of  the  shaft  of  the  bone,  having  taken  the  place  of  the 
yellow  marrow.  It  is  in  the  red  marrow  therefore  that  we  must  seek  the 
precursors  of  the  red  blood-corpuscles.  In  the  bird  the  crythroblasts, 
i.e.  the  precursors  of  the  red  blood-corpuscles,  form  a  sort  of  inner  lining 
to  the  dilated  capillaries  of  the  marrow  (Fig.  366).  Here  we  can  see  all 
grades  between  the  colourless  nucleated  corpuscle  which  lies  nearest  the 
periphery  and  the  fully  formed  red  oval  corpuscle  containing  haemoglobin, 
lying  next  the  lumen  and  ready  to  be  carried  away  in  the  blood- stream. 
If  blood  formation  has  been  stimulated  by  repeated  bleeding,  this  blood- 
forming  tissue  is  found  to  occupy  the  greater  part  of  the  lumen  of  the 
marrow  capillaries.  If,  however,  blood  formation  has  been  reduced  to  its 
lowest  extent  by  a  process  of  chronic  starvation,  the  erythroblasts  form 
a  single  layer  of  cells  just  inside  the  dilated  capillaries  and  intermediate 
stages  between  the  erythroblasts,  and  the  fully  formed  erythrocytes  are 
almost   entirely   wanting.     In    the   frog   this   process    of   blood-corpuscle 

27 


834  PHYSIOLOGY 

formation  occurs  only  at  one  period  of  the  year,  namely,  in  the  early  summer, 
and  it  is  only  at  this  time  that  the  bones  are  found  to  contain  red  marrow. 
In  mammals  the  process  is  very  similar.  In  the  red  marrow  are  a  number 
of  nucleated  cells  containing  hsemoglobin,  which  are  thought  by  Lowit 
to  be  themselves  derived  from  colourless  nucleated  cells.  In  the  confused 
medley  of  colourless  cells  which  exists  in  the  bone-marrow  and  are  pre- 
cursors of  all  the  varied  corpuscles  found  in  the  blood,  it  is  difficult  to  be 
certain  of  the  identity  of  the  colourless  erythroblasts  and  to  distinguish 
them  from  the  smaller  colourless  cells  engaged  in  bone  formation  or  in  the 
production  of  leucocytes.     The  haemoglobin- containing  cells  are  often  to 


mr 
Fig.  366.     Section  of  red  marrow  of  pigeon.     (Denys.) 
Ic,  eosinophile  leucocytes ;    eg,  fat  cells ;    e,  nucleus  of  endothelial  cell  of 
blood-vessel ;     ca,   blood-capillary ;     er,   erythroblasts  lying  within  vascular 
endothelium  ;  qlr,  fully  formed  red  corpuscles. 

be  seen  in  process  of  division,  and  the  nucleated  daughter-cells  appear  to 
undergo  a  process  of  nucleolysis,  the  nucleus  being  extruded  or  dissolved. 
When  blood  formation  is  quickened  as  the  result  of  previous  destruction 
or  loss,  some  of  these  immature  nucleated  blood-discs  may  make  their 
way  into  the  circulation  and  be  found  in  the  blood,  where  they  are  spoken 
of  as  normoblasts. 

How  long  a  corpuscle  continues  to  exist  in  the  circulating  blood  is  not 
known.  The  experiments  made  to  determine  the  length  of  time  during 
which  foreign  corpuscles  such  as  those  of  birds  can  be  recognised  after 
injection  into  the  circulation  of  a  mammal  are  evidently  beside  the  mark, 
since  these  foreign  cells  will  be  destroyed  by  the  serum  and  rapidly  taken 
up  by  the  phagocytes  of  the  body.  Sooner  or  later,  however,  every  cor- 
puscle undergoes  disintegration,  a  process  which  is  generally  ushered  in 
by  the  ingestion  of  the  corpuscle  by  some  phagocytic  cells.  Thus  in  the 
hsemolymph- glands  and  in  the  spleen  we  find  large  cells  which  have  englobed 
red  corpuscles  and  in  which  we  can  recognise  pigment- granules  obtained 
from  their  destruction.  The  chief  place  of  disintegration  of  the  haemoglobin 
is  certainly  the  liver,  i.e.  the  organ  where  the  hsematin  is  converted  into  bile- 


THE  RED  BLOOD-CORPUSCLES  835 

pigment.  Injection  of  haemoglobin  into  the  circulation  causes  increased 
secretion  of  bile-pigment.  A  section  of  normal  liver  immersed  in  potassium 
ferrocyanide  and  then  in  acid  alcohol  shows  the  presence  of  iron  by  the 
assumption  of  a  blue  colour.  The  amount  of  iron  which  can  be  demon- 
strated in  the  liver  in  this  way  is  enormously  increased  by  any  condition 
which  augments  the  rate  of  blood  destruction.  In  the  pathological  condition 
known  as  pernicious  anaemia,  as  well  as  after  poisoning  by  the  injection  of 
pyrogallic  acid  or  toluylene  diamine,  both  of  which  agents  cause  a  great 
destruction  of  red  blood-corpuscles,  the  hver  on  treatment  in  this  way 
assumes  a  deep  blue  colour.  In  some  cases  crystals  of  haemoglobin  have 
been  seen  within  the  nucleus  of  the  liver-cell.  In  the  destruction  of  the 
corpuscles  the  haemoglobin  is  dissociated  first  into  its  protein  and  chromo- 
genic  moieties  ;  the  haemochromogen  then  loses  its  iron  and  is  converted 
into  bile-pigment.  The  iron  remains  in  the  liver  and  is  probably  retained 
in  the  body  and  utilised  for  the  formation  of  the  fresh  haemoglobin  necessary 
for  the  newly  forming  red  blood-corpuscles  in  the  bone-marrow. 


SECTION  III 
THE  BLOOD-PLATELETS 


The  very  existence  of  these,  the  third  class  of   formed  elements  of   the 
blood,  is  still  a  matter  of  dispute.     If  a  drop  of  osmic  acid  be  placed  on  the 

finger,  which  is  then  pricked  through 
the  drop  so  that  the  shed  blood  may 
mix  with  the  fixing  fluid  directly  it 
leaves  the  vessels,  a  drop  of  the  mixture 
when  examined  under  high  powers  is 
seen  to  present  a  number  of  granular 
bodies  from  one-third  to  one-half  the 
diameter  of  a  red  blood-corpuscle.  Their 
number  has  been  variously  stated  from 
180,000  to  800,000  per  cubic  milhmetre, 
so  that  they  rank  second  in  point  of 
number  among  the  morphological  con- 
stituents of  the  blood.  Their  shape 
varies  considerably.  Some  are  bi-convex 
structures ;  others  are  flatter  with 
numerous  processes.  They  may  be  iso- 
lated or  agglutinated  into  clumps.  Their 
shape,  size,  and  number  vary  according  to  the  fluid  with  which  the  blood 
is  mixed  or  the  method  adopted  for  their  demonstration. 

When  blood  is  examined  in  Hayem's  fluid  *  nearly  all  the  blood  platelets  appear 
as  bi-convex  discs.  The  best  method  for  the  display  of  platelets  is  apparently  that 
given  by  Deetjen.  The  drop  of  blood  is  received  directly  from  the  vessels  on  to  a  sheet 
of  solid  agar  jelly  which  is  made  with  0-6  per  cent,  sodium  chloride  solution  with  the 
addition  of  sodium  metaphosphate  and  bipotassium  phosphate.  When  examined  on 
this  medium  large  numbers  of  platelets  are  seen,  each  of  them  provided  with  numerous 
processes  (Fig.  367).  Their  central  part  is  more  strongly  refracting  than  the  periphery 
and  stains  with  basic  dyes,  so  that  it  has  been  regarded  as  a  nucleus. 

Similar  platelets  are  observed  when  the  blood  is  received  into  normal 
salt  solution,  and,  as  the  mixture  clots,  the  filaments  of  fibrin  can  be  seen 


Fig.  367.  Blood- platelets,  highly  mag- 
nified, showing  the  amoeboid  forms 
which  they  assume  when  examined 
under  suitable  conditions,  and  also 
exhibiting  the  chromatic  particle 
which  each  platelet  contains,  and 
which  has  been  regarded  as  a  nucleus. 
(After  KopscH.) 


Hayem's  fluid  is  made  up  as  follows  : 
Distilled  water 
Sodium  chloride 
Sodium  sulphate 
Iodine  in  iodide  of  potassium 

836 


200  c.c. 
1  grm. 
5  grm. 
3-5  c.c. 


THE  BLOOD-PLATELETS  837 

often  to  radiate  from  a  disiutegrated  blood-plate  as  from  a  centre.  That 
the  blood-platelets  are  concerned  in  the  production  of  clots  is  shown  by 
the  fact  that  in  the  living  vessels  blood-platelets  aggregate  round  any 
injured  spot  in  the  vessel  wall,  and  later  fuse  together  so  as  to  form  an 
adherent  thrombus  or  clot  which  covers  the  seat  of  injury  and  helps  to 
repair  the  damage  and  to  prevent  the  escape  of  the  contents  of  the  blood- 
vessel. Blood-platelets  have  only  been  found  in  mammalian  blood  and 
are  certainly  absent  from  frogs'  blood  as  well  as  from  the  blood  of  fishes 
and  birds,  nor  can  they  be  demonstrated  in  any  of  the  serous  fluids  even  in 


Fig.  368,     Blood- corpuscles  and  blood-platelets,  within  a  small  vein. 
(ScHAFER  after  Osler.) 

mammals.  Certain  nucleated  spindle-shaped  cells  have  been  described 
in  frogs'  blood  as  blood-platelets,  but  these  are  probably  immature 
red  blood-corpuscles  and  not  homologous  with  the  blood-platelets  of 
mammals.  (Blood-platelets  themselves  were  regarded  by  Hayem  as  stages 
in  the  formation  of  red  blood-corpuscles.)  If  the  blood  of  an  animal  be 
defibrinated  by  bleeding,  continually  \vhipping  the  blood  and  returning  it 
to  the  veins  of  the  animal,  it  will  be  found  for  the  next  few  days  to 
be  quite  free  from  blood-platelets.  There  is  no  doubt  therefore  that 
it  is  possible  by  the  most  varied  means  to  demonstrate  the  existence 
of  blood-platelets  in  shed  blood.  According  to  the  method  adopted,  so 
do  the  number  and  form  of  these  platelets  vary.  Moreover  they  can 
be  seen  to  be  deposited  from  the  circulating  blood  in  the  living  animal 
on  any  injured  portion  of  the  vessel  wall  or  on  any  foreign  body  introduced 
into  the  blood-current  (Fig.  368).  On  the  other  hand,  it  is  possible  to 
obtain  blood  in  an  uncoagulated  state  from  the  vessels  in  which  no  trace 
of  platelets  is  to  be  observed.  As  Buckmaster  has  shown,  a  film  of  blood 
examined  in  a  platinum  loop  and  kept  carefully  at  the  temperature  of  the 
body  presents  no  platelets  on  microscopic  examination  ;  and  the  same 
absence  of  platelets  is  to  be  noted  when  blood  is  received  into  sterile  blood- 
serum  of  the  same  species  of  animal  and  kept  at  the  body  temperatrnw 
On  allowing  these  specimens  of  blood  to  cool,  blood  platelets  make  their 
appearance.  Many  specimens  of  non-coagulable  plasma,  such  as  peptone 
plasma  or  oxalate  plasma,  can  be  separated  by  means  of  the  centrifuge 
from  all  formed  elements.  If  the  plasma  be  cooled  to  0°  C.  for  twenty-four 
hours,  a  precipitate  indistinguishable  from  blood-platelets  is  found  to 
have  been  produced  under  the  action  of  cold.  We  are  therefore  probably 
justified  in  concluding  that  the  blood-platelets  do  not  form  a  constituent 
of  normal  living  blood,  but  are  produced  in  the  plasma  either  on  contact 
with  foreign  bodies  or  lowering  of  its  temperature  from  37°  C.  to  18°  or 


838  PHYSIOLOGY 

20°  C.  All  the  various  fixing  fluids  which  have  been  recommended  for  the 
display  of  blood-platelets  may  owe  their  virtues,  not  to  the  fact  that  they 
jjreserve,  but  to  the  fact  that  they  produce  platelets.  These  may  therefore 
be  regarded  as  precipitates  produced  in  the  plasma  directly  it  undergoes 
alterations,  their  appearance  being  the  first  sign  of  changes  in  this  fluid. 
They  consist  of  some  substance  probably  belonging  to  the  class  of  nucleo- 
proteins,  and  like  these  yield  a  precipitate  on  gastric  digestion,  and  have 
a  specific  affinity  for  basic  dyes.  Even  after  their  first  appearance  they 
are  unstable,  tending  to  undergo  further  alteration  and  to  give  off  sub- 
stances to  the  surrounding  plasma  which  play  an  important  part  in  the 
formation  of  fibrin-ferment  and  in  the  coagulation  of  the  blood. 


SECTION  IV 

THE  COAGULATION   OF  THE   BLOOD 

In  the  process  of  coagulation,  while  the  corpuscles  remain  to  a  large  extent 
intact,  the  plasma  becomes  solid  from  the  production  in  it  of  a  network  of 
fibrin,  being  converted  into  fibrin  -plus  serum.  The  question  of  coagulation 
involves  the  consideration  of  the  precursors  of  fibrin  and  of  the  conditions 
which  determine  the  conversion  of  these  precursors  into  fibrin.  It  is  evidently- 
impossible  to  arrive  at  any  conclusions  on  these  points  during  the  few  minutes 
which  elapse  between  the  time  at  which  the  blood  leaves  the  vessels  and  the 
appearance  of  the  clot.  We  must  therefore  find  some  means  of  retarding 
coagulation  so  that  we  may  obtain  the  plasma  free  from  corpuscles  and 
be  able  to  initiate  coagulation  in  this  cell-free  fluid  at  ^\^ll.  Having  suc- 
ceeded in  staying  the  process  of  coagulation,  it  is  always  possible  to  obtain 
a  cell-free  plasma  either  by  allowing  the  blood  to  settle  or,  better  still,  by  the 
employment  of  a  centrifugal  machine.  Under  the  influence  of  centrifugal 
force  the  corpuscles  are  thrown  rapidly  down  to  the  bottom  of  the  tube 
and  the  clear  supernatant  plasma  can  be  syphoned  off. 

METHODS  OF  PREVENTING  COAGULATION 

(1)  So  long  as  the  blood  is  in  contact  with  the  uninjui'ed  vessel  it  remains  fluid. 
If  the  jugular  vein  of  a  large  animal  such  as  the  horse  be  tied  in  two  places,  the  blood 

-contained  between  the  ligatures  will  remain  fluid,  sometimes  for  days.  If  the  tube  of 
vein  be  hung  up,  the  corpuscles  sink  to  the  bottom  and  the  plasma  in  the  upper  part 
of  the  tube  can  be  poured  from  one  vein  to  another  without  undergoing  coagulation. 
On  pouring  it  into  a  glass  vessel  or  bringing  it  into  contact  with  foreign  substances,  it 
undergoes  coagulation. 

(2)  When  an  incision  is  made  in  the  ordinary  way  into  a  blood-vessel  of  a  bird  the 
issuing  blood  clots  very  rapidly.  The  clotting  is  initiated  by  a  substance  contained  in 
the  tissues  surrounding  the  vessels.  If  therefore  the  vessel  be  isolated  and  a  perfect!}" 
clean  glass  cannula  be  inserted  into  it,  care  being  taken  not  to  bring  the  camiula  in 
contact  with  any  of  the  surrounding  tissues,  blood  can  be  drawn  off  into  a  sterilised 
beaker  perfectly  free  from  dust  and  will  remaiii  unclotted  for  days.  Such  blood  can 
be  centrifugcd  and  the  cell-free  plasma  used  for  experiment.  The  same  procedure 
does  not  apply  to  the  mammal,  where  even  the  most  scrupulous  care  to  prevent  con- 
tamination by  tlic  tissue  juices  will  not  prevent  the  blood  from  clotting  on  leaving  the 
vessels. 

(3)  Clotting  can  be  excited  even  in  tiie  living  vein  by  introducing  into  the  blood  any 
solid  substance  which  is  wetted  by  the  blood.  If  the  contact  of  the  blood  with  such 
substances  be  prevented  by  receiving  it  into  vessels  previously  coated  with  oil  or  with 
paraffin  and  scrupulously  free  from  dust,  clotting  may  often  be  delayed  for  many  hom-s. 

(4)  Cooled  plasma.     Horses'  blood  is  received  directly  into  a  narrow  vessel  immersed 

839 


840  PHYSIOLOGY 

in  ice,  so  as  to  cool  it  rapidly  to  between  0°  C.  and  1°  C.  At  tliis  temperature  it  remains 
fluid  for  an  indefinite  time.  The  corpuscles  sink,  and  the  supernatant  plasma  can 
be  decanted  and  filtered. 

(5)  Methods  involving  Mixture  u'ith  Neutral  Salts,  (a)  Magnesium  sulphate.  Blood 
from  any  animal  is  received  into  one-quaiter  its  bulk  of  a  25  per  cent,  solution  of 
magnesium  sulphate. 

(b)  Sodium  sulphate.  Blood  is  mixed  on  leaving  the  vessels  with  an  equal  volume 
of  half-saturated  sodium  sulphate  solution.  The  plasma  obtained  in  either  of  these 
ways  is  known  as  salt-plasma.  Clotting  is  indefinitely  delayed  in  either  case,  but  it 
can  be  induced  by  suitable  treatment  of  the  separated  plasma. 

(6)  Methods  depending  on  Decalcification  of  the  Blood.  Oxalate  plasma  is  obtained 
by  receiving  blood  into  a  solution  of  sodium  oxalate  so  that  the  total  blood  contains 
1  per  1000  of  the  oxalate.  Instead  of  oxalate  we  may  use  sodium  fluoride,  the  propor- 
tion in  this  cuse  being  3  parts  of  NaF  per  1000  blood. 

(7)  Methods  depending  on  the  iise  of  certain  Substances  of  Animal  Origin,  (a)  Peptone 
plasma  is  obtained  by  injecting  rapidly  into  the  veins  of  a  dog  or  cat  in  a  fasting  con- 
dition a  solution  of  commercial  peptone  in  the  proportion  of  0-3  grm.  peptone  per  kilo 
of  the  animal.  The  eifect  of  this  injection  is  to  cause  a  rapid  fall  of  blood-pressure 
and  hurried  respiration,  and  the  animal  then  passes  into  a  state  of  coma  which  may 
last  an  hovu-  or  two.  On  drawing  off  the  blood  immediately  after  the  fall  of  pressure 
has  taken  place  it  is  found  to  be  uncoagulable,  and  cell-free  plasma  can  be  obtained 
from  it  by  the  use  of  the  centrifuge.  A  number  of  animal  extracts  act  in  a  somewhat 
•similar  fashion,  such  as  extract  of  crayfish,  of  mussels,  &c. 

{b)  Leech  extract  or  hirudin  plasma.  Peptone  is  only  efficacious  in  retarding  clotting 
when  it  is  injected  into  the  animal's  veins  directly,  and  has  no  influence  in  this  direction 
if  it  be  mixed  with  the  blood  as  it  flows  out  of  the  A^essels.  It  has  long  been  familiar  to 
physicians  that  the  bites  made  by  leeches  continue  to  bleed  for  a  considerable  time, 
and  it  was  shown  by  Haycraft  that  this  is  due  to  the  presence  of  an  anticoagulating 
substance  in  the  buccal  glands  of  the  leech.  This  substance,  which  has  the  properties 
of  an  albumose,  can  be  extracted  by  boiling  from  the  anterior  half  of  the  leech.  It 
will  destroy  the  coagulability  of  the  blood  either  when  injected  into  the  blood-stream 
or  when  blood  is  received  into  a  solution  of  hirudin. 

By  any  of  these  methods  it  is  possible  to  obtain  blood-plasma  free  from 
formed  elements.  The  conditions  which  will  bring  about  coagulation  in  such 
plasmata  are  strikingly  diverse.  Thus  in  cooled  plasma  a  simple  rise  of 
temperature  is  often  sufficient  to  bring  about  coagulation.  If,  however, 
the  cooled  plasma  be  filtered  several  times  through  two  thicknesses  of 
filter-paper,  being  kept  at  a  temperature  of  about  1°  C.  during  the  whole  time, 
it  loses  this  spontaneous  coagulabihty  on  warming.  It  can  still  be  made  to 
clot  by  the  addition  of  certain  substances  such  as  blood-serum  or  the  washings 
of  a  blood-clot,  and  in  some  cases  by  the  addition  of  tissue  extracts. 

Oxalate  plasma  clots  on  simple  addition  of  lime  salts.  Sodium  sulphate 
plasma  clots  on  dilution.  Magnesium  sulphate  plasma  will  not  clot  on- 
dilution,  but  needs  in  addition  the  presence  of  some  blood-serum  or  some 
substance  derived  from  blood-serum.  In  both  these  cases  tissue  extracts 
have  no  influence.  By  a  careful  study  of  one  or  two  forms  of  plasma  we  can 
arrive  at  a  conception  of  the  processes  of  coagulation  which  enables  us  to 
understand  the  behaviour  of  all  these  various  types.  We  may  take  as 
our  type  oxalate  plasma.  Oxalate  plasma,  as  procured  by  centrifuging  a 
specimen  of  horse's  blood  containing  0-1  per  cent,  sodium  oxalate,  is  a  clear 
yellow  fluid,  perfectly  free  from  formed  elements,  which  evinces  no  tendency 


THE  COAGULATION  OF  THE  BLOOD  841 

to  clot.  On  adding  a  drop  of  calcium  chloride  to  such  plasma  we  see  that  it 
contains  an  excess  of  oxalate  from  the  production  of  a  precipitate  of  calcium 
oxalate.  If  calcium  chloride  be  added  drop  by  drop  so  as  to  be  present  in 
slight  excess  and  the  plasma  be  then  kept  warm,  it  will  clot  within  a  time 
varying  from  a  few  minutes  to  an  hour.  The  clot  thus  formed  is  perfectly 
firm  and  the  vessel  can  be  inverted  without  any  of  its  contents  flowing  out. 
Very  often  no  retraction  of  the  clot  takes  place,  but  if  it  be  pressed  with  a 
glass  rod  or  with  the  fingers  a  clear  serum  is  squeezed  out  and  a  mass  of  pure 
fibrin  remains.  The  place  of  lime  can  be  taken  by  strontium,  but  barium 
and  magnesium  are  powerless  to  initiate  clotting.  We  must  therefore 
conclude  that  the  presence  of  a  soluble  calciimi  salt  is  one  factor  of  those 
necessary  for  coagulation.  This  is  borne  out  by  the  fact  that  a  similar 
uncoagulable  blood  is  produced  by  the  action  of  sodium  fluoride.  Some 
difiiculty,  however,  was  felt  when  it  w^as  found  that  sodium  citrate  might  be 
used  instead  of  sodium  oxalate  or  fluoride,  since  sodium  citrate  does  not 
produce  in  the  blood  any  precipitate  of  insoluble  lime  salts.  Here  therefore 
we  have  a  blood  containing  hme  in  solution  and  yet  uncoagulable.  The 
difficulty  has  been  cleared  up  by  the  work  of  Sabbatani  and  C.  J.  Martin. 
When  sodium  citrate  is  added  to  a  lime  salt  a  double  salt  of  sodium  calcium 
citrate  is  formed  in  which  the  calcium  is  in  the  anion  and  forms  part  of  the 
acidic  radical.  The  mere  presence  of  dissolved  calcium  is  not  sufficient 
for  clotting  to  take  place.  It  is  necessary  that  the  calcium  should  be  in  the 
form  of  a  salt  and  in  an  ionised  condition,  such  as  calcium  chloride  or  calcium 
sulphate. 

Though  calcium  is  a  necessary  condition  for  the  occurrence  of  coagulation, 
it  cannot  be  regarded  as  a  precursor  of  the  protein  fibrin.  If  the  composition 
of  the  plasma  before  coagulation  has  been  set  up  be  compared  mth  that  of  the 
serum  which  has  separated  from  the  clot,  it  is  found  that  plasma  contains 
a  protein,  fibrinogen,  not  represented  in  the  serum,  which  must  therefore 
be  the  precursor  of  fibrin.  Fibrinogen  belongs  to  the  class  of  globulins.  It 
can  be  separated  from  oxalate  plasma  by  half-saturation  wdth  common  salt. 
An  equal  volume  of  a  saturated  solution  of  sodium  chloride  is  added  to  plasma 
so  that  the  whole  mixture  contains  16  per  cent,  sodium  chloride.  The  fluid 
gradually  becomes  turbid  from  the  production  of  a  precipitate  which,  at 
fiist  gi'anular,  rapidly  aggregates  to  form  a  stringy,  slimy  solid,  and  on  stirring 
aggregates  into  masses  which  adhere  to  the  glass  rod  used  for  stirring.  This 
mass  can  be  taken  out  of  the  fluid,  washed  by  kneading  with  half- saturated 
sodium  chloride  solution,  and  then  redissolved  by  the  addition  of  distilled 
water.  With  the  salt  adhering  to  the  precipitate  a  dilute  saline  fluid  is 
formed  in  which  the  fibrinogen  is  soluble.  The  fibrinogen  can  be  purified  by 
repeating  the  precipitation  and  solution,  though  it  tends  to  lose  its  solubility 
in  the  process,  so  that  purification  is  always  attended  \^^th  some  loss.  The 
solution  of  fibrinogen  thus  obtained  is  perfectly  clear  and  colourless.  On 
warming,  practically  the  whole  of  its  protein  is  thrown  down  between  56° 
and  60°  C.  The  same  precipitate  is  produced  on  heating  the  original  plasma, 
whereas  serum  obtained  by  the  expression  of  the  clot  does  not  give  any 

27* 


842  PHYSIOLOGY 

precipitate  on  heating  until  a  temperature  of  68''  to  7u°  C.  is  reached.  If  a 
sokition  of  fibrinogen,  obtained  by  precipitating  with  sodium  chloride  and 
dissolving  in  distilled  water,  be  treated  with  a  drop  or  two  of  calcium  chloride 
it  rapidly  clots  with  the  formation  of  typical  fibrin.  We  might  conclude 
from  this  experiment  that  fibrin  was  a  compound  produced  by  the  union 
of  calcium  salts  with  fibrinogen.  Further  experiments  show,  however,  the 
untenabihty  of  this  hypothesis.  If  the  fibrinogen  has  been  thoroughly 
pimfied  by  repeated  precipitation  and  re-solution,  calcium  salts  are  found 
to  have  entirely  lost  their  power  of  causing  coagulation.  Such  a  purified 
fibrinogen  can  still  be  made  to  clot  by  the  addition  either  of  serum  or  of  the 
washings  of  a  blood-clot,  or  of  the  watery  extract  of  alcohol-coagulated 
serum.  This  power  of  serum  to  convert  fibrinogen  into  fibrin  is  due  to  the 
presence  in  it  of  minute  quantities  of  a  substance  which  has  been  designated 
as  '  fibrin  ferment '  or  thrombin.  It  has  been  regarded  as  a  ferment  because 
it  is  active  in  minimal  quantities  and  is  stated  not  to  be  appreciably  used  up 
in  the  process  of  clotting.  Thus  if  we  add  some  serum  to  a  fibrinogen 
solution  we  can  cause  clotting,  and  then  on  squeezing  the  clot  obtain  a  serum 
which  will  bring  about  coagulation  when  added  to  a  fresh  portion  of  fibrino- 
gen. Considerable  doubt,  however,  has  been  thrown  on  the  ferment  nature  of 
thrombin  by  the  recent  work  of  Rettger  in  Howell's  laboratory.  Rettger 
shows,  in  the  first  place,  that  the  statement  of  the  preceding  sentence  is  only 
true  if  a  large  excess  of  thrombin  solution  be  made  use  of  in  the  first  instance. 
If  small  quantities  of  thrombin  solution  be  added  to  large  quantities  of 
plasma  or  of  pure  solutions  of  fibrinogen,  the  amount  of  fibrin  obtained 
is  proportional  to  the  amount  of  thrombin  added.  This  is  shown  in  the 
following  experiment : 

5  drops  of  thrombin  gave  0-2046  grm.  fibrin. 
10     „  „  0-3573     „       „ 

20      „  „  0-6089     „      „ 

40     „  „  1-5872     „       „ 

Moreover  the  action  of  thrombin  on  fibrinogen  solutions  is  almost 
independent  of  temperature,  occurring  practically  as  rapidly  at  17°  C.  as 
at  40°  C.  It  has  been  found  that  there  is  only  a  slight  increase  in  the  rate 
of  action  of  snake  venom  on  fibrinogen  solutions  on  warming  from  20°  to 
40°  C.  Rettger  therefore  regards  fibrin  as  formed  by  the  union  of  thrombin 
and  fibrinogen.  This  union  is  apparently  very  unstable.  If  fibrin  be 
extracted  with  a  3  per  cent,  salt  solution  for  some  time,  part  of  it  goes  into 
solution,  and  the  solution  is  found  to  contain  thrombin.  In  the  same  way  the 
thrombin  may  be  re- extracted  from  the  fibrin  if  the  latter  be  allowed  to 
putrefy. 

From  all  the  difierent  kinds  of  plasma  which  have  been  enumerated  above 
the  purified  fibrinogen  can  be  obtained  by  the  use  of  sodium  chloride,  and 
in  every  case  can  be  made  to  clot  by  the  addition  of  serum  or  of  a  solution  of 
thrombin.  The  last  change  in  the  act  of  clotting  is  therefore  the  change  from 
fibrinogen  to  fibrin,  and  this  event  is  brought  about  by  the  intervention  of 


THE  COAGULATION  OF  THE  BLOOD  843 

thrombin.  It  canuot  be  at  this  stage  of  the  process  that  the  calcium  salts 
exercise  their  influence,  since  '  fibrin  ferment '  or  thrombin  will  cause  the 
coagulation  of  fibrinogen  in  the  total  absence  of  soluble  calcium  salts  and 
even  in  the  presence  of  a  shght  amomit  of  ammonium  oxalate.  Moreover 
Hammarsten  has  shown  that  the  calcium  content  of  fibrin  is  no  greater  than 
that  of  the  fibrinogen  from  which  it  is  formed. 

The  fact  that  a  solution  of  pure  fibrinogen  is  made  to  clot  by  thrombin 
and  by  this  alone  renders  such  a  solution  an  excellent  reagent  for  the  presence 
of  the  '  ferment.'  By  this  means  we  can  show  that  thrombin  is  absent  in 
circulating  blood.  If  blood  be  received  direct  from  the  vessels  into  absolute 
alcohol  and  the  precipitate,  after  coagulation  by  alcohol,  be  extracted  by 
water,  the  extract  is  found  to  contain  no  trace  of  ferment.  The  same  state- 
ment applies  to  fresh  oxalate  plasma.  If,  however,  oxalate  plasma  be  made 
to  clot  by  the  addition  of  calcium  salts,  the  serum  squeezed  from  the  clot 
is  found  to  contain  thrombin.  In  the  process  of  coagulation  therefore  not 
only  is  there  a  conversion  of  fibrinogen  to  fibrin,  but  there  is  an  actual 
formation  of  the  agent  which  is  responsible  for  this  change,  namely,  thrombin 
or  fibrin  ferment.  Our  next  step  therefore  must  be  to  inquire  into  the 
precursors  of  the  thrombin  and  the  conditions  of  its  formation. 

If  oxalate  plasma  be  cooled  to  0°  C.  for  two  or  three  days  a  scanty 
granular  precipitate  is  produced.  This  can  be  centrifuged  o&  or  separated 
by  filtration  through  several  thicknesses  of  paper.  It  is  then  found  that  the 
remaining  plasma  can  no  longer  be  made  to  coagulate  by  the  addition  of 
lime  salts,  although  it  still  contains  fibrinogen,  which  is  converted  into  fibrin 
on  the  addition  of  thrombin.  If  the  precipitate  be  collected  and  treated 
with  calcium  chloride  and  the  mixture  added  to  the  oxalate  plasma  the 
latter  clots.  The  same  effect  is  produced  if  the  precipitate  plus  calcium 
be  added  to  a  pure  solution  of  fibrinogen.  We  must  conclude  that  the  pre- 
cipitate, though  itself  not  fibrin  ferment,  will  give  rise  to  fibrin  ferment  on 
treatment  with  lime  salts.  It  was  therefore  designated  by  Hammarsten 
'  prothrombin,'  and  regarded  as  the  precursor  of  thrombin. 

Thus  far  practically  all  workers  on  the  subject  are  agreed.  Coagulation 
of  the  blood  is  due  finally  to  the  coagulation  of  thrombin  and  fibrinogen. 
The  fibrinogen  is  present  as  such  in  the  circulating  plasma.  Thrombin  is 
not  contained  in  the  circulating  blood,  but  is  produced  from  some  precursor 
or  precursors  after  the  blood  has  been  shed.  For  the  production  of  thrombin 
the  presence  of  calcium  salts  is  necessary.  Further  research  on  the  nature 
of  the  precursor  prothrombin  has  shown  that  the  matter  is  not  quite  so 
simple  as  imagined  by  Hannnarsten.  In  the  following  account  we  shall 
adhere  chiefly  to  the  account  as  given  by  Morawitz,  reserving  most  of  the 
criticisms  and  limitations  to  be  made  to  this  theory  for  the  historical  sketch 
of  the  theories  of  clotting  at  the  end  of  this  section. 

Oxalate  plasma  which  has  been  separated  from  the  precipitate  of  pro- 
thrombin can  be  made  to  coagulate  by  the  addition  of  extracts  of  almost  any 
anmial  tissues  together  with  lime  salts,  and  these  therefore  were  supposed 
to  contain  prothrombin  similar  to  that  obtained  by  cooling  oxalate  plasma. 


844  PHYSIOLOGY 

These  extracts  even  on  mixture  with  calcium  are,  however,  without  efEect  on 
pure  solutions  of  fibrogen,  and  moreover  the  precipitate  produced  by  cold, 
if  thoroughly  washed  before  treatment  with  hme  salts,  loses  its  power  of 
evoking  coagulation  in  fibrinogen  solutions.  Prothrombin  is  therefore 
unable  by  itself,  even  on  addition  of  lime  salts,  to  produce  fibrin  ferment, 
but  needs  the  co-operation  of  some  other  substance  which  is  contained  in 
oxalate  plasma  and  which  generally  adheres  in  sufficient  quantities  to  the 
precipitate  produced  by  coohng.  Three  factors  are  therefore  necessary 
for  the  production  of  fibrin  ferment :  first,  Hme  salts  ;  secondly,  a  substance 
present  in  the  precipitate  of  prothrombin  as  well  as  in  most  animal  tissues  ; 
and  thirdly,  a  substance  present  in  solution  in  oxalate  plasma.  These  two 
latter  substances  have  been  designated  by  Morawitz  thrombokinase  and 
thrombogen.  Thrombokinase  is  contained  in  tissues  and  also  in  the  blood- 
platelets.  It  can  be  obtained  by  extraction  of  the  stroma  of  the  red  blood- 
corpuscles  or  of  the  bodies  of  lymph-cells  or  leucocytes.  Separation  of  the 
blood- platelets  by  cooling  in  the  form  of  the  disc-hke  precipitation  abolishes 
the  spontaneous  coagulabihty  of  any  form  of  plasma.  The  thrombogen 
is  contained  in  solution  in  oxalate  plasma.  It  is  therefore  concluded  that 
when  blood  leaves  the  vessels  there  is  a  disintegration  of  the  blood-platelets 
with  the  Uberation  of  thrombokinase.  This  acts  upon  thrombogen  in  the 
presence  of  hme  salts  and  produces  thrombin.  By  the  intermediation  of 
the  thrombin  the  fibrinogen  also  present  in  solution  in  the  plasma  is  con- 
verted into  fibrin.  The  changes  occurring  in  shed  blood  and  resulting  in  the 
production  of  a  clot  are  therefore  mainly  concerned  with  the  production  of 
the  fibrin  ferment.  This  view  of  the  essential  characters  of  coagula- 
tion is  borne  out  by  observations  on  other  forms  of  plasma,  especially  oi 
plasma  obtained  from  birds'  blood.  This  when  obtained  with  scrupulous 
cleanhness  so  as  to  avoid  any  contamination  with  dust  or  with  the  tissues 
remains  permanently  uncoagulable.  In  the  plasma  got  by  centrifuging 
the  blood  no  blood-platelets  are  to  be  seen,  and  no  precipitate  is  produced 
by  exposure  to  a  temperature  of  0°  C,  We  may  say  therefore  that  blood- 
platelets  with  their  contained  thrombokinase  are  absent  from  birds' 
blood,  and  with  them  the  property  of  spontaneous  coagulabihty.  It 
is  also  free  from  fibrin  ferment,  but  contains  thrombogen  as  well  as  soluble 
hme  salts.  It  is  only  necessary  therefore  to  add  thrombokinase  in  the 
shape  of  a  watery  extract  of  any  tissue  in  order  to  cause  the  appearance  of 
fibrin  ferment  and  the  conversion  of  the  fibrinogen  already  present  in  the 
plasma  into  fibrin. 

In  every  case  the  initiation  of  the  act  of  clotting  would  seem  to  depend 
on  the  setting  free  of  thrombokinase  in  the  plasma.  In  mammahan  blood, 
although  thrombokinase  can  be  derived  from  red  or  white  corpuscles,  we 
have  no  reason  to  believe  that  there  is  any  appreciable  disintegration  of  these 
formed  elements  when  the  blood  leaves  the  vessels.  In  oxalate  blood 
leucocytes  can  be  seen  alive  and  exercising  amoeboid  movements  two  or  three 
days  after  the  blood  has  left  the  vessels,  and  although  certain  observers  have 
assumed  the  presence  of  explosive  corpuscles  which  break  up  directly  the 


THE  COAGULATION  OF  THE  BLOOD  845 

blood  leaves  the  vessels,  the  presence  of  such  corpuscles  in  the  higher  animals 
has  not  been  demonstrated,  though  in  some  invertebrata  they  are  certainly 
present.  The  sole  source  therefore  of  the  thrombokinase  is  the  very  perish- 
able formed  elements  of  which  we  have  spoken  as  the  blood-platelets.  The 
very  existence  of  this  element  is  doubtful  in  normal  blood.  What  is  certain 
is  that  any  slight  change  in  the  plasma,  whether  due  to  contact  with  a  foreign 
object  or  to  cooling  of  the  blood,  causes  the  appearance  of  these  elements. 
The  first  act  therefore  in  coagulation  is  the  appearance  of  the  blood-platelet 
and  its  disintegration  with  the  setting  free  of  thrombokinase.  The  part 
played  by  the  platelets  in  coagulation  is  of  great  importance  in  maintaining 
the  integrity  of  the  vascular  system.  If  a  fine  needle  be  thrust  through  the 
wall  of  a  venous  capillary  which  is  kept  under  observation  by  the  microscope 
it  will  be  seen  that  the  blood,  as  it  flows  past  the  injured  spot,  deposits  blood- 
platelets  on  the  side  of  the  puncture.  These  aggregate  to  form  a  plug  closely 
adherent  to  the  wall  of  the  vessel,  which  effectively  prevents  any  escape  of 
the  contents  of  the  capillary.  The  blood-platelets  fuse  so  as  to  form  a  mass 
of  fibrin,  and  later  on  by  the  growth  of  the  adjacent  endothelial  cells  the 
thrombus  is  organised,  converted  into  connective  tissue,  and  covered  with 
a  layer  of  endothelium  continuous  with  the  rest  of  the  vessel.  The  same 
process  occurs  when  any  part  of  the  fining  membrane  of  a  large  vessel  is 
injured.  Thus  destruction  of  a  patch  of  endothelium  in  a  vein  leads  to  the 
deposition  of  blood-platelets  over  the  patch  and  the  formation  of  a 
'  thrombus  '  adherent  to  the  wall.  From  this  thrombus  coagulation  may 
spread  through  the  rest  of  the  contents  of  the  vessel  and  produce  thrombosis 
of  the  whole  vein.  Under  healthy  conditions  the  thrombus  serves  simply 
to  cover  the  bare  area  in  the  wall  of  the  vein  and  is  grown  over  later  by 
endothelium,  so  restoring  the  integrity  of  the  vessel  wall.  If  we  beheve 
in  the  pre-existence  of  blood-platelets  in  the  circulating  blood  we  must 
assume  the  first  act  in  coagulation  to  be  the  disintegration  of  these  elements 
and  the  setting  free  of  thrombokinase.  If  we  disbeHeve  in  their  pre-existence 
the  first  act  in  coagulation  must  be  a  change  in  the  plasma  itself  (which 
perhaps  can  be  regarded  as  a  dropsical  protoplasm),  leading  to  the  separa- 
tion of  an  unstable  substance,  thrombokinase,  in  the  form  of  a  disc-like 
precipitate  which  rapidly  undergoes  further  changes,  reacting  with  the 
thrombogen  remaining  in  solution  in  the  plasma  vnth  the  production  of  fibrin 
ferment. 

Why  does  the  blood  not  clot  in  the  vessel  ?  No  theory  of  coagulation 
can  be  satisfactory  which  does  not  account  at  the  same  time  for  the  preserva- 
tion of  the  fluidity  of  the  circulating  blood.  One  factor  at  any  rate  in  the 
prevention  of  intravascular  clotting  must  be  the  nature  of  the  surfaces  with 
which  the  blood  comes  in  contact.  The  blood,  even  of  mammals,  can  be 
prevented  for  a  time  from  clotting  if  it  be  kept  carefully  from  contact  with 
any  foreign  substance  which  is  wetted  by  it,  as,  for  instance.  Avhen  it  is 
received  into  vessels  free  from  dust  and  coated  with  a  layer  of  oil  or  paraffin. 
On  the  other  hand,  free  contact  with  such  substances,  as  occurs  when  the 
blood  is  whipped,  materially  hastens  the  process  of  coagulation.     One  must 


846  PHYSIOLOGY 

therefore  conclude  that  mere  contact  with  a  foreign  body  has  a  direct 
destructive  action  either  on  the  plasma  leading  to  the  formation  of  blood- 
platelets,  or  on  the  latter,  leading  to  their  disintegration  and  the  discharge 
of  thrombokinase.  Birds'  blood,  for  instance,  can  be  made  to  clot  without 
the  addition  of  tissue  juice  if,  by  increasing  the  mechanical  insult,  as  by 
violent  whipping,  filtration  through  a  clay  cell,  or  addition  of  water,  we 
destroy  the  leucocytes  and  red  blood-corpuscles,  so  leading  to  the  liberation 
of  their  contained  thrombokinase.  Another  factor  is  probably  the  presence 
of  what  we  may  call  antithrombins  in  circulating  blood.  Although  evidence 
of  the  existence  of  these  bodies  is  still  somewhat  uncertain,  the  fact  that 
blood-serum  often  has  an  inhibitory  effect  on  the  action  of  a  solution  of  fibrin 
ferment  points  to  the  presence  in  the  serum  of  some  antibody  to  the  ferment. 
One  must  assume  too  that  processes  of  disintegration  are  continually  oc- 
curring in  the  blood  and  involving  the  plasma,  blood-platelets,  and  leucocytes, 
just  as  we  know  them  to  affect  the  red  blood-corpuscles.  In  the  healthy 
animal  the  hberation  of  thrombokinase  which  must  take  place  under  these 
circumstances  has  no  influence  in  producing  clotting.  The  organism  therefore 
must  possess  means  of  neutralising  the  presence  of  small  quantities  either  of 
kinase  or  of  fibrin  ferment.  When  small  quantities  of  either  of  these  sub- 
stances are  injected  into  the  blood-stream  no  coagulation  takes  place,  but  the 
blood  obtained  after  the  injection  clots  with  less  readiness  than  before,  a 
change  which  can  only  be  ascribed  to  the  production  in  the  body  of  anti- 
kinase  or  of  antithrombin.  This  production  of  anticoaguhns  must  be 
continually  taking  place  and  must  co-operate  in  the  preservation  of  the  fluid 
state  of  the  blood  while  in  the  vessels. 

INTRAVASCULAR  CLOTTING.  On  account  of  the  protective  mechan- 
isms with  which  the  animal  organism  is  endowed  the  production  of  clotting 
in  the  vessels  of  the  living  animal  is  not  readily  effected  by  the  injection 
of  thrombin.  Solutions  obtained  by  Schmidt's  method  from  alcohol- 
coagulated  serum  are  generally  without  effect,  and  we  have  to  inject  a 
very  strong  solution  of  thrombin  or  the  strong  fibrin  ferment  contained  in  the 
venom  of  certain  snakes  in  order  to  bring  about  coagulation  of  the  blood  in 
the  vessels.  Intravascular  clotting  is  more  easily  effected  by  the  injection  of 
thrombokinase.  It  was  shown  by  Wooldridge  that  normal  saline  extracts 
of  tissues  rich  in  cells,  such  as  the  thymus,  lymph-glands,  or  testis,  causes 
invariably  extensive  thrombosis.  If  such  extracts  be  acidified  with  acetic 
acid  a  precipitate  is  produced  which  is  soluble  in  dilute  alkalies,  and  on 
gastric  digestion  yields  a  precipitate  rich  in  phosphorus.  Alkaline  solutions 
of  the  acid  precipitate  bring  about  intravascular  clotting  when  injected  into 
the  blood-stream.  According  to  Wooldridge  the  injected  substance  takes 
part  in  the  formation  of  the  clot,  and  he  therefore  gave  it  the  name  of  '  tissue 
fibrinogen.'  It  is  usual  to  regard  these  tissue  fibrinogens  as  nucleo-proteins. 
They  are  certainly  rich  in  lecithin,  and  the  precipitate  obtained  from  them  on 
gastric  digestion  may  contain  as  much  as  25  per  cent,  of  this  substance. 
They  must  be  derived  either  from  the  cytoplasm  or  from  the  interstitial 
fluid  of  the  tissues,  and  it  is  still  doubtful  whether  we  are  justified  in  giving 


THE  COAGULATION  OF  THE  BLOOD  847 

them  the  name  of  niicleo-proteins  or  whether  we  should  not  rather  chissify 
them  with  the  phospho-proteins  which  play  so  great  a  part  in  the  building  up 
of  the  cytoplasmic  part  of  the  cell.  We  may  explain  the  action  of  these 
tissue  extracts  as  due  to  their  containing  thrombokinase*  Their  injection 
would  resemble  therefore  the  liberation  of  thrombokinase  which  normally 
occurs  when  blood  leaves  the  vessels.  More  difficult  to  understand  is  the 
result  of  injecting  small  amounts  of  these  tissue  extracts  or  large  amounts 
in  small  doses.  A  minute  quantity  of  tissue  extract  injected  into  the  blood- 
stream produces,  not  intravascular  clotting,  but  a  delay  of  the  coagulation 
time.  Repeated  injections  of  small  doses  may  absolutely  annul  the  coagula- 
bility of  the  blood,  which  can  be  collected  by  opening  the  blood-vessels  and 
will  remain  unclotted  for  many  days.  The  same  double  effect  may  be 
observed  even  with  a  larger  dose.  Li  rabbits  and  in  dogs  after  a  full  meal 
the  intravascular  coagulation  which  occurs  is  complete,  extending  through 
the  whole  vascular  system.  If,  however,  the  injection  be  made  into  a  fasting 
dog  the  thrombosis  produced  is  limited  to  the  portal  vein.  There  is  a  sudden 
fall  of  blood-pressure,  from  which  the  animal  gradually  recovers.  If  a  vessel 
be  opened  during  the  period  of  low  pressure  the  blood  which  flows  out  is 
totally  uncoagulable,  and  if  the  animal  be  killed  at  this  time  a  clot  will  be 
found  filling  up  the  whole  portal  vein.  Wooldridge  described  these  two 
effects  of  injection  of  tissue  extracts,  namely  the  coagulation  and  the  loss  of 
coagulability,  as  the  ^positive  and  negative  'phases  respectively.  Since  the 
negative  phase  has  not  been  observed  in  any  form  of  extra- vascular  plasma 
we  must  ascribe  it  to  a  reaction  on  the  part  of  the  living  cells,  and  probably, 
since  it  is  so  rapid  in  its  establishment,  to  the  action  of  the  cells  lining  the 
blood-vessels.  The  interest  of  these  observations  lies  in  the  relation  which 
they  bear  to  the  production  of  immunity.  If  a  toxin  such  as  that  of  diph- 
theria or  tetanus  be  injected  into  an  animal,  an  anti-toxin  is  produced  in 
the  course  of  two  or  three  days.  If  now  further  doses  of  toxin  be  injected 
its  first  effect  is  to  destroy  the  whole  of  the  anti-toxin  present  in  the  circu- 
lating blood.  In  the  course  of  a  day  or  two  the  anti-toxin  gradually  returns, 
and  at  the  end  of  three  days  is  found  in  larger  quantities  in  the  blood  than 
were  present  before  the  second  injection.  Every  toxin  has  therefore  a 
positive  as  well  as  a  negative  phase  of  action.  Tissue  extracts  in  their 
effect  on  coagulation  have  a  similar  positive  and  negative  phase,  but  these 
phases  are  established  within  a  feAv  seconds  instead  of  taking  two  oi-  three 
days  for  their  development.  One  cannot  but  believe  that  a  renewed  study 
of  the  conditions  of  intravascular  clotting  might  shed  important  light  on  the 
chemical  mechanism  of  production  of  immunity. 

FATE  OF  THE  FIBRIN  FERMENT.  The  substances  which  interact  for 
the  production  of  thrombin  in  shed  blood  as  well  as  thrombin  itself  are  not 
entirely  used  up  in  the  process  of  clotting.  Blood  serum,  though  free  from 
fibrinogen,  contains  traces  of  thrombokinase  (which  can  be  precipitated  by 

*  According  to  Howell,  these  tissue  fibrinogens  consi.st  of  |)liosphaticle3  in  associa- 
tion with  protein.  When  separated  from  the  protein  they  are  thermostable,  and  their 
thrombo plastic  effect  is  due  to  their  jiower  of  neutralising  antithronibin. 


84S  PHYSIOLOGY 

the  addition  of  dilute  acetic  acid)  and  thrombogen,  as  well  as  a  fairly  strong 
solution  of  thrombin.  Thrombin,  however,  rapidly  disappears  from  serum, 
so  that  a  blood-serum  which  has  been  kept  for  two  or  three  days  may  be 
almost  free  from  fibrin  ferment.  Such  a  serum  can  be  reactivated  by  the 
addition  of  small  traces  either  of  acid  or  alkali.  It  has  been  suggested  that 
the  thrombin  undergoes  a  modification  into  an  inactive  form  which  is  called 
metatJiromhin.  This  substance  has  no  relation  to  the  precursors  of  fibrin 
ferment  which  we  have  already  considered.  It  is  unaltered  by  lime  salts  or 
by  the  addition  of  thrombokinase,  but  can  be  reconverted  into  thrombin  by 
means  of  acids  or  alkahes.  According  to  Rettger  the  disappearance  of  throm- 
bin from  serum  is  due  to  its  combination  with  some  of  the  proteins  of  the 
serum.  This  combination,  Hke  that  of  thrombin  with  fibrinogen  to  form 
fibrin,  is  unstable  and  can  be  broken  up  by  the  action  of  alkalies,  acids,  or  even 
of  putrefaction.  Thrombin  itself  seems  to  be  extremely  stable  and  will 
even  withstand  the  temperature  of  boihng  water  for  a  short  time.  If 
solutions  containing  thrombin  be  evaporated  to  dryness  the  dry  residue  can 
be  heated  to  135°  C.  without 'destruction  of  the  thrombin. 

We  are  now  in  a  position  to  see  how  far  the  theory  of  coagulation  evolved  from  a 
study  of  two  forms  of  plasma  will  serve  to  explain  the  behaviour  of  the  many  other 
kinds  of  plasma  which  have  been  the  subject  of  investigation. 

Cooled  plasma  contains  the  thrombokinase  in  the  form  of  blood-platelets  or  a 
disc-like  precipitate.  This  precipitate  can  be  separated  by  centrifuging  at  a  low 
temperature  or  by  filtration.  The  remaining  plasma  contains  only  thrombogen,  lime 
salts,  and  fibrinogen,  and  can  be  made  to  clot  by  the  addition  of  tissue  extracts  or  of 
fibrin  ferment,  but  will  not  clot  on  warming. 

In  soDruM  SULPHATE  PLASMA  the  interaction  of  the  fibrin  factors  is  merely  impeded 
by  the  excess  of  salt.  All  are  still  present,  and  it  is  therefore  sufficient  merely  to  dilute 
the  plasma  in  order  to  produce  clotting. 

Magnesium  sulphate  plasma  behaves  somewhat  differently.  If  the  blood  be 
received  directly  into  magnesium,  sulphate  solution  and  the  mixture  centrifuged  while 
still  warm,  a  clear  magnesium  sulphate  plasma  is  obtained  which  will  clot  on  simple 
dilution.  If  the  blood  be  left  for  twenty-four  hours  before  centrifuging,  the  plasma 
will  not  clot  on  dilution  nor  on  addition  of  tissue  extracts.  It  contains  fibrinogen  only 
and  is  therefore  an  excellent  reagent  for  the  presence  of  fibrin  ferment.  Magnesium 
sulphate  not  only  hinders  the  interaction  of  the  fibrin  factors  but  actually  slowly 
precipitates  the  thrombokinase,  so  that  if  time  be  allowed  for  this  precipitation  to  be 
complete  the  remaining  plasma  contains  only  fibrinogen. 

Sodium  fluoride  plasma  might  be  expected  to  act  like  oxalate  plasnia  since  sodium 
fluoride  is  a  precipitant  of  lime  salts.  This  salt  has,  however,  the  additional  property 
of  causing  a  certain  amount  of  fixation  of  the  formed  elements  of  the  blood  as  well  as 
of  the  blood-platelets.  If  it  be  thoroughly  centrifuged  so  that  the  plasma  is  obtained 
free  from  these  constituents  it  will  no  longer  clot  with  lime  salts  *  nor  even  with  lime 
salts  plus  tissue  extracts,  but  will  clot  readily  on  addition  of  thrombin.  Although  it 
still  contains  a  certain  amount  of  thi-ombogen,  this  is  entangled  and  carried  down  in 
the  precipitate  of  calcium  fluroide  which  is  produced  by  the  addition  of  lime  salts,  so 
that  the  thrombokinase  has  nothing  on  which  to  exercise  its  effect.  Sodimn  fluoride 
plasma  is  therefore  useful,  like  magnesium  sulphate  plasma,  as  a  test  for  the  presence 
ol  thrombin.  If  water  be  added  to  the  sodium  fluoride  blood  so  as  to  destroy  some  of 
the  formed  elements  and  liberate  their  constituents  into  the  plasma,  it  is  possible  to 
produce  clotting  by  the  simple  addition  of  lime  salts. 

*  According  to  Rettger  this  statement  is  incorrect. 


THE  COAGULATION  OF  THE  BLOOD  849 

Hirudin  PLASMA.  The  action  of  hirudinis  that  of  ananti-thrombin.  It  apparently 
combines  with  and  neutralises  fibrin  ferment.  Hirudin  plasma  can  therefore  be  made 
to  clot  by  the  addition  of  fibrin  ferment  in  sufficiently  large  quantities  to  combine  with. 
all  the  hirudin  present  and  leave  an  excess  over  in  the  fluid. 

Peptone  plasma  presents  many  difficulties  in  the  explanation  of  its  behaviour. 
Peptone  itself  has  apparently  no  influence  on  the  coagulation  of  the  blood.  Blood 
received  into  peptone  solution  clots  as  rapidly  as  when  received  into  salt  solution.  On 
the  other  hand,  if  blood  be  received  into  peptone  blood  obtained  by  the  injection  of 
large  doses  of  peptone  into  the  veins  of  another  animal,  the  mixture  does  not  clot, 
showing  that  peptone  blood  contains  some  substance  which  inhibits  the  processes  of 
coagulation.  This  '  anticoagulin  '  must  be  produced  by  the  organism  itself  as  a  result 
of  the  injection  of  peptone,  and  evidence  has  been  brought  forward  by  Delezenne  and 
others  that  the  seat  of  formation  of  the  anticoagulin  is  in  the  liver.  Whether  the  anti- 
substance  partakes  of  the  characters  of  an  anti-tlirombin  or  of  an  antikinase  has  not 
yet  been  definitely  ascertained.  Peptone  plasma  can  be  made  to  clot  by  the  addition 
of  tissue  extracts  even  in  small  quantities.  It  still  contains  all  the  fibrin  factors  since 
it  will  clot  on  simple  dilution  or  on  the  passage  of  a  current  of  carbon  dioxide.  It  needs, 
however,  the  addition  of  large  quantities  of  fibrin  ferment  to  bring  about  coagulation. 

THE  TRANSUDATIONS 

The  earlier  work  on  the  mechanism  of  coagulation  was  largely  carried  out 
on  the  fluids  obtained  from  the  pericardial  or  pleural  ca\nties  or  on  hydrocele 
fluid  from  the  tunica  vaginalis.  These  as  a  rule  can  be  kept  indefinitely 
without  clotting,  but  will  clot  readily  on  addition  of  a  few  drops  of  blood 
or  the  washings  of  a  blood-clot  or  fibrin  ferment.  They  -^nll  not  clot  on  the 
addition  of  tissue  extracts  containing  thrombokinase.  Though  they  con- 
tain leucocytes  and  even  some  red  corpuscles,  they  are  free  from  blood-plate- 
lets. Their  behaviour  is  readily  explained  by  the  assumption  that  they 
contain  fibrinogen,  but  are  free  from  thrombokinase  or  thrombogen.  In 
order  to  produce  coagulation  it  is  therefore  necessary  to  add  two  fibrin 
factors,  thrombokinase  and  thrombogen,  as  happens  when  we  add  blood,  or 
to  treat  them  with  fully  formed  thrombin  or  fibrin  ferment. 

HISTORY  OF  THE  COAGULATION  QUESTION.  It  is  not  surprising  that  the 
coagulation  of  the  blood,  with  the  antecedent  changes  which  lead  to  the  appearance 
of  thrombin  and  probably  represent  the  successive  stages  in  the  disintegration  of  a  fluid 
labile  protoplasmic  molecule,  i.e.  the  change  from  life  to  death  of  the  plasma,  should 
have  been  the  subject  of  a  very  large  number  of  investigations,  and  that  even  at  the 
present  time  the  interpretation  of  the  salient  facts  presents  manj-  difficulties.  Some 
help  may  be  given  to  the  future  clearing  up  of  these  difficulties  b}'  a  study  of  the  steps 
by  which  our  present  standpoint  has  been  arrived  at.  The'  universal  practice  of  bleeding 
as  a  therapeutic  measure  naturally  afforded  many  opportunities  to  phj-sicians  for  ob- 
serving the  processes  of  coagulation  under  diseased  as  well  as  healthy  conditions.  The 
general  result  was,  however,  in  most  cases,  a  crop  of  ill-founded  and  uncritical  theories, 
and  it  is  not  till  the  time  of  Hewson  (1772)  that  we  meet  with  investigations  of  the 
question  carried  out  on  modern  lines  with  reference  to  observation  and  experiment 
at  each  stage.  We  owe  to  Hewson  the  discovery  that  coagulation  can  be  inhibited 
indefinitely  by  the  addition  of  neutral  salts,  such  as  sodium  sulphate,  and  it  was  by  a- 
study  of  such  bloods  that  Hewson  arrived  at  the  conclusion  that  the  formed  elements 
of  the  blood  take  no  part  in  the  production  of  the  clot.  Johamies  jNIiiller  in  1832  came 
to  the  same  conclusion  from  a  study  of  frog's  blood.  ■  This  he  diluted  with  sugar  solution 
and  filtered  through  filter-paper.  The  large  corpuscles  were  retained  by  the  meshes 
of  the  filter-paper  and  the  clear  fluid  which  came  through  slowly  underwent  coagulation. 


850  PHYSIOLOGY 

The  beginning  of  our  modern  ideas  on  the  subject  must  be  ascribed  to  Buchanan, 
though  many  of  the  facts  discovered  by  this  observer  escaped  general  recognition  and 
were  later  re-discovered  by  Alexander  Schmidt.  Buchanan  worked  chiefly  on  hydrocele 
fluid  and  showed  that  this  coiUd  be  made  to  yield  fibrin  by  treatment  with  fresh  blood 
or  by  adding  it  to  the  washings  of  a  blood-clot.  He  compares  the  action  of  the  latter 
to  that  of  rennet  on  the  protein  of  milk.  His  experiments  showed  that  '  fibrin  has 
not  the  least  tendency  to  deposit  itself  spontaneously  in  the  form  of  a  coagulimi,  that, 
like  albumin  and  casein,  fibrin  often  coagulates  under  the  influence  of  suitable  reagents, 
and  that  the  blood,  like  most  other  liquids  of  the  body  which  appear  to  coagulate 
spontaneously,  only  do  so  in  consequence  of  their  containing  at  once  fibrin  and  sub- 
stances capable  of  reacting  upon  it  and  so  occasioning  coagulation.'  He  held  therefore 
that  the  coagulation  of  the  blood  is  due  to  the  conversion  of  a  soluble  constituent  of 
the  liquor  sanguinis  into  fibrin  by  an  action  exerted  probably  by  the  colourless  corpuscles 
and  comparable  to  the  action  which  rennet  exerts  in  effecting  the  coagulation  of  milk. 
Furthermore,  the  liquid  which  accumulates  in  certain  serous  sacs  may  be  made  to  yield 
a  coagulum  of  fibrin  when  subjected  to  the  action  of  liquids  or  solids  rich  in  the  cellular 
elements  with  which  the  coagulent  action  appeared  to  be  associated  (Gamgee). 

Denis  in  1856  attempted  to  separate  this  precursor  of  fibrin.  He  received  the  blood 
into  one-sixth  of  its  volume  of' saturated  sodium  sulphate,  allowed  the  corpuscles  to 
settle,  and  filtered  off  the  supernatant  plasma.  On  satxirating  this  with  sodium  chloride 
a  precipitate  was  produced  which  Denis  designated  '  plasmine.'  This  precipitate,  on 
solution  in  water,  slowly  underwent  coagulation  and  was  apparently  split  into  two 
substances — a  solid  fibrin  and  a  soluble  protein.  Clotting  therefore,  according  to  Denis, 
was  dependent  on  the  splitting  of  a  single  protein  into  two  different  proteins,  one  of 
which  was  insoluble.  A  few  years  later  the  subject  was  taken  up  by  Alexander  Schmidt, 
who  devoted  the  remaining  thirty  years  of  his  life  to  the  investigation  of  the  coagulation 
of  the  blood.  Working  first,  as  Buchanan  had  done,  on  fluids  obtained  from  serous 
cavities,  he  noticed  that  these  could  be  made  to  clot  by  the  addition  of  serum,  and  he 
concluded  that  coagulation  was  due  to  the  interaction  or  combination  of  two  different 
proteins,  one  fibrinogen,  contained  in  the  serous  fluid,  and  the  other  '  fibrinoplastin,' 
which  was  contained  in  the  serum  and  could  be  precipitated  by  acidification  or  by 
dilution  and  passage  of  a  stream  of  carbon  dioxide.  This  fibrinoplastin  was  identical 
with  what  we  should  nowadays  call  paraglobulin,  but  had  adherent  to  it  fibrin  ferment. 
Schmidt  later  on  found  that  in  many  cases  it  was  not  sufficient  to  mix  these  two  sub- 
stances together,  but  that  a  third  factor  was  necessary,  which  could  be  obtained  either 
from  serum  or  from  blood-clot  which  had  been  coagulated  by  alcohol.  This  third 
factor  he  compared  to  a  ferment,  so  that  the  theory  put  forward  by  Schmidt  in  1872 
was  that  coagulation  depends  on  the  interaction  of  two  substances — fibrinogen  and 
fibrinoplastin — under  the  influence  of  a  third  substance,  fibrin  ferment  or  thrombin. 
A  few  years  later  Hammarsten,  of  Upsala,  in  a  very  careful  series  of  experiments, 
proved  conclusively  that  the  fibrinoplastin  of  Schmidt  was  not  a  necessary  factor. 
Hammarsten  discovered  the  method  which  we  use  at  the  present  time  for  separation 
of  fibrinogen,  namely,  precipitation  by  half-saturation  with  common  salt,  and  showed 
that  the  fibrinogen  obtained  in  this  way  and  purified  by  repeated  precipitation  and  re- 
solution would  yield  a  clot  of  fibrin  on  the  addition  of  fibrin  ferment  prepared  by  Schmidt's 
process.  According  to  Hammarsten,  therefore,  clotting  was  due  to  the  conversion  of 
the  fibrinogen  present  in  the  circulating  plasma  into  fibrin  by  the  action  of  fibrin 
ferment,  which  was  probably  yielded  by  the  disintegration  of  the  white  blood-corpuscles. 
Schmidt's  later  work  was  directed  chiefly  to  determining  the  mode  of  origin  of  the 
fibrin  ferment.  Though  his  researches  yielded  a  number  of  important  facts,  especially 
as  to  the  part  played  by  tissue-cells  in  furnishing  the  precursors  of  the  ferment  or  in 
influencing  the  processes  of  clotting,  they  did  not  result  in  clarifying  the  views  of 
physiologists  generally  on  the  subject  of  clotting.  Perhaps  their  most  useful  effect 
was  to  demonstrate  the  complexity  of  the  processes  which  occur  in  the  blood  after  it 
leaves  the  vessels,  and  to  show  that  in  the  maintenance  of  the  fluid  condition  in  the 
vessels  as  well  as  in  the  production  of  a  clot  outside  the  vessels,  there  must  be  an  interac- 
tion between  the  opposing  factors,  some  of  which  hinder  and  some  of  which  favour 


THE  COAGULATION  OF  THE  BLOOD  851 

the  occurrence  of  coagulation.  According  to  Schmidt  the  plasma  is  itself  derived  from 
the  cells  of  the  body,  the  fibrinogen  being  formed  through  the  stages  of  paraglobulin 
and  cytoglobulin.  The  thrombin  is  derived  from  a  precursor  prothrombin  under  the 
action  of  a  zjnnoplastic  substance  also  derived  from  the  cells.  In  the  presence  of  the 
propsr  concentration  of  salts  the  thrombin  acts  upon  fibrinogen  to  produce  fibrin.  His 
views  may  be  roughly  expressed  by  the  following  schema  given  by  Howell : 

Cells 

I 
Plasma 


Cytoglobulin  Zymoplastic  Prothrombin 

substance 


Paraglobulin 

I 
Fibrinogen 


Thrombin 


Soluble  fibrm  -  Salts  =  Fibrin 


Some  important  light  was  thi'owTi  on  the  subject  by  the  researches  of  Wooldridge. 
Working  chiefly  with  peptone  plasma,  he  showed  in  the  first  place  that  such  plasma 
contained  all  the  factors  necessary  for  the  production  of  fibrin,  and  therefore  that  the 
co-operation  of  leucocytes  was  not  a  necessary  part  of  the  process.  Peptone  plasma, 
separated  entirely  from  leucocytes  and  red  corpuscles,  could  be  made  to  clot  by  dilution, 
by  the  passage  of  a  stream  of  carbon  dioxide  or  filtration  through  a  clay  cell.  This 
jjDwer  of  clotting  without  addition  of  any  other  substances  depended  on  the  presence  in 
the  plasma  of  a  substance  called  by  Wooldi'idge  '  A-fibrinogen,'  which  was  tIu:oTSTQ 
down  as  a  disc-like  precipitate  on  cooling  to  0°  C.  On  separating  this  precipitate, 
which  he  regarded  as  ecpiivalent  to  the  blood-platelets,  by  means  of  the  centrifuge, 
the  remaining  plasma  would  only  clot  on  the  addition  of  extracts  of  tissues.  Since 
neither  the  original  plasma  nor  the  plasma  after  separation  of  the  A-fibrinogen  would 
clot  on  the  addition  of  fibrin  ferment,  Wooldridge  thought  that  the  fibrinogen  of 
Hammarsten  was  absent  from  such  plasma,  which  only  contained  two  fibrinogens, 
A-  and  B-fibrinogen.  Clotting  therefore  consisted  essentially  in  an  interaction  between 
A-  and  B-fibrinogen,  and  was  inaugurated  by  the  appearance  of  A-fibrinogen  as  a  disc- 
like precipitate.  In  tliis  interaction  he  showed  that  ferment  was  produced,  and  the 
weakest  part  of  liis  theory  was  that  it  gave  practically  no  office  to  the  ferment  pro- 
duced during  the  first  steps  of  the  process  imagined  by  him.  The  B-fibrinogen  could 
bs  tlu'own  down  by  the  action  of  dilute  acid  or  of  salt  from  the  plasma  after  separation, 
of  the  A-fibrinogen.  After  precipitation  and  re-solution  two  or  three  times  it  would 
clot  with  fibrin  ferment,  and  was  coagulated  at  a  temperature  of  56^  C,  and  was  there- 
fore the  tj^aical  fibrinogen  of  Hammarsten.  According  to  Wooldridge,  therefore, 
previous  observers  had  been  working,  not  with  the  fibrinogens  of  the  plasma,  but  with 
a  fibrinogen  altered  by  repeated  precipitation  and  re-solution.  One  fact  discovered 
by  him  which  at  once  attained  universal  recognition  was  the  production  of  intravascular 
clotting  by  the  injection  of  tissue  extracts.  These  tissue  extracts  contained  tissue 
fibrinogens  which  he  compared  with  A-fibrinogen.  According  to  him  clotting  could 
be  inaugurated  either  by  the  action  of  A-fibrinogen  on  the  B-fibrinogen,  or  by  the 
action  of  tissue  fibrinogen  on  the  B-fibrinogen  of  the  plasma.  In  every  case  fibrin 
ferment  resulted  and  could  therefore  effect  the  conversion  of  any  C-fibrinogen  of 
Hammarsten  which  might  be  present  in  the  fibrin.  It  will  be  seen  that  this  theory  of 
Wooldridge  presents  a  striking  similarity  to  that  which  is  generally  accepted  at  the 
present  day.  If  we  change  the  names  of  A-fibrinogen  to  thrombokina.se,  of  B-fibrinogei\ 
to  thrombogcn,  we  see  that  the  only  difference  between  Wooldridge's  theory  and  that 
of  Morawitz  is  that  the  former  ignored  the  importance  of  lime  salts  in  the  process  and 


852  PHYSIOLOGY 

imagined  that  the  interaction  of  thrombokinase  and  thrombogen  resulted  in  the  direct 
production  of  fibrin  as  well  as  ferment,  instead  of  recognising  that  the  interaction  of  the 
two  substances  was  simply  a  first  stage  and  that  thrombin  was  formed  in  this  process 
for  the  subsequent  conversion  of  the  fibrinogen  into  fibrin. 

Attention,  however,  was  largely  diverted  from  Wooldridge's  work  by  the  discovery 
of  the  necessity  of  calcium  salts  for  clotting.  Green  had  already  shown  that  the  clotting 
of  many  forms  of  salt  plasma  could  be  hastened  by  the  addition  of  calcium  sulphate, 
whereas  the  coagulation  of  serous  fluid  was  not  affected  by  this  salt.  Green  suggested 
that  possibly  a  zymogen  of  the  ferment  was  activated  by  the  calcium  salt.  The  absolute 
necessity  of  the  presence  of  this  salt  was  first  demonstrated  by  Arthus  and  Pages  (1890) 
on  oxalate  and  fluoride  plasma.  At  first  Arthus  was  inclined  to  regard  the  part  played 
by  calcium  salts  in  the  coagulation  of  the  blood  as  analogous  in  all  respects  to  that  played 
in  the  coagulation  of  milk  by  rennet,  and  suggested  that  the  conversion  of  fibrinogen 
into  fibrin  was  actually  the  combination  of  fibrinogen  with  calcium  salts,  the  combina- 
tion being  effected  by  the  agency  of  the  ferment.  It  was  shoAvn,  however,  by  Pekel- 
haring  that  the  power  of  lime  salts  to  produce  clotting  in  oxalate  plasma  was  annulled 
if  the  body  precipitable  by  cold  had  been  previously  removed,  and  Hammarsten  proved 
conclusively  that  the  action  of  calcium  salts  was  on  this  prothrombin  and  not  on  the 
fibrinogen,  careful  analyses  of  fibrinogen  and  fibrin  respectively  giving  practically 
equal  figiures  for  calcium.  Hammarsten  pointed  out  moreover  that  fibrin  ferment 
would  convert  fibrinogen  into  fibrin  in  the  total  absence  of  soluble  calcium  salts  and 
even  in  the  presence  of  a  slight  excess  of  oxalate. 

Later  experiments  have  had  reference  chiefly  to  the  nature  of  the  prothrombin 
precipitate  and  to  the  question  of  the  origin  of  the  fibrin  ferment  from  the  blood-plasma. 
Recent  advances  in  the  subject  were  much  facilitated  by  the  discovery  by  Delezenne 
that  birds'  blood  could  be  prevented  from  clotting  by  the  simple  expedient  of  collecting 
it  free  from  any  contact  with  the  tissues.  A  careful  study  of  this  blood  and  a  comparison 
of  its  behaviour  with  that  of  other  forms  of  uncoagulable  plasma  by  Fuld  and  Spiro, 
and  especially  by  Morawitz,  have  resulted  in  the  further  separation  of  the  precursor 
of  fibrin  into  two  substances,  thrombokinase  and  thrombogen.  Further  investigations 
by  NoLf  have  dealt  especially  with  the  question  of  the  interaction  which  is  continually 
taking  place  between  the  vessel  wall  and  the  contained  blood,  and  which  may  result, 
according  to  the  circmnstances,  in  the  diminution  or  increase  in  the  coagulability  of 
the  blood.  According  to  Nolf  the  essential  factors  in  the  production  of  blood-clotting 
are  three  proteins,  namely,  fibrinogen,  thrombogen,  and  thrombozym.  The  two  former 
are  produced  in  the  liver,  while  the  thrombozym  is  formed  from  the  leucocytes.  The 
clotting  depends,  not  on  a  ferment  action,  but  on  a  mutual  interaction  and  precipitation 
of  colloids  with,  as  a  result,  either  fibrin  or  thrombin.  Thrombin  differs  from  fibrin 
merely  in  containing  less  fibrinogen.  For  this  reaction  to  take  place  the  presence  of 
calcium  is  necessary  as  well  as  certain  thromboplastic  substances  which  act  as  centres 
of  precipitation.  The  fluid  condition  of  the  blood  in  the  vessel  depends  on  the  presence 
of  antithrombin  formed  in  the  liver.  Nolf  thus  agrees  with  Wooldridge  in  regarding 
thrombin  as  a  product  of  coagulation  rather  than  a  cause.  Tlu-ombin,  according  to 
him,  is  merely  an  unsaturated  compound  which  is  capable  of  taking  up  or  uniting  with 
more  fibrinogen  to  form  fibrin.  Nolf  would  regard  the  formation  of  fibrin  as  an  import- 
ant preparatory  step  in  the  nutrition  of  the  cells.  He  compares  these  actions  occurring 
in  the  blood  to  the  actions  of  digestive  ferments  on  proteins.  Just  as  casein  is  first 
precipitated  and  then  digested  by  pepsin,  so  fibrinogen  is  first  precipitated  as  fibrin  by 
union  with  thrombozym  and  thrombogen.  This  fibrin  is  then  hydrolysed  and  dissolved 
by  the  further  action  of  the  thrombozym,  which  he  regards  as  essentially  proteolytic 
in  character.  That  the  whole  blood  does  not  coagulate  within  the  vessels  he  explains 
by  assuming  that  the  cells  of  the  blood  and  tissues  are  covered  normally  with  an  ultra- 
microscopic  layer  of  fibrin.  This  forms  a  neutral  sin-face,  like  a  paraffined  vessel, 
which  has  no  thromboplastic  effect  upon  the  plasma. 

According  to  Mellanby  the  prothrombin  in  the  plasma  is  constantly  associated  with 
the  fibrinogen.  It  may  be  converted  to  thrombin  either  by  the  action  of  calcivun  and 
thrombokinase,  or  by  the  action  of  calcium  and  alkali,  or  possibly  by  the  action  of 


THE  COAGULATION  OF  THE  BLOOD  853 

calcium  alone.  The  latest  work  on  the  subject  by  Rctlger  has  tended  fromcwhat  to 
the  simplification  of  this  extremely  complex  problem.  In  the  first  place,  he  regards 
the  formation  of  fibrin  as  non-fermentative  in  character,  thus  agreeing  with  Nolf, 
fibrin  being  produced  by  the  simple  union  of  fibrinogen  and  thrombin,  though  a  very 
small  amount  of  thrombin  may  produce  a  much  larger  amount  (about  200  times  its 
weight)  of  fibrin.  He  finds  no  evidence  of  the  pre-existence  in  the  blood  of  a  thrombin 
or  pro-ferment,  and  is  inclined  to  regard  the  action  of  so-called  kinases,  which  can  be 
extracted  from  animal  tissues,  as  similar  to  that  of  such  agents  as  dust,  threads  of  linen, 
which  can  produce  a  similar  coagulating  effect  in  birds'  blood.  The  thrombin  he 
regards  as  derived  from  the  formed  elements  at  the  moment  of  their  rapid  disintegra- 
tion when  placed  under  abnormal  circumstances.  For  the  formation  of  active  thrombin 
a  minimal  amount  of  calcimn  salts  must  enter  into  the  molecular  complex.  We  thus 
return  to  the  simpler  expression  of  the  processes  of  coagulation  as  given  by  Pekelharing 
and  Hammarsten,  the  prothrombin  which  is  formed  from  the  platelets  and  leucocytes 
by  secretion  or  process  of  disintegration  being  activated  to  tlu'ombin  by  the  calcium 
salts  present,  and  the  thrombin  so  formed  combining  quantitatively  with  the  fibrinogen 
to  form  fibrin.  The  prothrombin  is  not  readily  destroyed.  It  may  remain  in  calcium 
free  serum  for  days  and  when  activated  form  thrombin  quickly.  Thrombin,  on  the 
other  hand,  disappears  very  rapidly  from  active  serum  in  coixsequence  of  combining 
with  some  of  the  proteins  of  the  scrum.  This  property  of  combining  with  the  fibrinogen 
and  disappearing  from  the  serum  is  not  shared  by  the  prothi'ombin. 


SECTION   V 

THE  QUANTITY   AND  COMPOSITION   OF  THE 
BLOOD   IN   MAN 

A.     THE  TOTAL  QUANTITY  OF  BLOOD  IN  THE  BODY 

The  amount  of  blood  contained  in  the  body  can  be  estimated  by  Welcker's 
method.  It  is  not  sufficient  simply  to  open  one  of  the  blood-vessels  and 
allow  the  animal  to  bleed  to  death,  because  it  is  not  possible  in  this  way 
to  obtain  the  whole  of  the  blood  present  in  the  body,  and  the  blood  which 
is  obtained  gradually  becomes  more  dilute  in  consequence  of  absorption 
from  the  tissue  spaces  as  bleeding  continues.  A  small  sample  of  blood  is 
therefore  taken  from  a  blood-vessel  and  diluted  100  times  with  distilled 
water  to  serve  as  a  standard  of  comparison.  The  animal  is  then  bled  from 
a  cannula  placed  in  a  large  artery,  while  at  the  same  time  normal  salt 
solution  is  led  into  a  vein  so  as  to  maintain  the  vascular  system  as  full  as 
possible  and  allow  of  its  being  washed  out  by  the  action  of  the  heart.  When 
the  heart  ceases  to  beat,  the  blood-vessels  are  thoroughly  washed  out  by 
a  stream  of  normal  salt  solution  from  the  aorta.  The  animal  is  then  minced 
up  thoroughly  and  extracted  with  distilled  water,  and  filtered  so  as  to 
dissolve  out  the  haemoglobin  still  adherent  to  the  tissues  and  especially 
contained  in  the  red  marrow.  These  washings  are  mixed  with  the  whole 
diluted  blood  and  the  strength  of  the  mixture  in  haemoglobin  is  compared 
with  that  of  the  standard  solution.  In  this  way  it  is  possible  to  estimate 
the  total  haemoglobin  present  in  the  body  in  terms  of  the  sample  and  so 
find  the  total  amount  of  circulating  fluid.  It  has  been  found  that  the  dog 
contains  about  7-7  per  cent,  of  his  body  weight  as  circulating  blood,  and 
although  smaller  figures  were  obtained  on  other  animals,  such  as  the  rabbit, 
the  number  of  one-thirteenth  has  been  taken  as  applicable  to  man  on  the 
basis  of  two  observations  made  long  ago  on  executed  criminals.  Haldane 
has  shown  recently  that  this  estimate  is  much  too  high,  the  average  amount 
of  blood  in  man  being  only  about  4-9  per  cent,  of  the  body  weight,  i.e. 
about  one-twentieth  ;  in  some  cases,  as  in  fat  individuals,  it  may  be  as 
little  as  one-thirtieth.  Since  the  determination  of  the  total  volume  of  the 
circulating  blood  plays  an  important  part  in  the  consideration  of  the 
pathology  of  certain  diseases  such  as  anaemia  and  heart  disease,  the  ingenious 
method  adopted  by  Haldane  for  this  determination  in  the  living  animal 
may  be  here  described.     The  method  depends  on  the  fact  that  carbon 

854 


QUANTITY  AND  COMPOSITION  OF  BLOOD 


855 


monoxide  gas  when  inhaled  combines  with  ha-moglobin,  expelling  the 
oxygen  from  the  oxyhyemoglobin.  If  therefore  we  allow  a  man  to  breathe 
a  certain  volume  of  carbon  monoxide  until  it  is  entirely  absorbed  and  then 
find  that  one-fifth  of  the  haemoglobin  in  his  blood  is  saturated  with  carbon 
monoxide,  we  know  that  the  w^hole  blood  could  take  up  five  times  the  bulk 
of  carbon  monoxide  which  the  man  has  inspired.  We  therefore  in  this 
way  determine  the  total  '  carbonic  oxide  capacity  '  of  the  blood,  and  since 
CO-haemoglobin  contains  the  same  volume  of  carbon  monoxide  as  oxy- 
haemoglobin  does  of  oxygen,  the  same  figure  gives  us  the  total  '  oxygen 
capacity.'     The  total  oxygen  capacity  enables  us  to  determine  the  total 


Fig.  369. 


Haldanc's  CO  method  for  determinino;  total  blood  volume  in  man 


amount  of  haemoglobin  in  the  body,  and  if  wq  know  the  percentage  amount 
of  hoemoglobin  in  the  blood  it  is  easy  to  calculate  the  total  volume  of 
circulating  fluid. 

Before  the  carbonic  oxide  is  administered  the  percentage  oxygen  capacity,  i.e.  the 
volume  of  oxygen  capable  of  being  taken  up  by  the  haemoglobin  of  100  c.c.  of  the  blood, 
is  determined  as  follows  :  The  oxygen  capacity  of  a  sample  of  fresh  ox  blood  is  accurately 
determined  by  the  ferricj^anide  method  {v.  p.  859).  The  ox  blood  is  then  compared 
colorimetrically  with  blood  obtained  in  the  ordinary  way  by  means  of  a  haemoglobin- 
ometer  needle  from  the  finger  of  the  subject  of  the  experiment,  and  the  oxygen  capacity 
of  the  latter  blood  calculated  from  the  result  of  the  comparison.  The  subject  is  now 
made  to  breathe  tlu'ough  a  mouthpiece  A  (Fig.  369)  into  a  bladder  B  of  about  2  litres 
capacity.  The  carbon  dioxide  produced  during  the  experiment  is  absorbed  by  the  soda 
lime  vessel  between  the  mouthpiece  and  the  bladder.  The  oxj'gen  as  it  is  used  up  is 
replaced  from  an  oxygen  cylinder  through  the  tube  c.  D  is  a  graduated  vessel  contain- 
ing pui'e  carbonic  oxide  gas.  Wliile  the  subject  is  breathing  in  and  out  of  the  bag  a 
given  volmne  of  carbon  monoxide  is  admitted  into  the  bag,  being  driven  out  from  the 
tube  D  by  allowing  water  to  How  tlu'ough  the  tap  e.  The  requited  volume  of  carbon 
monoxide  is  gradually  di'iven  in  fi-om  the  mcasm-ing  cylinder  at  the  rate  of  about  30  c.c. 
every  two  minutes.  When  the  required  quantity  has  been  di-iveu  in  and  pushed  forward 
by  the  oxygen  an  interval  of  two  or  three  minutes  is  allowed  to  elapse.      After  this  a 


856 


PHYSIOLOGY 


drop  of  blood  is  taken  for  analysis.  It  contains  a  certain  amount  of  CO-hsemoglobin. 
The  relative  saturation  of  the  blood  in  carbon  monoxide  is  determined  by  the  colorimetric 
method.  A  number  of  narrow  test-tubes  of  exactly  equal  diameter  and  each  holding 
about  6  c.c.  are  taken,  and  2  c.c.  of  water  saturated  with  air  measured  off  into  each. 
Two  cubic  millimetres  of  the  blood  of  the  subject  are  measm'ed  off  in  the  ordinary  way 
by  means  of  a  haemoglobinometer  pipette  into  each  of  the  six  tubes,  the  solutions  being 
well  mixed.  Four  cubic  millimetres  of  this  blood  are  thoroughly  saturated  with  coal 
gas  and  placed  in  another  shorter  tube,  which  is  filled  full  and  tightly  corked.  In  this 
tube  the  haemoglobin  is  completely  saturated  with  carbon  monoxide.  After  the  subject 
has  breathed  the  carbon  monoxide,  a  sample  of  liis  blood  is  taken  and  diluted  as  before. 
The  solution  in  this  tube  is,  of  course,  pinker  than  those  in  the  other  tubes.  A  standard 
solution  of  carmine  is  now  added  from  a  narrow  burette  to  one  of  the  tubes  of  normal 
blood  solution  until  its  tint  is  the  same  as  that  of  the  blood  taken  after  the  inhalation. 
Addition  of  the  carmine  is  then  continued  until  the  tint  is  equal  to  that  of  the  blood 
solution  which  is  entirely  saturated  with  carbon  monoxide.  Supposing  that  0-45  c.c. 
of  carmine  was  required  to  produce  equality  of  tint  with  that  of  the  blood  taken  during 
the  experiment  and  2-5  c.c.  to  produce  equality  of  tint  with  that  of  the  satmated  blood, 
then  as  2-5  c.c.  of  carmine  in  4-5  c.c.  of  liquid  were  required  to  produce  satvu-ation  tint, 
and  only  0-45  c.c.  of  carmine  in  2-45  c.c.  of  liquid  to  produce  the  tint  of  the  blood  under 
examination,  the  percentage  saturation  of  the  latter  could  be  calculated  by  the  following 
sum : 

2-5        -45 

4^  •  2^ 
.-.  X  =  33-1 


100 


Although  this  method  requires  careful  execution  in  order  to  avoid 
fallacies,  it  is  possible  to  attain  results,  as  has  been  shown  by  Douglas, 
closely  agreeing  with  Welcker's  method.  The  error  is  probably  not  greater 
than  10  per  cent.,  which  is  negligible  in  comparison  with  the  large  changes 
in  total  blood  volume  which  have  been  found  to  occur  in  certain  cases  of 
disease.  The  total  record  of  two  such  observations  by  Haldane  and  Lorrain 
Smith  may  be  here  quoted  ; 

Normal  Individual 


Body  weight 

in 
liilogrammes. 

72-9 

89-0 

Oxygen  capacity 

per  100  c.c.  of 

blood  in  c.c. 

18-7 
18-2 


Volume  of  dry  CO. 

absorbed  in  c.c. 

at  0°  C. 

116 

116 

Total  amount 

of  blood 

in  grammes. 

3455 

2970 


Percentage 

saturation  of 

Hb  with  CO. 

18-9 

22-7 

Grammes  of  blood 

per  100  grm.  of 

body  weight. 

4-75 

3-34 


Dry  oxygen 
capacity  of 
blood  in  c.c. 

614 

511 

C.c.  of  oxygen 
per  100  grm. 
body  weight. 

0-84 

0-57 


In  applying  this  method  in  cases  of  disease  it  is  important  not  to  give  too 
large  a  dose  of  carbonic  oxide  gas.  In  a  normal  individual  30  per  cent, 
of  the  haemoglobin  may  be  combined  with  carbon  monoxide  before  any 
oxygen  hunger  is  felt,  and  it  is  possible  to  saturate  half  the  hsemoglobin 
with  this  gas,  though  with  considerable  discomfort  to  the  individual.  In 
cases  such  as  heart  disease,  where  the  patient  is  at  the  very  margin  of  his 
resources,  even  30  per  cent,  diminution  of  the  oxygen  capacity  of  the  blood 
may  have  serious  results,  and  the  carbon  monoxide  inspired  must  be  there- 
fore kept  at  the  lowest  limit  at  which  it  is  possible  to  carry  out  a  reliable 


QUANTITY  AND  COMPOSITION  OF  BLOOD  857 

determination   of   the    relative    carbonic   oxide    saturation    of    the    blood 
sample. 

The  total  blood  volume  probably  varies  appreciably  with  alterations 
in  the  conditions  of  the  anirnal,  and  may  be  found  different  on  two  suc- 
ceeding days.  It  is  certainly  influenced  by  the  height  of  the  blood  pressure 
as  well  as  by  the  oxygen  tension  in  the  air  breathed,  and  therefore  alters 
with  the  altitude.  Some  of  these  variations  we  shall  have  to  consider  more 
fully  in  a  later  section.  Any  lowering  of  blood  pressure  causes  an  absorp- 
tion of  fluid  from  the  tissues  into  the  blood,  so  that  the  latter  becomes  more 
dilute.  The  blood  content  during  the  last  stages  of  bleeding  may  contain 
little  more  than  50  or  60  per  cent,  of  the  haemoglobin  which  was  present 
in  the  first  samples  of  blood,  pointing  to  a  corresponding  dilution  of  the 
blood  during  these  few  minutes  by  means  of  tissue  lymph.  By  this  means, 
i.e.  the  absorption  of  fluid  from  tissues,  the  volume  of  circulating  blood 
after  a  limited  haemorrhage  is  rapidly  brought  up  to  normal,  so  that  there 
is  a  circulation  of  a  fluid  impoverished  in  corpuscles.  The  latter  are  made 
up  in  the  course  of  a  few  weeks  as  a  result  of  increased  activity  in  the 
bone-marrow. 

RELATIVE  AMOUNT  OF  PLASMA  AND  CORPUSCLES 

The  relative  amount  of  corpuscles  in  a  given  sample  of  blood  is  most 
easily  determined  by  Blix's  method.  The  blood  is  mixed  with  a  definite 
amount  of  2-5  per  cent,  potassium  bichromate,  and  the  mixture  is  put 
into  small  graduated  capillary  tubes,  which  are  then  placed  in  a  centrifuge 
revolving  about  10,000  times  per  minute.  The  corpuscles  rapidly  accumu- 
late in  an  almost  solid  mass  at  the  bottom  of  the  tube,  and  their  volume 
can  be  directly  read  off.  It  is  often  possible  by  working  quickly  to  receive 
blood  into  such  graduated  capillary  tubes  and  to  centrifuge  it  rapidly 
before  it  has  had  time  to  coagulate.  The  corpuscles  are  hurried  dowTi  to 
the  bottom  of  the  tube  within  two  or  three  minutes  and  their  volume  can 
be  in  this  way  directly  determined.  An  indirect  method  for  the  same 
purpose  was  devised  by  Hoppe-Seyler.  The  total  proteins  of  defibrinated 
blood  are  determined  and  compared  with  the  total  proteins  of  the  washed 
corpuscles  and  of  the  serum.  Thus  in  one  experiment  100  grm.  of  de- 
fibrinated pigs'  blood  contained  18-90  grm.  protein  plus  haemoglobin.  The 
blood-corpuscles  of  100  grm.  of  the  same  blood  contained  15-07  grm. 
proteins  plus  haemoglobin  ;  therefore  the  serum  of  the  same  100  grm.  of 
blood  contained  18-90*- 15-07  =  3-83  grm.  proteins.  One  hundred  grammes 
of  serum  contain  6-77  grm.  protein.  From  these  figures  the  amount  of 
serum  in  the  100  grm.  of  defibrinated  blood  may  be  computed  as  follows  : 

3-83 

^-==•.100  =  56-6  per  cent,  serum. 

100—56-6  —  43 --4  per  cent,  blood  corpuscles. 

The  average  volume  of  corpuscles  in  human  blood  can  be  taken  as  50  per 
cent,  of  the  total  amount,  difierent  estimations  having  given  figures  varying 


858  PHYSIOLOGY 

from  -48  to  54  per  ceut.     In  the  horse  the  volume  of  corpuscles  is  53  per 
cent.,  in  the  dog  36  per  cent. 

THE  ENUMERATION  OF  THE  CORPUSCLES 
In  order  to  enumerate  the  red  corpuscles  the  blood  is  diluted  with  a 
known  amount  of  an  isotonic  fluid  and  the  number  is  counted  in  a  measured 
volume  of  the  mixture.  The  average  number  of  red  corpuscles  is  about 
5,000,000  per  cubic  milhmetre  in  adult  men  and  rather  fewer,  about  4,500,000 
in  adult  women.  The  enmneration  of  corpuscles  is  subject  to  considerable 
errors,  probably  not  less  than  10  per  cent.  Moreover  different  conditions 
of  the  circulation  may  cause  variations  in  the  relative  distribution  of  plasma 
and  corpuscles  respectively  in  difierent  parts  of  the  circulation,  so  that  the 
blood-count  of  a  specimen  from  the  capillaries  of  the  finger  or  lobe  of  the 
ear  may  vary  considerable  from  a  similar  count  of  the  corpuscles  in  blood 
obtained  directly  from  a  minute  vein  or  artery.  More  important  therefore 
is  the  determination  of  the  haemoglobin.  For  this  purpose  a  measured 
quantity  of  the  blood,  2  to  5  c.mm.,  is  obtained  in  a  capillary  pipette  and 
mixed  with  a  given  volume  of  water.  The  red  fluid  thus  obtained  is  com- 
pared with  a  standard.  This  latter  in  von  Fleischl's  instrument  is  a  prism 
of  coloured  glass.  In  Oliver's  instrument  the  standard  consists  of  a  series 
of  tinted  glasses,  one  of  which  represents  the  colour  of  a  measured  quantity 
of  normal  blood  diluted  with  water  and  placed  in  a  flat  glass  cell  of  a  certain 
size,  while  the  others  represent  percentages  of  haemoglobin  below  and  above 
the  normal.  The  most  accurate  method  is  that  due  to  Hoppe-Seyler  and 
Haldane,  namely,  the  conversion  of  the  blood  sample  into  CO-haemoglobin 
and  its  comparison  with  a  standard  specimen  of  CO-haemoglobin,  which  is 
stable  in  solution  and  can  therefore  be  kept  in  a  sealed  glass  vessel  for  any 
length  of  time. 

THE  OXYGEN  CAPACITY  OF  THE  BLOOD 

Instead  of  determining  the  haemoglobin  we  may  measure  directly  the 
oxygen  capacity  of  the  blood,  since  the  oxygen-binding  power  of  this  fluid 
is  entirely  dependent  on  the  amount  of  haemoglobin  it  contains.  For  this 
purpose  we  may  make  use  of  the  fact  discovered  by  Haldane,  that  the 
combined  oxygen  in  oxyhaemoglobin  is  liberated  rapidly  and  completely 
on  addition  of  a  solution  of  potassium  ferri-cyanide  to  laked  blood,  and 
may  thus  be  easily  measured  with  the  help  of  an  apparatus  similar  to  that 
used  for  determining  urea  in  urine  by  the  hypobromite  method. 

The  following  description  of  the  method  is  given  by  Haldane  : 
"  Twenty  cubic  centimetres  of  the  oxalated  or  defibrinated  blood,  thoroughly 
satiu-ated  with  air  by  swinging  it  round  in  a  large  flask,  are  measured  out  from  a  pipette 
into  the  bottle  a,  which  has  a  capacity  of  about  120  c.c.  As  it  is  important  to  avoid 
blowing  expired  air  into  the  bottle  the  last  drops  of  blood  are  expelled  from  the  pipette 
by  closing  the  top  and  warming  the  bulb  with  the  hand."  Thirty  cubic  centimetres 
are  then  added  of  a  solution  prepared  by  diluting  ordinary  strong  ammonia  solution 
(sp.  gr.  0-88)  with  distilled  water  to  g^y-  The  ammonia  prevents  carbonic  acid  from 
coming  off,  while  the  distilled  water  lakes  the  corpuscles.     The  blood  and  ammonia 


QUANTITY  AND  COMPOSITION  OF  BLOOD 


859 


fiiolution  arc  tlioroughly  mixed  by  shaking,  and  at  tlie  end  of  this  operation  the  solution 
should  appear  perfectly  transparent  when  tilted  up  against  the  sides  of  the  bottle.* 
About  4  c.c.  of  a  satiurated  solution  of  potassium  ferricyanide  are  then  poured  into  the 
small  tube  b  (the  lengthof  which  should  slightly  exceed  the  width  of  the  bottle)  and 
placed  upright  in  a.  The  rubber  stopjjer,  which  is  provided,  as  shown,  with  a  bent 
glass  tube  connected  with  the  burette  by  stout  rubber  tubing  of  about  1  mm.  bore,  is 
then  firmly  put  in,  and  the  bottle  placed  in  the  vessel  of  water  c,  the  temperature  of 
which  should  be  as  nearly  as  possible  that  of  the  room  and  of  the  blood  and  water  in 
the  bottle.  If  the  stojjper  is  not  heavy  enough  to  sink  the  bottle  the  latter  should  be 
weighted.  By  opening  to  the  outside  the  three-way  tap  (or  T-tube  and  clip)  on  the 
burette,  and  raising  the  levelling  tube,  which  is  held  by  a  spring  clamp,  the  water  in 


co/vr/?oi  ri'se- 


FiG.  370.     Haldane's  method  for  determining  the  oxygen  capacity  of  the  blood. 

the  burette  is  brought  to  a  level  close  to  the  top.  The  tap  is  then  closed  to  the  outside, 
and  the  reading  of  the  burette  (which  is  graduated  to  -05  c.c,  and  may  be  read  to  -Olc.c.) 
taken  after  careful  levelling. 

The  water-gauge  (which  has  a  bore  of  about  1  mm.)  attached  to  the  temperature 
and  pressure-control  tube  is  now  accurately  adjusted  to  a  definite  mark.  This  is  easily 
accomplished  by  sliding  the  rubber  tube  backwards  or  forwards  on  the  piece  of  glass 
tubing  D.  The  control  tube  is  an  ordinary  test-tube  containing  some  mercury  to  sink 
it,  and  connected  with  the  gauge  by  stout  rubber  tubing  of  about  1mm.  bore. 

As  soon  as  the  reading  of  the  burette  is  constant,  which  it  will  probably  be  within 
two  or  three  minutes,  the  bottle  is  tilted  so  as  to  upset  B,  and  is  shaken  as  long  as  gas  is 
evolved.  During  this  operation  b  should  be  repeatedly  emptied,  as  otherwise  the  oxygen 
dissolved  in  its  liquid  might  not  be  completely  given  off.  When  the  evolution  of 
oxj'gen  has  ceased  the  bottle  is  replaced  in  the  Avater.  If,  as  is  probable,  the  pressui-e- 
gauge  indicates  an  alteration  in  the  temperature  of  the  water,  cold  water  from  the  tap, 
or  warmed  water,  is  added  till  the  original  temperature  has  been  re-established,  and  the 


*  If   the  solution  were  not  transparent  this  would  indicate   that  the   hiking  was 
incomplete,  and  more  ammonia  solution  would  need  to  be  added. 


860  PHYSIOLOGY 

reading  of  the  burette  noted  as  soon  as  it  is  constant.  The  bottle  is  again  shaken,  &c., 
until  a  constant  result  is  obtained,  for  which  about  fifteen  minutes  from  the  beginning 
of  the  operations  are  required.  The  temperature  of  the  water  in  the  jacket  of  the 
burette,  and  the  reading  of  the  barometer,  are  now  taken,  and  the  gas  evolved  is  reduced 
to  its  dry  volume  at  0°  and  760  mm.  To  calculate  the  oxygen  evolved  from  100  c.c.  of 
blood,  allowance  must  be  made  for  the  fact  that  a  20  c.c.  pipette  does  not  deliver  20  c.c. 
of  blood,  but  only  about  19-6  c.c.  The  actual  amount  of  shortage  for  a  given  pipette 
can  easily  be  determined  by  weighing  the  jiipette  after  water,  and  again  after  blood, 
has  been  delivered  from  it.  A  further  slight  correction  is  necessary  on  account  of  the 
fact  that  the  air  in  the  bottle  at  the  end  of  the  operation  is  richer  in  oxygen  than  at  the 
beginning,  so  that,  as  oxygen  is  about  twice  as  soluble  as  nitrogen,  slightly  more  gas  will 
be  in  solution.  With  a  bottle  of  120  c.c.  capacitj^  and  20  per  cent,  of  oxygen  in  the  blood, 
the  air  in  the  bottle  at  the  end  will  evidently  contain  about  27  per  cent,  of  oxygen,  so 
that,  assuming  that  the  coefficients  of  absorption  of  oxygen  and  nitrogen  in  the  54  c.c. 
of  liquid  within  the  bottle  are  nearly  the  same  as  in  water,  the  correction  will  amount 
at  15°  C.  to  -06  c.c.  in  the  reading  of  the  biu-ette,  or   +  0-30  per  cent,  in  the  result." 


THE  SPECIFIC  GRAVITY  OF  THE  BLOOD 

The  specific  gravity  of  the  blood  may  be  determined  by  directly  weighing 
a  sample,  or  more  conveniently  by  collecting  blood  in  a  capillary  tube  and 
discharging  drops  of  it  into  a  series  of  vessels  containing  glycerin  and  water 
mixed  in  varying  proportions.  When  it  is  found  that  the  drop  of  blood 
as  it  leaves  the  capillary  vessel  neither  rises  nor  falls  in  the  glycerin  and 
water  mixture,  we  know  that  the  specific  gravity  of  the  blood  is  identical 
with  that  of  the  mixture.  A  graduated  series  of  these  mixtures  is  kept 
in  bottles  and  their  specific  gravity  is  generally  determined  before  the 
experiment.  Hammerschlag's  method  consists  in  placing  a  drop  of  blood 
in  a  mixture  of  chloroform  and  benzene  and  then  adding  chloroform  or 
benzene,  as  the  case  may  be,  until  the  drop  neither  rises  nor  falls.  The 
specific  gravity  of  the  mixture  is  then  taken.  The  specific  gravity  varies 
in  man  between  1057  and  1066,  and  in  woman  from  1054  to  1061.  It 
is  increased  by  loss  of  water,  as  after  profuse  perspiration,  or  by  passive 
congestion  of  the  part  from  which  the  sample  is  taken.  It  is  also  increased 
as  a  result  of  any  operation  upon  a  serous  cavity  in  consequence  of  exuda- 
tion of  plasma  in  the  inflamed  or  irritated  part.  It  is  diminished  as  the 
result  of  bleeding.  The  specific  gravity  of  serum  is  1028  to  1032,  of  cor- 
puscles about  1090.  It  is  interesting  to  note  that  the  specific  gravity  of 
the  blood  is  highest  in  the  foetus  at  full  term,  when  it  amounts  to  1066, 
contrasting  with  that  of  the  mother  at  the  same  time,  the  specific  gravity 
of  whose  blood  is  only  1050.  The  specific  gravity  rapidly  falls  to  the 
latter  figure  after  birth. 

THE  REACTION  OF  THE  BLOOD 

The  blood  is  alkaline  to  litmus.  This  fact  can  be  demonstrated  by 
allowing  a  drop  to  fall  on  a  piece  of  glazed  litmus  paper  and  then  wiping 
away  the  blood  with  a  piece  of  linen  moistened  with  distilled  water  or  neutral 
saline  solution.  In  order  to  estimate  the  alkalinity  a  small  definite  quantity 
of  the  blood  is  mixed  with  sulphate  of  soda  solution  containing  a  definite 


QUANTITY  AND  COMPOSITION  OF  BLOOD  861 

amount  of  tartaric  acid.  The  acid  mixture  is  then  titrated  against  a 
decinormal  sokitiou  of  sodium  hydrate  until  the  mixture  gives  a  blue  stain 
when  a  drop  of  it  is  placed  on  glazed  litmus  paper.  The  alkalinity  of 
normal  blood  as  determined  in  this  way  amounts  on  the  average  to  0-2  grm. 
NaHO  per  100  c.c.  of  blood.  If  the  blood  be  laked  the  alkalinity  rises  to 
as  much  as  04  grm.  NaHO  per  100  c.c. 

All  these  questions  of  reaction  depend,  however,  on  the  indicator 
employed.  A  neutral  salt  might  react  alkaline  to  litmus  if  the  acid  radical 
of  the  salt  were  capable  of  being  displaced  by  the  coloured  acid  radical 
of  the  indicator  with  the  production  of  a  blue  alkaline  salt  of  litmus. 
Sodium  bicarbonate  may  be  acid  or  neutral  to  litmus  and  alkahne  to  methyl 
orange.  The  absolute  alkalinity  of  any  fluid  may  be  expressed  by  the 
number  of  free  OH  ions  which  it  contains,  just  as  the  acidity  is  a  measure 
of  the  free  H  ions.  The  number  of  free  OH  ions  in  the  blood  can  be  deter- 
mined by  an  electrical  method,  and  is  found  to  be  very  small,  very  little 
more  in  fact  than  that  contained  in  distilled  water.  The  alkalinity  of  the 
blood  as  ordinarily  determined  by  the  litmus  method  gives  us,  however, 
more  important  knowledge  than  this  determination  of  its  absolute  alkalinity, 
since  on  its  relative  alkalinity  to  litmus  depends  to  a  large  extent  its  power 
of  combining  with  carbon  dioxide  and  therefore  acting  as  a  carrier  of  this 
gas  from  the  tissues  to  the  lungs. 

THE  OSMOTIC  PRESSURE  OF  THE  BLOOD 
Since  the  blood  serves  as  a  circulating  medium  by  means  of  which 
the  composition  of  the  tissues  juices  forming  the  immediate  environment 
of  all  the  cells  of  the  body  is  maintained  constant,  its  osmotic  pressure 
must  be  of  considerable  importance  in  regulating  the  normal  exchanges 
of  the  cells  with  their  surrounding  fluid.  The  osmotic  pressiu'e  of  the 
blood  depends  on  its  molecular  concentration  and  can  be  determined  by 
any  of  the  methods  mentioned  earlier  (p.  125).  Of  these  the  most  con- 
venient is  the  determination  of  the  freezing-point.  The  depression  of 
freezing-point,  A,  of  mammalian  blood  is  about  0-56  and  varies  between 
0-54  and  0-60.  The  depression  of  the  freezing-point  observed  in  blood 
is  equal  to  that  of  a  0-9  per  cent,  sodium  chloride  solution,  which  is  there- 
fore taken  as  isotonic  with  the  blood.  Since  the  corpuscles  are  in  osmotic 
equilibrium  with  the  plasma,  their  osmotic  pressure  must  be  equal  to  that 
of  the  plasma,  and  laking  the  blood  does  not  alter  its  freezing-point  or  its 
osmotic  pressure.  The  blood  of  the  frog  has  a  lower  osmotic  pressure, 
the  normal  saline  fluid  for  the  fiog's  tissues  being  equivalent  to  0-65  per 
cent,  sodium  chloride  solution. 

THE  ELECTRICAL  CONDUCTIVITY  OF  THE   BLOOD 

In  a  solution  it  is  only  the  dissociated  ions  which  have  the  power  of 
carrying  electric  discharges.  The  conductivity  of  a  solution  of  pure  urea 
or  pure  glucose  would  not  difl'er  appreciably  from  that  of  distilled  water, 


862  PHYSIOLOGY 

since  neitlier  of  these  substances  is  ionised  in  solution.  The  conductivity 
of  blood- serum  is  therefore  determined  almost  entirely  by  its  content  in 
salts.  Since  this  is  approximately  constant,  the  conductivity  of  serum 
varies  within  very  narrow  limits.  The  conductivity  of  defibrinated  blood 
varies,  however,  within  wide  limits,  since  the  outer  limiting  layer  of  the 
corpuscles  is  impermeable  to  many  of  the  ions  of  the  salts  of  the  serum. 
The  corpuscles  present  a  resistance  to  the  passage  of  the  charged  ions  and 
therefore  of  the  electric  current  through  them,  so  that  the  larger  the  number 
of  corpuscles  contained  in  a  given  specimen  of  blood  the  lower  will  be  the 
conductivity  of  the  latter.  Stewart  has  made  use  of  this  fact  as  a  basis 
for  a  method  of  determining  the  relative  volume  of  corpuscles  and  plasma. 

The  Electrical  Conductivity  of  the  Entire  Blood  as  compared  with  that 
OF  ITS  Serum.     (Stewart.) 

The  relative  amount  of  serum  can  be  given  by  the  formula  : 

where  2>  is  the  number  of  cc.  of  seruminlOO  c.c.  of  blood  ;  \  (&),  \(s),  the  conductivity 
respectively  of  the  blood  and  serum  (both  measured  at  or  reduced  to  5°  C.  and  expressed 
in  reciprocal  Ohms  x  10^).  A  reciprocal  Ohm  is  the  conducti^aty  of  a  mercury  column 
1  -063  metres  long  and  1  square  millimetre  in  section. 

THE  GENERAL  COMPOSITION  OF  THE  BLOOD 

The  general  composition  of  the  blood  has  been  determined  by  Karl 
Schmidt  in  man,  and  by  Abderhalden  in  the  horse  and  bullock.  The 
results  are  given  in  the  Tables  on  pages  863  and  864. 

The  important  points  to  be  drawn  from  these  analyses  may  be  sum- 
marised as  follows.  Blood  contains  from  rather  over  one-third  to  one-half 
of  its  weight  of  corpuscles.  It  contains  from  20  per  cent,  to  25  per  cent, 
solids.  Blood-plasma  is  resolved  by  clotting  into  serum  and  fibrin.  The 
fibrin  forms  only  0-2  to  0-4  per  cent,  of  the  total  weight  of  blood.  The 
serum  contains  in  100  parts  8  to  9  parts  of  soUds,  of  which  7  to  8  parts 
consist  of  proteins,  while  the  salts  make  up  about  1  part.  The  chief  salt 
present  in  the  serum  is  sodium  chloride,  which  constitutes  60  per  cent, 
of  the  ash.  Next  to  this  comes  sodium  carbonate,  about  30  per  cent., 
and  besides  these  two  we  find'  traces  of  potassium,  sodium,  and  calcium 
chlorides  and  phosphates.  Traces  of  fats,  cholesterin,  lecithin,  dextrose, 
urea,  and  other  nitrogenous  extractives  are  constantly  found  in  the  serum. 
The  fats  are  much  increased  after  a  meal  rich  in  them  and  may  give  the 
serum  a  milky  appearance.  The  red  corpuscles  contain  from  30  to  40  per 
cent,  total  sohds.  Of  the  solid  constituents  haemoglobin  forms  nine-tenths  ; 
the  other  tenth  corresponds  to  the  stroma  consisting  of  stroma  protein 
(nucleo-protein),  lecithin,  cholesterin,  and  salts.  There  is  a  striking  con- 
trast between  the  salts  of  the  corpuscles  and  those  in  the  serum,  the  former 
consisting  chiefly  of  potassium  phosphate,  the  latter  of  sodium  chloride, 
which  in  some  animals  is  entirely  wanting  in  the  corpuscles. 


QUANTITY  AND  COMPOSITION  OF  BLOOD 


863 


Q 

O 
O 

CO 

O 
W 

o 

I— I 
OQ 

>H 
-Si 


ft'S 
(-1 1— 
o »-- 

^>> 

ft_=s 

2  '=' 
o  o 

O   o 

61315 

386-84 

315-08 

56-78 

0-388 
3-973 

1 

0-095 

4-935 

CO 

CO       1 

1— 1 

Magnesia  .                 0-0809 
Chlorine     .          .       1-949 
Phosphoric  acid        1-901 
Inorganic     phos- 
phoric acid      .       1-458 

Water 

Solids 

Haemoglobin 

Protein 

Svigar 

Cholesterin 

Lecithin     . 

Fat  . 

Phosphoric    acic 

as  nuclein 
Soda 
Potash 

O 

4^ 

'S 
.g 

C3 

fl 
O 
C^ 

O 
O 

<D 

a 

.3 
t-i 

-O 

c« 

01 

'^ 

CO 

ft 

o 
o 
o 

a 

3 
(-< 

<D 

CO 
CO 

6 

424-23 
46-07 

39-62 
0-551 
0-140 
0-8089 
0-6113 

0-0094 
2-0853 
01237 

(M 

p 
O 

0-0211 
1-7523 
0-1128 

0-0336 

Water 
Solids 

Protein 
Sugar 
Cholesterin 
Lecithm     . 
Fat  . 
Phosphoric    acic 

as  nuclein 
Soda 
Potash 

O 

Magnesia  . 
Chlorine     . 
Phosphoric  acid 
Inorganic    phos 
phoric  acid 

ft 

O 

05 
(M 

324-79 

204-91 

166-90 

30-08 

0-206 
2-105 

0-0500 
2-6143 

o 
00 

!M      1 

Op 

O 

0-0429 
1-0327 
1-0072 

0-7724 

Water 

Solids 

Haemoglobin 

Protein 

Sugar 

Cholesterin 

Lecithin     . 

Fat  . 

Phosphoric    acic 

as  nuclem 
Soda 

Potash       . 
Iron  oxide 
Lime 

Magnesia  . 
Chlorine     . 
Phosphoric  acid 
Inorganic    phos 
phoric  acid 

ft.g 

O    03 

2§ 

902-05 
97-95 

84-24 
1-176 
0-298 
1-720 
1-300 

0-020 
4-434 
0-263 

CO 

1— 1 

1    '—' 

1      r-l 
O 

0-045 
3-726 
0-240 

0-0715 

Water 
Solids 

Protein 
Sugar 
Cholesterin 
Lecithin     . 
Fat   . 
Phosphoric    acic 

as  nuclein 
Soda 
Potash       . 

Iron  oxide 

Lime 

Magnesia   . 
Chlorine     . 
Phosphoric  acid 
Inorganic     phos 
phoric  acid 

r-<     Q 
O 

OOOOCOCOCOr-H             O-^OO 

(MOOOOCMTtH-H^           CDOJCO 
OPpt:'>9Cppp           pOt;- 
CjOCOOiOOC^lO           OC^C^I 

TjH  lo  CO  CO 

t--   <M    rt 

00     -H 

C^J    IQ 

00   O 

6  6 

0-064 
2-785 
1-120 

0-806 

Water 

Solids 

Haemoglobin 

Protein 

Sugar 

Cholesterin 

Lecithin 

Fat     . 

Phosphoric      acic 

as  nuclein 
Soda  . 
Potash 

il 

Magnesia     . 
Chlorine 
Phosphoric  acid 
Inorganic      phos 
phoric  acid 

864  PHYSIOLOGY 

Blood  of  a  Man  Twenty-five  Yeaes  of  age. 
One  thousand  Orammes  of  Blood  contain 
51 3 -02  Blood-corpuscles. 


Water     ..... 

349-69 

Substances   not  vapourising  at 

120°              .... 

163-33 

7-70         (including  0  -512  iron) 

Hsematin         .... 

'  Blood-casein,'  &c. 

151-89 

Inorganic  constituents 

3-74         (excluding  iron) 

Chlorine.          .... 

0-898^ 

^Chloride  of  potassium 

1-887 

Sulphuric  acid 

0-031 

Sulphate  of  potassium     . 

0-068 

Phosphoric  acid 

0^695 

Phosphate  of  potassium  . 

1-202 

Potassiiun       .... 

1-586 

■=■ 

Phosphate  of  sodium 

0-325 

Sodium  ..... 

0-241 

Soda     .... 

0-175 

Phosphate  of  lime    . 

0-048 

Phosphate  of  lime 

0-048 

Phosphate  of  magnesium 

0-031 

Phosphate  of  magnesium 

0-031 

Oxygen 

0-206^ 

^ 

Total 


486-98  Interstitial  Fluid  {Plasma). 

Water 439-02 

Substances  not  vaporising  at 

120° 47-96 


Fibrin    . 

'  Albumen,'  &c. 

Inorganic  constituents 


Chlorine . 
Sulphuric  acid 
Phosphoric  acid 
Potassium 
Sodium  . 

Phosphate  of  lime 
Phosphate  of  magnesium 
Oxygen  . 


3-93 

39-89 

4-14 


1-722] 

r 

0-063 

0-071 

0-153 

1-661 

11 

0-145 

0-106 

0-221 

. 

'Sulphate  of  potassium 
Chloride  of  potassium 
Chloride  of  sodium 
Phosphate  of  sodium 
Soda     . 

Phosphate  of  lime 
Phosphate  of  magnesium 


Total 


3-736 


0-137 
0-175 
2-701 
0-132 
0-746 
0.145 
0-106 

4-142 


Specific  gravity  =  1  -0599 


THE  PROTEINS  OF  THE  PLASMA 

The  plasma  is  generally  described  as  containing  a  number  of  different 
proteins  belonging  to  the  class  of  coagulable  proteins.  No  albumoses  or 
peptones  are  present.  Since  the  plasma  in  clotting  gives  rise  to  fibrin 
and  serum  we  may  divide  its  protein  constituents  into  those  which  are 
the  precursors  of  fibrin  and  those  which  are  still  contained  in  the  serum. 

THE  PRECURSORS  OF  FIBRIN.  Most  of  these  have  been  dealt  with 
in  discussing  the  causation  of  coagulation.  It  only  remains  for  us  here 
to  mention  some  of  the  chemical  features  of  fibrinogen  and  its  product 
fibrin.  Fibrinogen  is  best  separated  by  Hammarsten's  method,  namely, 
half-saturation  with  sodium  chloride,  or  by  the  use  of  ammonium  sulphate. 
Fibrinogen  is  precipitated  between  13  and  28  per  cent,  saturation  with 


QUANTITY  AND  COMPOSITION  OF  BLOOD  865 

ammonium  sulphate,  whereas  210  other  globuhns  are  precipitated  until 
the  saturation  amounts  to  29  per  cent,  of  ammonium  sulphate.  Fibrinogen 
obtained  in  either  of  these  ways  can  be  purified  by  re-solution  and  re- 
precipitation,  but  loses  its  solubihty  in  the  process,  so  that  every  time  it 
is  precipitated  some  of  the  substance  becomes  insoluble.  The  insoluble 
fibrinogen  resembles  fibrin  in  many  characters,  but  does  not  swell  in  the 
presence  of  dilute  acids  as  fibrin  does.  Fibrinogen  is  soluble  in  dilute 
alkah,  from  which  it  may  be  precipitated  by  careful  neutralisation.  Fib- 
rinogen in  salt  solution  coagulates  at  56°  C.  A  small  amount,  however, 
remains  in  solution  and  is  not  coagulated  until  65°  C.  is  reached.  Fibrinogen 
can  be  therefore  described  as  a  globulin  occurring  in  the  plasma  and  con- 
verted on  coagulation  into  fibrin.  The  other  precursors  of  fibrin,  namely, 
those  involved  in  the  production  of  thrombin  and  called  thrombokinase 
and  thrombogen,  seem  to  be  phosphorus-containing  proteins  perhaps 
belonging  to  the  class  of  nucleo-proteins.  Their  chief  characteristics  have 
already  been  dealt  with. 

FIBRIN.  Fibrin  is  easily  obtained  by  whipping  blood  as  it  flows  from 
the  vessels  with  a  bundle  of  wires  or  twigs  and  then  washing  the  stringy 
threads  so  obtained  under  a  stream  of  water.  As  prepared  in  this  way 
it  always  contains  fragments  of  leucocytes,  blood-platelets,  and  stromata, 
which  have  become  entangled  in  its  meshes.  In  order  to  prepare  fibrin 
in  a  pure  state  it  is  necessary  to  get  it  by  the  action  of  fibrin  ferment  on 
a  pure  solution  of  fibrinogen.  Fibrin  is  a  white  stringy  substance  insoluble 
in  water  and  in  dilute  salt  solutions.  It  slowly  dissolves  in  5  per  cent, 
solutions  of  sodium  chloride,  sodium  sulphate,  potassium  nitrate,  &c., 
but  is  converted  in  this  process  into  soluble  globuhns.  It  is  probable 
that  its  solution  is  efi'ected  by  the  agency  of  minute  traces  of  proteol}i:ic 
ferment  present  in  the  blood  and  adherent  to  the  fibrin  as  it  is  precipitated. 
This  probability  is  strengthened  by  the  fact  that  a  certain  amount  of 
albumoses  is  always  found  in  the  fluid  along  with  the  soluble  globulins. 
In  dilute  acid,  such  as  0-2  per  cent,  hydrochloric  acid,  fibrin  swells  into  a 
clear  jelly  which  very  slowly  undergoes  solution  with  the  formation  of  acid 
albumen  and  proteoses. 

THE  PROTEINS  OF  THE  SERUM.  The  serum  proteins  are  generally 
grouped  in  two  classes,  namely,  the  sermn  albumens  and  the  serum  globulins. 
All  the  proteins  are  completely  precipitated  by  saturation  with  ammonium 
sulphate.  By  half-saturation  with  this  salt  only  the  globuhns  are  pre- 
cipitated and  can  be  separated  from  the  serum  albumens  by  filtration. 
The  proportion  of  globulin  to  albumen  as  determined  in  this  way  is  known 
as  the  '  protein  quotient.'  It  varies  in  different  animals,  but  in  the  same 
individual  it  is  almost  constant  in  the  blood,  serimi,  lymph,  and  serous 
transudations,  though  the  total  amounts  of  protein  in  these  may  be  very 
different. 

SERUM  ALBUMEN.  Serum  albumen  remains  in  the  serum  after  half- 
saturation  with  ammonium  sulphate.  It  can  be  precipitated  from  this  by 
complete  saturation  with  ammonium  sulphate  or  sodio-magnesium  sulphate, 

28 


866  PHYSIOLOGY 

or  in  the  crystalline  form  by  slight  acidification,  as  in  Hopkin's  method 
described  on  p.  80.  Serum  albumen  is  soluble  in  distilled  water.  Its 
solutions  therefore  can  be  dialysed  indefinitely  without  any  precipitation 
taking  place. 

THE  GLOBULINS.  The  globuhns  of  serum,  known  as  para-globulin  or 
serum  globulin,  are  obtained  by  half-saturation  with  ammonium  sulphate. 
Their  solutions  in  salt  coagulate  at  about  75°  C.  Since  globuhn  is  insoluble 
in  distilled  water  it  is  precipitated  on  dialysing  serum  against  distilled 
water.  The  precipitate  obtained  in  this  way  is  not,  however,  so  great  in 
extent  as  that  obtained  on  half- saturation,  and  on  this  account  the  globulin 
fraction  of  the  serum  proteins  has  been  divided  into  two  fractions,  namely, 
euglobulin,  precipitable  by  dialysis,  and  pseiido- globulin,  not  precipitable  by 
dialysis,  but  thrown  down  on  half- saturation  with  ammonium  sulphate. 

A  thorough  study  of  serum  globulin  by  Hardy  has  shown  that  this 
body  forms  adsorption  combinations  with  acids,  alkalies,  or  neutral  salts. 
With  acids  and  alkalies  the  globulin  forms  '  salts  '  which  ionise  in  solution 
so  that  in  an  electric  field  the  entire  mass  of  protein  moves.  These  salts 
cannot  be  precipitated  by  dialysis.  In  them  the  globulin  acts  much  more 
strongly  as  an  acid  than  as  a  base,  so  that  a  weak  acid,  such  as  acetic  acid, 
has  a  much  smaller  dissolving  power  over  globulin  than  has  the  equivalent 
amount  of  hydrochloric  acid,  and  boracic  acid  has  a  very  slight  power 
indeed.  The  weak  basic  character  of  globulin  causes  its  salt  in  weak  acids 
to  undergo  hydrolysis  with  separation  of  globulin,  so  that  in  order  to  reach 
the  same  grade  of  solution  with  a  weak  acid  as  with  a  strong  acid  a  great 
excess  of  the  acid  is  necessary.  Owing  to  the  much  stronger  acid  character 
of  globulin  it  is  found  that  weak  ammonia  dissolves  it  almost  as  well  as 
strong  alkalies.  With  neutral  salts  globuhns  form  molecular  compounds 
which  are  soluble,  but  are  readily  decomposed  by  water  with  liberation 
of  the  insoluble  globulin.  They  are  therefore  only  stable  in  the  presence 
of  a  comparatively  large  excess  of  salt.  The  globulins  differ  from  the 
albumens  of  the  serum  in  containing  constantly  organic  phosphorus  as  an 
integral  part  of  their  molecule.  In  all  its  solutions  globulin  is  present  in 
large  molecular  aggregates,  so  that  it  is  impossible  to  filter  a  globulin 
solution  through  a  porous  clay  cell. 

THE  CONDITION  OF  THE  PROTEINS  IN  THE  BLOOD-SERUM 
Although  it  is  easy  by  such  simple  means  as  the  addition  or  removal 
of  neutral  salts  to  separate  one  or  more  different  forms  of  protein  from 
serum,  we  have  strong  evidence  that  these  proteins  do  not  exist  side  by 
side  in  the  serum,  but  are  combined  to  form  what  we  may  term  serum 
protein,  which  acts  as  a  whole  and  differs  in  its  qualities  from  many  of 
those  of  its  constituent  globulins  or  albumens.  When  a  current  is  passed 
through  blood-serum  no  movement  of  protein  takes  place  (Hardy).  Alkali 
globulin  therefore  cannot  be  present.  Salt  globulin  might  be  assumed 
to  be  present  since  it  does  not  ionise  in  solution,  but  serum  is  not  preci- 
pitated by  simple  addition  of  acid,  which  would  readily  precipitate  salt 


QUANTITY  AND  COMPOSITION  OF  BLOOD  867 

globulin  in  alkaline  solution.  Moreover  serum  can  be  readily  filtered 
through  a  porous  cell,  and  this  method  is  adopted  for  obtaining  it  free 
from  contamination  by  micro-organisms.  Globulin  in  any  of  its  solutions 
will  not  pass  through  a  porous  cell.  If  globuhn  be  present  as  such  in  the 
serum  it  is  therefore  not  ionised,  but  the  agent  which  dissolves  it  must  be 
something  more  than  alkali  or  salt,  since  either  alone  or  together  they  will 
not  produce  a  solution  which  will  pass  through  a  porous  cell.  Serum  has 
still  the  power  of  taking  up  globulin  and  will  dissolve  almost  its  own  volume 
of  precipitated  globulin,  though  in  oxalate  serum  there  is  not  a  trace  of 
alkali  globuhn  nor  of  any  ionised  protein.  We  are  justified  therefore  in 
concluding  that  serum  protein  may  be  regarded  as  a  complex  unit.  By 
simple  means,  such  as  dialysis,  dilution,  or  addition  of  salt,  this  unit  can 
be  broken  up  with  the  separation  of  the  various  proteins  which  we  have 
designated  as  serum  albumen  and  serum  globulin,  &c.  The  question 
naturally  suggests  itself  whether  in  plasma  we  have  not  a  similar  com- 
bination of  all  its  varied  colloidal  constituents  to  form  one  labile  mass  of 
fluid  protoplasm. 


CHAPTER  XIII 
THE  PHYSIOLOGY  OF  THE  CIRCULATION 

SECTION  I 

GENERAL  FEATURES  OF  THE  CIRCULATION 

In  order  that  the  nutrition  of  the  tissues  may  be  properly  carried  out,  and 
that  they  may  receive  a  continual  supply  of  nourishment  from  the  ali- 
mentary canal,  and  of  oxygen  from  the  lungs,  and  be  able  to  free  themselves 
of  their  waste  products,  the  blood  which  flows  through  them  must  be 
continually  renewed.  For  this  purpose  every  part  of  the  body  is  supplied 
with  tubes — blood-vessels — of  various  sizes  and  structures. 

In  the  tissues  the  blood  is  passing  continuously  through  a  thick  mesh- 
work  of  capillaries,  hair-like  vessels  with  walls  consisting  of  a  single  layer 
of  delicate  endothelial  cells  which  permit  of  a  free  interchange  of  material 
by  diffusion  between  the  blood  within  and  the  tissue  fluid  outside  the 
vessel.  The  movement  of  the  blood  is  maintained  by  a  hollow  muscular 
organ,  the  heart,  placed  in  the  chest,  the  blood  being  brought  from  the 
heart  to  the  tissues  by  thick-walled  tubes,  the  arteries,  and  being  carried 
back  from  the  tissues  to  the  heart  by  a  system  of  thin-walled  vessels,  the 
veins. 

In  all  the  vertebrates  the  vascular  system  is  closed,  i.e.  communicates 
at  no  point  with  the  tissue  spaces  or  coelomic  cavity.  It  is  found  in  its 
simplest  form  in  fishes  (Fig.  371,  a),  where  the  heart  consists  of  one  auricle 
and  one  ventricle.  The  blood  is  received  from  the  great  veins  into  the 
auricle.  The  walls  both  of  auricle  and  ventricle  contract  rhythmically. 
By  the  contraction  of  the  auricle  the  blood  is  forced  into  the  ventricle, 
and  this,  when  it  contracts,  sends  the  blood  on  into  the  bulbus  arteriosus. 
From  the  bulbus  the  blood  passes  through  the  branchial  arteries  into  the 
gills,  where  it  takes  up  oxygen  from  the  surrounding  water,  and  then  flows 
on  into  the  aorta,  by  which  it  is  distributed  to  the  various  organs  of  the 
body.  From  the  capillaries  of  these  organs  the  blood  is  collected  by  the 
veins  and  is  carried  once  more  back  to  the  auricle.  The  fish  heart  is  thus 
entirely  on  the  venous  side  of  the  vascular  system. 

In  amphibia,  such  as  the  frog,  the  heart  consists  of  two  auricles  and 
one  ventricle.  The  right  auricle  receives  venous  blood  from  the  body  by 
means  of  the  venae  cava)  and  forces  it  by  its  contraction  into  the  ventricle. 

868 


GENERAL  FEATURES  OF  THE  CIRCULATION 


869 


From  the  ventricle  the  blood  passes  into  the  aorta,  whence  it  is  carried 
partly  by  the  pulmonary  artery  to  the  lungs,  partly  by  arteries  to  the 
different  organs  of  the  body.  The  blood  which  has  passed  through  the 
lungs  and  been  arteriahsed  flows  through  the  pulmonary  veins  to  the  left 
auricle,  whence  it  passes  into  the  ventricle  and  mixes  with  the  venous 
blood  which  is  arriving  from  the  right  auricle.  The  pulmonary  circulation 
is  thus  merely  a  branch  of  the  general  or  systematic  circulation.  The 
bulbus  aortae  in  the  frog  is  divided  into  two  parts  by  means  of  a  spiral 


Fic!.  371.     Diagram  of  circulatory  system  iii  A,  fish  ;   B,  amphibian  (frog) ;   C,  mammal. 
V,  ventricle  ;    o,  auricle  ;    K,  gill  capillaries  ;   A,  aorta  ;    c,  systemic  capillaries  ; 
L,  lung  capillaries  ;   r,  I,  right  and  left  auricles  ;   rV,  IV,  right  and  left  ventricles. 


valve,  by  which  a  partial  separation  of  the  blood  coming  from  the  right  and 
left  auricles  is  effected,  and  the  venous  blood  from  the  right  auricle  directed 
especially  into  the  pulmonary  artery. 

In  birds  and  mammals  the  heart  has  become  entirely  divided  into  two 
halves,  right  and  left,  which  have  no  communication  with  one  another 
except  by  way  of  the  blood-vessels  and  capillaries.  The  right  auricle 
receives  the  venous  blood  from  all  parts  of  the  body  and  sends  it  on  to 
the  right  ventricle,  whence  it  is  forced  into  the  lungs  along  the  pulmonary 
artery.  In  the  lungs  it  takes  up  oxygen  and  becomes  arterial  and  is 
returned  by  the  pulmonary  veins  to  the  left  auricle  and  so  to  the  left 
ventricle.  The  rhythmic  contractions  of  the  left  ventricle  then  force  the 
blood  into  the  aorta,  whence  by  the  branching  arteries  it  is  carried  to  all 
parts  of  the  body.  The  whole  vascular  system  is  distensible  and  elastic, 
so  that  its  capacity  ^^^ll  increase  with  the  pressure  of  the  blood  contained 
in  it.     Since  the  driving  force  is  fm-nished  by  the  heart  the  pressure  which 


870  PHYSIOLOGY 

causes  the  flow  of  blood  through  the  system  must  dechne  as  we  pass  from 
the  arterial  to  the  venous  side.  The  chief  function  of  the  large  arteries  is 
to  serve  as  elastic  conduits,  whereas  the  small  arteries  or  arterioles  leading 
from  the  arteries  to  the  capillaries  have  in  addition  the  function  of  regu- 
lating the  amount  of  blood  flowing  through  the  capillary  area  of  the  organs 
which  they  supply.  The  veins  have  the  function  of  conducting  blood  at 
a  low  pressure  from  capillaries  to  heart  and  of  storing  up  any  excess  of 
blood  which  is  not  immediately  taken  up  by  the  heart.  Corresponding 
to  this  difference  in  function  we  find  variations  in  the  structure  of  the 
blood-vessels  according  to  their  situation  in  the  circuit. 

The  vessels  which  carry  the  blood  from  the  heart  to  the  tissues,  the 
arteries,  are  thick- walled,  and  contain  an  abundance  of  muscular  and  elastic 
elements  in  their  walls.     The  typical  medium- sized  artery  is  described  as 


Fig.  372.     Transverse  section  of  part  of  the  wall  of  the  posterior 
tibial  artery  (  x  75). 
a,  endothelial  and  sub-endothelial  layers  of  intima  ;   h,  lamina  of  elastic  tissue  ; 
c,  media  consisting  of  muscle  fibres  ;  d,  adventitia.     (Schafer.) 

consisting  of  three  coats  (Fig.  372)  :  an  intima  lined  by  a  continuous  layer 
of  flattened  endothelial  cells,  which  rest  on  a  well-marked  lamina  of  yellow 
elastic  tissue  ;  a  media  composed  of  unstriated  muscular  fibres  arranged 
longitudinally  and  circularly  ;  and  an  external  coat  or  adventitia  of  fibrous 
tissue,  with  a  number  of  longitudinal  elastic  fibres.  Near  the  heart,  in  the 
great  vessels  such  as  the  aorta  and  its  larger  branches,  there  is  a  pre- 
ponderance of  elastic  tissue  as  compared  to  the  muscular  ;  and  we  find 
in  the  media  alternate  layers  of  muscle  fibres  and  fenestrated  elastic  mem- 
branes. In  the  smallest  arteries,  on  the  other  hand,  the  arterioles,  the 
elastic  element  entirely  disappears,  so  that  the  wall  consists  of  muscle 
fibres,  chiefly  circular,  lined  by  the  endothelium.  In  the  latter  vessels  a 
contraction  of  their  walls  may  result  in  an  entire  obliteration  of  the  lumen, 
so  shutting  off  altogether  the  supply  of  blood  to  the  capillaries  beyond. 
In  the  veins  the  same  three  coats  can  be  distinguished  as  in  the  typical 
artery,  but  the  wall  of  the  vessel  is  much  thinner  in  proportion  to  the  lumen. 
In  the  vein  moreover  there  is  a  preponderance  of  the  fibrous  tissue  elements, 
the  muscular  and  elastic  tissue  being  but  little  marked.  On  this  account 
the  vein  collapses  unless  it  is  distended  by  some  internal  pressure.  The 
histological  difference  between  veins  and  arteries  is  of  considerable  import- 
ance for  the  understanding  of  the  distribution  of  pressures  in  the  vascular 
system,  since  the  distensibility  and  reaction  to  pressure  of  these  vessels 


GENERAL  FEATURES  OF  THE  CIRCULATION 


871 


are  conditioned  by  their  structure.  In  Fig.  373  is  represented  the  extensi- 
bility, i.e.  the  increase  in  capacity  of  an  artery  and  a  vein  under  gradually 
increasing  internal  pressure.  It  will  be  seen  that  an  artery  which  has  a 
certain  capacity  at  zero  pressure  gradually  distends  with  increasing  pressure. 
The  increase  in  capacity  is  small  at  first,  and  becomes  most  rapid  between 
90  and  KXJ  mm.  Hg.  After  this  point  every  increment  of  pressure  brings 
about  a  gradually  diminishing  increment  of  capacity.  Thus  a  change  of 
internal  pressure  causes  the  greatest  change  in  capacity  when  the  pressure 
in  the  artery  corresponds,  as  we  shall  see,  to  the  average  arterial  pressure 
ill  the  normal  animal.  In  the  vein,  on  the  other  hand,  the  capacity,  which 
is  nothing  at  zero  pressure,  becomes  considerable  on  raising  the  pressure 
to  1  mm.  Hg.     A  further  rise  of  pressure  to  10  mm.  Hg  causes  a  consider- 

Capacity  in  c.c. 


— 1. [ 1 f- 

/  I 


mm.  Hg. 

Fig.  373.  Curves  of  distensibility  of  an  arteiy  (thick  line)  and  of  a  vein  (thin  line).  The 
figures  at  the  left  side  of  the  diagram  represent  the  capacity  of  a  section  of  the  vessel 
when  distended  under  a  certain  pressure,  expressed  by  the  figures  on  the  base  line  in 
mm.  Hg.     (Constructed  from  figures  given  by  Roy.) 

able  increase  in  volume,  but  from  this  point  the  increments  of  volume 
with  rising  pressure  rapidly  diminish.  Whereas  the  artery  is  most  dis- 
tensible at  about  100  mm.  Hg,  the  vein  has  its  limits  of  optimum  distensi- 
bility between  0  and  10  mm.  Hg. 

As  the  arteries  branch,  although  each  branch  is  smaller  than  the  parent 
vessel,  the  total  area  of  the  two  branches  into  which  the  vessel  divides  is 
greater.  Thus  there  is  a  continual  increase  in  the  cross  area  of  the  bed 
of  the  blood-stream  as  we  pass  from  the  heart  towards  the  periphery. 
This  increase  is  especially  marked  at  the  junction  between  the  capillaries 
and  the  arterioles  at  one  side  and  the  vemiles  on  the  other,  so  that  the 
total  area  of  the  bed  in  the  region  of  the  capillaries  can  be  taken  as  about 
800  times  that  of  the  area  of  the  aorta  where  the  blood  leaves  the  heart. 

On  cutting  through  an  artery,  blood  escapes  from  the  central  end,  i.e. 
that  nearest  the  heart,  with  great  force  and  in  a  series  of  jerks,  each  of 
which  corresponds  to  a  contraction  of  the  ventricles.     This  manner  of 


872 


PHYSIOLOGY 


escape  shows  that  in  the  arteries  the  blood  is  at  a  high  pressure,  and  that 
the  flow  from  the  heart  to  the  periphery  is  a  pulsatory  one.  The  same 
lesson  may  be  learnt  by  connecting  a  long  tube  with  the  central  end  of  a 
divided  artery.  This  experiment,  which  was  first  performed  by  the  Rev. 
Stephen  Hales,  may  be  described  in  his  own  words  : 

"  In  December  I  caused  a  mare  to  be  tied  down  alive  on  her  back  ;  she  was  fourteen 
hands  high,  and  about  fourteen  years  of  age,  had  a  Fistula  on  her  Withers,  was  neither 
very  lean,  nor  yet  lusty :  Having  laid  open  the  left  crural  Artery  about  three  inches 
from  her  belly,  I  inserted  into  it  a  brass  Pipe,  whose  bore  was  one  sixth  of  an  inch  in 
diameter  ;  and  to  that,  by  means  of  another  brass  Pipe  which  was  fitly  adapted  to  it, 
I  fixed  a  glass  Tube,  of  nearly  the  same  diameter,  wliich  was  nine  feet  in  length  :  Then 
untying  the  Ligature  on  the  Artery,  the  blood  rose  in  the  Tube  eight  feet  three  inches 
perpendicular  above  the  level  of  the  left  Ventricle  of  the  heart :  But  it  did  not  attain 
to  its  full  height  at  once  ;  it  rushed  up  about  half  way  in  an  instant,  and  afterwards 
gradually  at  each  Pulse  twelve,  eight,  six,  four,  two,  and  sometimes  one  inch  :  When 
it  was  at  its  full  height,  it  would  rise  and  fall  at  and  after  each  Puke  two,  three,  or  four 
inches  ;  and  sometimes  it  would  fall  twelve  or  fourteen  inches,  and  have  there  for  a 
time  the  same  Vibrations  up  and  down  at  and  after  each  Puke,  as  it  bad,  when  it  was 
at  its  full  height  ;  to  which  it  would  rise  again,  after  forty  or  fifty  Pulses." 

The  method  adopted  by  Hales  of  measuring  the  lateral  pressure  of 
blood  in  the  vessels  offers  very  considerable  drawbacks.  The  manipula- 
tion of  such  long  tubes  is  awk- 
ward, and  the  blood  which  escapes 
into  the  tubes  very  soon  clots  and 
renders  further  observation  impos- 
sible. It  is  therefore  customary 
when  we  desire  to  gain  an  idea  of 
the  average  pressure  in  any  blood- 
vessel, especially  in  an  artery,  to 
use  a  mercurial  manometer  for  this 
purpose.  This  instrument,  which 
was  first  applied  to  physiological 
purposes  by  Ludwig,  consists  of  a 
U-tube  with  two  vertical  limbs 
about  eighteen  inches  in  height, 
which  is  half-filled  with  clean 
mercury.  On  the  surface  of  the 
mercury  of  one  limb  is  a  float  of 
vulcanite  from  which  a  stiff  fine 
rod  of  straw,  glass,  or  steel  rises, 
bearing  on  its  upper  end  the 
writing-point.  This  point  may  be 
adjusted  so  as  to  write  on  the 
blackened  glazed  surface  of  a 
(The  arrangement  for  imparting 
of   glazed    paper   is   known    as   a 


"^^ 


Fig.  374.    Arrangement  of  an  apparatus  for 

taking  Vjlood-pressure  tracing. 
a,   artery  (carotid);    c,    cannula;    d,  three- 
way  cock  ;    m,  mercurial  manometer  ;    b,  drum 
covered  with  smoked  paper  ;    x,  tube  to  pres- 
sure bottle. 


moving  sheet    of    paper   (Fig.   374). 

a    continuous    movement    to    a    sheet 

kymograph.)      Instead    of   smoking   the   paper   a   pen  may  be   fitted   to 

the  end  of  a  rod  and  its  excursions  recorded  in  ink  on  a  moving  band  of 


GENERAL  FEATURES  OF  THE  CIRCULATION  873 

white  paper.  The  other  limb  of  the  manometer  is  connected  by  a  flexible 
inextensible  tube  with  a  small  tube  or  cannula  which  is  tied  into  the  central 
end  of  an  artery,  a  cUp  being  previously  placed  on  the  artery  so  as  to 
prevent  the  escape  of  blood  during  the  insertion  of  the  cannula.  To  the 
manometer  is  connected  a  three-way  tap  by  means  of  which  the  mano- 
meter can  be  placed  in  communication  with  the  artery  alone,  or  with  the 
artery  and  a  pressure  bottle.  By  means  of  the  latter  the  whole  system  is 
filled  with  magnesium  sulphate  solution  (25  per  cent.)  or  a  half- saturated 
solution  of  sodium  sulphate,  at  a  pressure  of  150  mm.  Hg.  The  pressure 
bottle  is  then  cut  off  so  that  the  manometer  remains  in  connection  only 
wth  the  cannula,  the  mercury  in  one  hmb  being  150  milhmetres  above 
that  in  the  other.  The  chp  is  then  taken  off  the  artery.  The  pressure  in 
the  cannula  being  greater  than  that  in  the  artery,  a  small  amount  of  the 
fluid  used  to  fill  the  tubes  runs  into  the  circulation.     The  mercury  in  the 


A  (J  \- 

I!A 


Fig.  375.    Scheme  of  blood -pressure  in — A,  the  ai-teries  ;  c,  capillaries  ;  and  v,  veins. 

00,  line  of  no  pressure;  lv,  left  ventricle;  ka,  right  auricle;  bp,  height  of 

blood-prdssure. 

manometer  drops  to  a  height  of  100  to  120  mm.  Hg  and  stays  about  that 
level,  rising  and  falling  slightly  with  each  heart-beat  (Fig.  37(i).  The 
blood  which  enters  the  cannula  at  each  heart-beat  does  not  clot  for  a 
considerable  time  owing  to  its  admixture  with  the  saline  fluid  used  for 
filhng  the  cannula  and  connecting  tubes. 

If  a  vein  be  ligatured,  it  swells  up  on  the  distal  side  of  the  ligature. 
If  the  vein  be  cut  across,  blood  escapes  chiefly  from  the  peripheral  end, 
and  instead  of  spurting  out  to  a  considerable  distance  with  each  heart- 
beat it  flows  steadily,  but  with  very  httle  force,  so  that  light  pressure  by 
a  bandage  is  sufficient  to  restrain  the  haemorrhage.  If  a  mercurial  man- 
ometer be  connected  with  the  vein  the  pressure  in  its  interior  is  found  to 
amount  to  only  a  few  mm.  Hg. 

By  taking  the  pressure  at  dift'erent  parts  of  the  circulation  we  obtain 

a  distribution  which  is  represented  roughly  in  the  accompanying  diagram 

(Fig.  375).     The  blood  pressure,  which  is  about  100  to  120  mm.  Hg  in 

the  large  arteries  near  the  heart,  falls  only  slowly  in  these  arteries,  so  that 

in  the  radial  artery  it  is  not  very  much  below  that  in  the  aorta.     Between 

the  medium-sized  arteries  and  capillaries  there  is  a  very  extensive  fall  of 

pressure  as  the  blood  passes  through  the  arterioles,  so  that  in  the  capillaries 

the  pressure  on  an  average  may  be  taken  as  20  to  40  mm.  Hg ;   from  the 

capillaries  to  veins  the  blood-pressure  falls  steadily  until  in  the  big  veins 

near  the  heart  it  may  be  negative. 

28* 


SECTION  II 


THE   BLOOD-PRESSURE  AT  DIFFERENT  PARTS 
OF  THE  VASCULAR  CIRCUIT 

THE  ARTERIAL  BLOOD-PRESSURE,  The  arterial  blood-pressure  as 
recorded  by  a  mercurial  manometer  exhibits  a  series  of  pulsations  corre- 
sponding to  each  heart-beat  (Fig.  376).  These  pulsations  are  due  to  the 
fact  that  the  artery  becomes  fuller  each  time  the  ventricle  forces  more 

blood  into  it  during  its  systole.     Between  the 

beats  of  the  heart,  i.e.  during  diastole,  the  aortic 
valves  are  closed,  and  blood  escapes  from  the 
arteries  into  the  capillaries  and  veins,  so  that 
the  blood-pressure  falls.  The  mercurial  mano- 
meter does  not  register  these  rapid  changes  of 
pressure  in  the  artery  with  any  accuracy.  The 
A  inertia  of  the  mercury  is  such  that  it  takes  some 
time  to  be  set  into  movement  by  the  rise  of 
pressure  in  the  artery,  and  before  it  has  attained 
its  full  height  the  pressure  in  the  artery  has 
already  begun  to  fall.  With  a  very  wide-tubed 
manometer  the  oscillations  may  be  almost  im- 
perceptible owing  to  the  mass  of  mercury  that 
has  to  be  moved  at  each  heart-beat.  Such  a 
manometer  gives  a  true  record  of  what  is  known  as  the  '  mean  arterial 
pressure.'  In  order  to  determine  the  true  course  of  the  pressure  in  the 
heart  it  is  necessary  to  diminish  to  the  utmost  possible  extent  the  inertia 
of  the  moving  parts  of  the  recording  instrument,  and  to  employ  some 
manometer  such  as  that  of  Hiirthle  or  of  Frank,  in  which  the  pressure  is 
measured  by  recording  the  stretching  of  an  elastic  membrane.  Such 
instruments  will  be  described  later  in  dealing  with  the  changes  of  pressure 
in  the  ventricle  during  contraction. 

In  the  living  animal  the  variation  in  the  arterial  pressure  at  each  heart- 
beat is  much  greater  than  would  be  anticipated  from  an  inspection  of  the 
tracing  given  by  the  mercurial  manometer.  The  highest  pressure  which 
occurs  while  blood  is  passing  from  the  heart  into  the  aorta  is  called  the 
systolic  arterial  pressure  ;  the  pressure  at  the  end  of  diastole,  just  before 
the  heart  begins  to  force  a  fresh  quantity  of  blood  into  the  aorta,  is  the 
diastolic  -pressure  ;    and  the  range  between  these  two  extremes  is  known 

874 


Fig.  376.  Blood-pressure 
tracing  taken  with  ner- 
curial  manometer  (from 
carotid  of  rabbit). 
A,  abscissa  or  line  of 
no  pressure. 


THE  BLOOD-PRESSURE 


875 


as  the  pulse  pressure.  Thus  in  the  dog,  with  a  mean  pressure  of  about 
120  mm.  Hg  in  the  aorta,  the  systolic  pressure  may  be  as  much  as  160, 
while  the  diastolic  pressure  is  only  100  mm.  In  this  case  the  pulse  pressure 
would  be  60  mm.  Hg.  In  man  the  systolic  pressure,  as  measured  in  the 
brachial  artery,  is  under  normal  conditions  about  110  mm.,  while  the 
diastolic  pressure  is  only  65  to  75  mm.,  so  that  the  pulse  pressure  is  about 
45  mm.  Hg.  As  we  pass  outwards  towards  the  periphery  the  pulse  pressure 
becomes  less  and  less  marked,  until  finally  in  the  capillaries  and  veins 
there  is  no  pulse- wave  perceptible. 


THE   DETERMINATION  OF  THE  BLOOD-PRESSURE  IN  MAN 

It  is  important  for  clinical  purposes  to  be  able  to  determine  even  approximately  the 
blood-pressure  in  the  different  parts  of  the  vascular  system  in  man,  and  various  methods 
have  b3en  devised  for  this  purpose.  The  determination  of  the  systolic  blood-i^ressure 
in  the  arteries  is  easily  carried  out  by  the  use  of  Riva  Rocci's  sphygmomanometer. 
This  apparatus  (Fig.  377)  consists  of  a  leather  or  canvas  band  about  10  cm.  wide,  which 
can  be  buckled  closely  round  the  upper  arm.  Inside  this  band  is  a  rubber  bag  of  the 
same  shape,  which  communicates  by  a  rubber  tube  with  a  mercurial  manometer  and  by 


Fig.  377.     Riva  Rocci's  sphygmomanometer. 
(C.  J.  Martin's  pattern.     Haavksley.) 


B 


Fiu.  378. 


a  three-way  tap  with  a  pressure  bulb  or  bicycle  pump,  or  with  the  external  air.  The 
band  is  buckled  round  the  arm  and  the  fingers  of  the  observer  are  placed  on  the  radial 
pulse.  The  bag  is  then  distended  with  air  so  that  it  exercises  a  pressure  on  the  arm, 
the  pressure  being  indicated  on  the  mercurial  manometer.  Air  is  forced  in  until  the 
radial  pulse  disappears.  By  means  of  the  three-way  tap  the  air  is  then  let  slowly  out 
of  the  bag  until  the  radial  pulse  is  just  perceptible.  The  height  of  the  mercurial  mano- 
meter at  this  moment  is  equal  to  the  systolic  pressure  in  the  main  arterial  trunk  from 
which  the  brachial  artery  takes  origin.  The  principle  of  this  method  will  be  made 
clear  by  reference  to  the  diagram  (Fig.  378).  If  wo  imagine  a  as  a  segment  of  the  brachial 
artery  passing  through  the  tissues  which  are  surrounded  by  the  rubber  bag,  we  see  tiiat 
so  long  as  tlie  pressure  in  the  interior  of  the  artery  is  greater  than  that  on  the  exterior 
exerted  by  the  tissues,  the  artery  will  be  patent  and  the  pulse  can  pass  through.  If, 
however,  the  pressure  in  the  tissues  becomes  greater  than  the  maximum  pressure 
inside  the  artery  at  any  time  of  the  heart-beat,  the  segment  of  artery  will  collapse  (as 
in  b),  thus  stopping  the  transmission  of  blood  and  of  the  pulse-wave.  If  we  exclude  the 
elasticity  of  the  tissues  themselves  we  may  take  the  pressure  in  the  bag  as  representing 
the  pressure  in  the  tissue  fluids  surrounding  the  artery,  so  tliat  the  pulse-obliterating 
pressure  in  the  bag  will  correspond  to  tlie  maximum  or  systolic  pressure  in  the  artery. 
By  a  slight  modification  of  the  apparatus  it  is  ])ossible  to  determine  also  the  diastolic 
pressure.  For  this  purpose  the  rubber  bag  is  connecled  also  with  a  manometer  of  small 
inertia,  giving  a  true  representation  of  the  actual  changes  of  pressure.     It  is  evident 


876 


PHYSiriL'jGY 


that  when  the  pressure  in  the  bag  and  in  the  tissues  stirrounding  the  arterv  exactly 
corresponds  to  the  diastolic  pressure,  the  artery  -nill  be  completely  collapsed  when  the 
pressure  arrives  at  its  lowest  point  and  will  then  dilate  almost  to  the  utmost  with  the 
systolic  rise  of  pressure.  If  we  are  taking  a  record  of  the  pressure  changes  in  the  bag 
in  this  way,  the  pulse-waves  as  recorded  by  the  manometer  will  slowly  increase  in  size 
as  the  pressure  in  the  bag  is  gradually  raised.  At  one  point  the  waves  rapidly  increase 
and  reach  a  maxLmum.  marking  the  pressure  at  which  the  artery  is  just  completely 


^'^ 


1 


Fig.  379.     Erlangers  apparatus  for  recording  systolic  and  diastolic 
blood-piessuies. 

collapsed  at  the  lowest  point  of  each  puise-wave  (the  diastolic  pressure).  As  the  pressure 
is  still  further  raised  the  excursions  of  the  manometer  tend  to  diminish  in  size,  first 
slowly  and  then  rapidly,  and  the  point  of  rapid  diminution  corresponds  to  the  systolic 
pressure.  Above  this  point  the  manometer  still  shows  small  oscillaticns,  due  to  the 
impact  of  the  unoccluded  stump  of  the  artery  on  the  upper  border  of  the  india.-rabber 
bag. 

ilany  different  methods  have  been  introduced  for  the  purpose  of  recording  the 
pressure  oscillations  in  the  h&g.  In  Erlangers  apparatus  the  rubber  bag  is  put  into 
connection  with  a  thick  waUed  rubber  ball  PS  contained  in  a  glass  chamber.  The 
chamber  (Fig.  379)  communicates  with  a  sensitive  tambour  and  also  by  means  of  a 
capillary  opening  provided  with  a  stop-cock  with  the  external  air.  By  this  means  the 
slow  expansion  of  the  ball  ps  is  not  recorded  by  the  tambour,  which  only  moves  with 
the  sudden  oscillations  of  pressure  due  to  each  heart-beat.  T^'ith  this  instrument  it  is 
easy  to  read  on  the  accompanying  mercurial  manometer  the  point  at  which  the  oscilla- 


THE  BLOOD-PRESSURE 


877 


tions  of  pressure  in  the  bag  suddenly  became  maximal,  and  so  to  determine  approxi- 
m  itely  the  diastolic  pressure  in  the  artery. 

VENOUS  PRESSURE.  To  determine  the  venous  pressure  in  man  we  may  use 
some  modification  of  von  Recklinghausen's  method.  A  circular,  disc-shaped,  incom- 
plete rubber  bag  (Fig.  3^0)  is  made  by  cementing 
together  at  the  circumference  two  rubber  discs, 
each  of  which  lias  a  hole  in  the  centre.  This  is 
placed  over  a  peripheral  vein  and  a  glass  plate 
laid  on  the  top  (Fig.  3S1).  A  tube  leads  from 
the  interior  of  the  annular  rubber  bag  to  a  water 
manometer  and  to  a  bicycle  pump  or  bellows  for 
the  injection  of  air.  On  blowing  air  into  the  bag 
the  pressure  in  its  interior  rapidly  increases.  If  the 
skin  and  glass  plate  have  been  previously  smeared 
with  gh'cerine,  the  air  does  not  escape  but  distends 
the  bag.  pressing  it  against  the  skin  on  the  one 
hand  and  the  glass  plate  on  the  other.  Through 
the  hole  in  the  rubber  bag  it  is  easy  to  see  the 
pressure  at  which  the  vein  collajjses — that  is  to  say, 
the  point  at  which  the  pressure  in  the  bag  is  equal 

to  the  pressure  within  the  vein.  By  a  similar  method,  using  a  smaller  tag,  we  may 
determine  the  pressure  which  is  just  sufficient  to  obliterate  the  capillaries  in  any  given 
area  of  the  skin,  so  causing  a  blanching  of  the  skin  lying  under  the  bag. 


@- 


Fig.  380. 


Fig.  381.    r] 

The  following  Table  may  serve  to  give  an  idea  of  the  average  height 
of  the  mean  blood- pressure  (not  systohc)  at  different  parts  of  the  vascular 
system  in  man,  in  the  horizontal  position.  The  pressures  are  all  subject 
to  considerable  variations  according  to  the  activity  of  the  indi\ndual  and 
the  physiological  activity  of  the  various  parts  and  organs  of  the  body  : 

.     90  mm.  mercury  (65-110). 


Large  arteries  (cgr.  carotid) 

Medium  arteries  {e.g.  radial) 

Capillaries 

Small  veins  of  arm 

Portal  vein 

Inferior  vena  cava 

Large  veins  of  neck 


oo  mm.         ,, 

about       15  to  40  mm.  mercury. 

9  mm.  mercury. 

10  mm.         ,, 

,       3  mm.        „ 

from       0  to  -8  mm.  mercury. 


The  cause  of  these  peculiarities  in  the  circulation  in  cUfferent  parts  of  the  vascular 
system  will  be  rendered  clearer  by  a  study  of  a  flow  of  fluid  thiough  a  tube  of  uniform 
•bore  (Fig.  382).  If  the  tube  ag  be  connected  with  the  reservoir  K,  fluid  will  flow  from 
A  to  o  under  the  influence  of  the  pressure  difference  between  the  fluid  in  the  reservoir 
and  that  at  g.  The  pressure  on  the  fluid  at  each  part  of  the  tube  can  be  measured  by 
attaching  at  a  series  of  points — e.g.  at  B,  c,  D,  E,  F — vertical  tubes  in  which  the  fluid 
will  rise  to  a  height  corresponding  to  the  lateral  pressure  existing  at  these  several 
points.     When  fluid  is  flowing  from  a  to  G  it  will  be  found  that  the  heights  of  the  fluid 


878 


PHYSIOLOGY 


in  the  tubes  show  a  continuous  descent,  so  that  the  line  joining  the  tops  of  the  fluid 
in  the  various  tubes  is  a  straight  one.  The  movement  of  the  fluid  from  B  to  c  can  be 
regarded  as  due  to  the  difference  of  the  pressm'e  between  B  and  c,  i.e.  Pa-Ps-  It  will 
be  noticed  in  the  diagram  that  the  straight  line  joining  the  tops  of  the  fluid  does  not 
strike  the  surface  of  the  fluid  in  B,  but  falls  a  little  below  it.  Of  the  total  pressure  in  R, 
H,  the  large  portion  h'  is  employed  in  overcoming  the  resistance  of  the  tube  AG,  while  a 
small  portion  h  represents  the  force  necessary  to  give  to  the  fluid  as  it  leaves  the  reservoir 


at  A  a  certain  velocity.  If  the  flow  of  fluid  be  diminished  by  partially  clamping  the 
end  at  G  the  rate  of  fall  of  the  pressures  will  be  diminished.  The  same  effect  will  be 
produced  either  by  raising  the  level  of  G  or  by  lowering  the  level  of  the  reservoir  and  so 
the  pressure  at  a. 

The  difference  of  pressure  between  any  two  points,  i.e.  between  d  and  e,  may  be 
regarded  as  that  pressure  which  is  necessary  to  maintain  a  certain  velocity  of  the  fluid 


against  the  resistance  offered  by  the  friction  of  the  fluid  in  contact  with  the  walls  of 
the  tube.  This  friction,  and  therefore  the  resistance  to  the  flow,  can  be  altered  by 
diminishing  the  diameter  of  the  tube,  when  a  larger  difference  of  pressure  will  be 
necessary  in  order  to  maintain  the  same  velocity  of  flow.  This  can  be  shown  by  in- 
troducing a  resistance  between  d  and  e  by  partially  clamping  the  tube  at  this  point 
(Fig.  383).  The  continuity  of  the  fall  of  pressures  in  the  vertical  tube  is  at  once  abolished. 
Between  a  and  d  there  is  a  continuous  fall,  which  is  succeeded  by  a  steep  fall  between 
D  and  E,  and  this  again  by  a  gradual  fall  between  e  and  G.  In  any  system  of  tubes 
therefore  through  which  fluid  is  flowing  the  fall  of  pressure  between  any  two  points 


THE  BLOOD-PRESSITRE  879 

will  be  proportional  to  the  velocity  of  the  flow  between  these  two  points.  The  velocity, 
on  the  other  hand,  will  vary  directly  as  the  difference  of  pressures,  and  inversely  as  the 
resistance  between  the  two  points,  which  may  be  expressed  by  the  formula 

P 
^    ^   R 

In  the  vascular  system,  while  the  circulation  is  maintained,  the  largest 
difference  of  pressure  exists  between  the  arteries  on  the  one  side  and  the 
small  veins  on  the  other,  a  great  fall  occurring  between  the  arteries  and 
the  capillaries  themselves.  This  distribution  of  pressure  points  to  the 
chief  resistance  in  the  vascular  system  as  being  situated  in  the  arterioles. 
The  resistance  presented  by  these  vessels  is  due  to  the  fact  that  they  are 
maintained  in  a  state  of  tonic  contraction  by  the  agency  of  the  central 
nervous  system.  The  total  bed  of  the  stream  in  the  region  of  the  arterioles, 
while  greater  than  that  of  the  arteries,  is  considerably  less  than  that  of 
the  rich  meshwork  of  capillaries,  while  the  difference  between  the  diameters 
of  arterioles  and  capillaries  is  not  very  great.  On  this  accomit  the  velocity 
of  the  blood  in  the  arterioles  is  very  much  greater  than  that  obtaining  in 
the  capillaries,  and  since  friction  and  therefore  the  resistance  varies  as  the 
square  of  the  velocity,  the  resistance  to  the  flow  of  blood  through  the 
arterioles  must  be  much  greater  than  that  presented  by  the  capillaries. 
The  large  part  taken  by  the  arterioles  in  determining  the  difference  of 
pressure  between  the  arteries  and  veins  is  shown  by  the  fact  that  this 
difference  can  be  diminished  to  one  half  by  any  means  which  causes  a 
dilatation  of  the  arterioles,  as,  for  example,  destruction  of  the  vasomotor 
centre. 

THE  CONVERSION  OF  AN  INTERMITTENT  INTO  A 
CONSTANT  FLOW 

Not  only  is  the  blood-pressure  in  the  veins  much  lower  than  in  the 
arteries,  but  the  flow  of  blood  has  been  converted  on  its  passage  through  the 
peripheral  resistance  from  a  pulsatory  into  a  continuous  flow.  This  change 
is  connected  with  the  distensible  elastic  nature  of  the  arterial  walls. 

Since  this  is  a  purely  mechanical  question  it  will  be  more  easily  under- 
stood by  a  simple  illustration.  The  heart  may  be  regarded  as  a  pump, 
forcing  a  certain  amount  of  blood  (in  man  about  60  c.c.)  into  the  circulation 
at  each  stroke.  If  a  pump  be  connected  with  a  rigid  tube,  every  time 
that  a  certain  amount  is  forced  into  the  beginning  of  the  tube  an  exactly 
equal  quantity  will  be  forced  out  at  the  other  end.  Increasing  the  peri- 
pheral resistance  by  partial  closure  of  the  end  of  the  tube  A\nll  not  affect 
the  intermittent  character  of  the  flow,  but  will  merely  serve  to  diminish 
the  quantity  thrown  in,  as  well  as  the  quantity  which  escapes  at  the  other 
end  of  the  tube,  supposing  that  the  work  done  by  the  pump  is  equal  in 
both  cases.  If  instead  of  a  rigid  tube  we  employ  an  elastic  tube  and  the 
end  be  left  open  so  that  no  resistance  is  offered  to  the  outflow  of  the  fluid, 
the  effect  will  be  the  same  as  when  we  used  the  rigid  tube  ;  the  outflow  will 
correspond  exactly  to  the  inflow  and  will  be  just  as  intermittent.  But 
now,  if  the  end  of  the  elastic  tube  be  clamped  so  as   to    increase    the 


880  PHYSIOLOGY 

resistance  to  the  outflow,  there  will  be  a  marked  diflerence  from  the  results 
obtained  when  the  rigid  tube  was  partially  obstructed.  Each  stroke  of 
the  pump  forces  a  certain  amount  of  fluid  into  the  tube.  Owing  to  the 
peripheral  resistance  this  cannot  all  escape  at  once,  and  so  part  of  the 
force  of  the  piunp  is  spent  in  distending  the  walls  of  the  tube,  and  part 
of  the  fluid  that  was  forced  in  remains  in  the  tube.  The  distended  elastic 
tube  tends  to  empty  itself  and  forces  out  the  fluid  which  over-distends 
it  before  the  next  stroke  of  the  pump  occurs.  So  now  the  outflow  may  be 
divided  into  two  parts,  one  part  which  is  forced  out  by  the  immediate 
eflect  of  the  stroke  of  the  pmnp,  and  another  part  which  is  forced  out  by 
the  elastic  reaction  of  the  tube  between  the  strokes.  If  the  strokes  be 
rapidly  repeated  before  the  tube  has  time  to  empty  itself  thoroughly,  it 
wiU  get  more  and  more  distended.  Greater  distension  means  stronger 
elastic  reaction,  and  therefore  stronger  outflow  of  the  fluid  between  the 
beats.  This  distension  goes  on  increasing  till  the  fluid  forced  out  between 
the  strokes  by  the  elastic  reaction  of  the  wall  of  the  tube  is  exactly  equal  to 
that  entering  at  each  stroke,  and  the  flow  thus  becomes  continuous. 

The  same  thing  occurs  in  the  living  body.  A  man's  heart  at  each  beat 
or  contraction  forces  about  60  c.c.  of  blood  into  the  already  distended 
aorta.  The  first  effect  of  this  is  to  distend  the  aorta  still  further.  The 
elastic  reaction  of  the  walls  drives  on  another  portion  of  blood,  which 
distends  the  next  segment  of  the  arterial  wall,  and  so  the  wave  of  distension 
is  transmitted  with  gradually  decreasing  force  along  the  arteries.  This 
wave  of  distension  is  what  we  feel  on  the  radial  artery,  or  any  exposed 
artery,  as  the  pulse.  After  each  heart-beat  the  arteries  tend  to  return 
to  their  original  size,  and  drive  the  blood  on  through  the  arterioles  (the 
peripheral  resistance)  into  the  capillaries  and  so  into  the  veins.  By  the  time 
the  blood  has  reached  the  veins  all  trace  of  the  heart-beat  has  disappeared 
and  the  pressure  has  fallen  to  a  few  millimetres  of  mercury. 

INFLUENCE  OF  THE  CAPACITY  OF  THE  VASCULAR  SYSTEM 
ON  THE  CIRCULATION 

So  far  we  have  only  considered  the  influence  of  changes  of  pressure 
and  resistance  in  a  system  of  tubes  with  a  head  of  pressure  at  one  end  and 
a  free  outflow  at  the  other.  In  the  body,  however,  the  vascular  system 
is  a  closed  circuit  of  elastic  tubes  presenting  varying  resistances  to  the 
flow  of  blood,  and  of  varying  distensibility  at  different  parts  of  their  course. 
In  this  closed  system  is  inserted  a  pump,  the  heart,  with  the  function  of 
driving  the  blood  through  the  system.  Since  all  the  blood-vessels  are 
elastic  and  distensible  the  capacity  of  the  system  is  not  fixed,  but  must 
vary  with  the  internal  pressure  to  which  the  vessels  are  subjected.  More- 
over the  position  of  the  different  parts  of  the  circulation  must  have  an 
influence  on  the  capacity  of  the  system,  since  the  dependent  vessels  will 
be  distended  not  only  by  the  average  pressure  of  the  fluid  throughout  the 
system  but  also  by  the  hydrostatic  pressure  due  to  the  weight  of  the  column 
of  fluid  pressing  on  them.     The  elasticity  of  the  tubes  is  also  a  varying 


THE  BLOOD -PRESSUEE 


881 


factor  and  can  be  considerably  altered  by  the  contraction  of  the  muscular 
coats  of  the  vessels,  or  by  pressure  on  the  vessels  exerted  by  the  surrounding 
muscular  and  elastic  structures. 

It  will  simplify  the  discussion  of  the  main  factors  of  the  circulation 
in  a  closed  system  if,  for  the  present,  we  neglect  the  variable  factors  and 


Fig.  384.  Artificial  schema  to  demonstrate  the  main  features  of  the  circulation. 
The  heart  is  an  enema  syringe  with  valves  at  v  and  v.  The  artery  is  a  thick-walled 
rubber  tube.  On  the  venous  side  is  placed  a  length  of  wide  thin-walled  tubing, 
to  represent  the  large  thin- walled  distensible  veins.  The  arterioles  and  caijillaries 
(peripheral  resistance)  are  represented  by  wide  glass  tubes  packed  with  sponges. 
By  opening  the  clamp  on  the  tube  d  ('  splanchnic  area  arterioles  ')  the  peripheral 
resistance  can  be  removed,  and  a  free  passage  of  fluid  allowed  from  arterial  to 
venous  side. 

see  what  would  take  place  in  such  a  system  of  elastic  tubes  all  situated 
on  one  horizontal  plane.  Such  a  system  is  represented  in  the  diagram 
(Fig.  385),  and  a  working  model  of  it  in  Fig.  384. 

The  heart  h  is  interpolated  at  one  part  of  the 
circuit,  while  the  free  outflow  of  the  fluid  from  b 
to  D  is  impeded  by  the  presence  of  a  peripheral 
resistance  at  c.  Such  a  system  would  have  a 
definite  capacity  at  zero  internal  pressure,  but 
a  very  much  greater  amount  of  fluid  might  be 
forced  into  it  under  a  positive  pressure.  We  will 
assume  that  the  pressure  throughout  the  system 
is  equal  to  10  mm.  Hg,  i.e.  the  elastic  tubes  are 
all  slightly  distended.  If  the  heart  h  now  begins 
to   contract   it   will   pump   fluid   fi'om  e  into  a. 

The  pressure  in  e  will  fall  from  10  mm.  to  0  mm.,  while  that  in 
A  will  rise  to  a  corresponding  extent,  the  resistance  at  c  preventing 
the  free  escape  of  fluid  from  b  to  d  and  so  causing  the  heart  to  pile  up 
the  fluid  which  it  has  taken  from  e  into  a. 

If  the  texture  of  the  tubes  were  uniform  throughout  the  system  it  is 
evident  that  the  rise  of  pressure  in  A  wotild  approximate  very  nearly  to 
the  fall  of  pressure  in  e.     In  the  vascular  system  the  veins  are,  however, 


882  PHYSIOLOGY 

much  more  easily  distended  than  the  arteries.  In  Fig.  373  (p.  871)  is 
shown  the  distensibihty  of  corresponding  sections  of  arteries  and  veins 
under  gradually  increasing  internal  pressures.  An  artery  has  a  certain 
capacity  even  at  zero  pressure.  As  the  pressure  in  its  interior  is  increased 
the  artery  is  distended,  and  its  capacity  rises  first  slowly  and  then  more 
rapidly,  the  increment  in  capacity  being  greatest  between  90  and  110  mm. 
Hg.  The  vein,  on  the  other  hand,  is  collapsed  when  there  is  no  distending 
force  in  its  interior,  so  that  at  zero  pressure  its  capacity  is  nothing.  The 
shghtest  rise  of  pressure,  even  of  1  mm.  Hg  causes  a  considerable  increase 
in  its  capacity,  and  the  capacity  rises  rapidly  with  increasing  pressure  up  to 
about  20  mm.  Hg.  Whereas  the  artery  is  most  distensible  at  100  mm.  Hg., 
the  vein  is  at  its  optimum  distensibihty  at  about  10  mm.  Hg.  If  therefore 
the  tubes  at  e  are  made  of  thin-walled  rubber  tubing  they  will  be  consider- 
ably distended  under  a  pressure  of  10  mm.  Hg,  which  has  practically  no 
influence  on  the  thicker- walled  arterial  tube  a. 

A  small  amount  of  fluid  taken  from  e  would  cause  very  little  fall  of 
pressure  on  this  side.  A  considerable  force  will  be  necessary  to  send  this 
fluid  into  the  more  resistant  arterial  tube,  so  that  on  pumping  a  given 
amount  of  fluid  from  e  to  A  the  pressure  in  e  may  fall  5  mm.,  while  the 
pressure  in  a  has  to  be  raised  from  50  to  100  mm.  Hg  in  order  to  distend 
the  arteries  to  such  an  extent  that  they  will  accommodate  the  fluid  taken 
from  E. 

In  such  a  system,  when  the  heart  is  at  rest,  the  pressure  all  over  the 
system  will  be  uniform,  and  in  the  example  we  have  chosen  the  mean 
systemic  pressure  was  10  mm.  Hg.  When  the  heart  contracts  it  takes 
up  fluid  from  the  venous  side  and  piles  it  up  on  the  arterial  side  until  the 
pressure  on  the  arterial  side  is  sufficient  to  cause  exactly  the  same  amount 
of  fluid  to  flow  through  the  peripheral  resistance  into  the  veins  as  is  taken 
by  the  heart  from  the  veins  at  each  beat.  This  rise  of  pressure  in  the 
arteries  may  be  many  times  greater  than  the  fall  of  pressure  in  the  veins. 
If  more  fluid  is  injected  into  the  system  when  the  heart  is  at  rest  the  whole 
system  will  be  more  distended  and  the  mean  systemic  pressure  will  rise. 
When  the  heart  contracts  it  will  raise  the  pressure  on  the  arterial  side  and 
lower  that  on  the  venous  side  as  before,  but  it  is  evident  that  according 
to  the  force  of  the  heart-beat  the  arterial  pressure  may  be  less  than,  equal 
to,  or  greater  than  the  pressure  attained  before  the  introduction  of  fluid. 
Since,  however,  the  mean  systemic  pressure  is  raised,  the  increased  amount 
of  fluid  must  be  accommodated  somewhere,  so  that  if  the  arterial  pressure 
is  as  great  as  before,  the  venous  pressure  must  be  greater.  In  the  same 
way  the  withdrawal  of  a  certain  amount  of  fluid  may  lower  the  mean 
systemic  pressure,  say  from  10  to  5  mm.  Hg.  It  is  still  possible  for  the 
pump  to  maintain  an  arterial  pressure  equal  to  that  produced  when  the 
mean  systemic  pressure  was  10  mm.  Hg,  but  to  produce  this  effect  the 
relative  distribution  of  blood  must  be  altered  and  the  veins  must  be  more 
empty  than  they  were  previously.  The  maintenance  of  a  constant  arterial 
pressure  with  varying  amount  of  fluid  in  the  system  can  therefore  be 


THE  BLOOD -PRESSURE  883 

accomplished  either  by  alterations  in  the  work  of  the  heart  or  by  altera- 
tions in  the  peripheral  resistance,  and  therefore  in  the  ease  with  which  the 
blood  is  allowed  to  escape  from  the  arterial  to  the  venous  side. 

Alterations  of  the  capacity  of  the  system  will  have  the  inverse  efiect 
to  alterations  of  its  contents.  Thuf-.  diminution  in  the  volume  of  veins, 
such  as  might  be  caused  in  the  living  body  by  the  contraction  of  their 
walls  and  which  may  be  imitated  in  our  model  by  pressure  on  the  veins 
from  without,  will  drive  the  fluid  into  other  parts  of  the  system  and  there- 
fore raise  the  mean  systemic  pressure.  This  rise  of  pressure  may  be 
confined  to  the  arteries  by  increased  action  of  the  heart,  or  it  may  be 
confined  to  the  veins  by  diminished  action  of  the  heart  or  decreased 
constriction  of  the  arterioles  forming  the  peripheral  resistance. 

Similar  change  in  capacity  may  be  brought  about  if  we  bring  in  the 
effects  of  hydrostatic  pressure.  If  in  the  model  illustrated  (Fig.  384)  we 
allow  the  thin- walled  vein  to  hang  over  the  edge  of  the  table  the  pressure 
of  the  column  of  fluid  within  it  causes  it  to  dilate  and  therefore  to  accom- 
modate more  fluid,  and  this  increased  capacity  might  be  so  great  that  the 
pressure  in  the  section  of  the  vein  near  the  heart  might  sink  to  nothing 
and  the  heart  receive  no  blood  when  it  started  to  contract.  The  whole 
arterial  system  might  in  this  way  be  allowed  to  drain  under  the  influence 
of  gravity  into  the  distensible  dependent  segment  of  the  venous  tube. 

All  the  conditions  in  our  artificial  schema  have  their  exact  analogue  in 
the  living  body.  The  determination  of  the  mean  systemic  pressure  in 
the  hving  body  is  difficult  to  carry  out  with  accuracy.  If,  for  instance, 
we  stop  the  heart,  which  we  can  do  by  stimulation  of  the  vagus  nerve,  the 
arteries  will  gradually  empty  themselves  through  the  peripheral  resistance 
into  the  veins,  and  this  process  will  tend  to  go  on  imtil  the  pressures  are 
identical  throughout  the  system.  Before  this  equihbrium  is  arrived  at, 
however,  reaction  takes  place  on  the  part  of  the  animal,  tending  to  restore 
the  failing  circulation.  Thus  the  vessels  contract  strongly,  so  diminishing 
the  capacity.  Movements  take  place  causing  pressui'e  on  the  veins  of  the 
abdomen  and  the  suction  of  the  blood  into  the  big  veins  of  the  thorax. 
Moreover  the  vessels  in  an  animal  are  not  all  on  one  plane,  and  if  the  animal 
is  in  a  vertical  position  the  hydrostatic  pressure  of  the  colunm  of  blood 
between  the  heart  and  the  dependent  parts  of  the  body  may  distend  the 
veins  to  such  an  extent  that  the  whole  of  the  blood  is  taken  up  in  these 
veins  and  none  returned  to  the  heart.  The  fact  that  after  stoppage  of  the 
heart  the  pressure  is  positive  at  all  parts  of  the  vascular  system  in  the 
animal  with  open  thorax  shows  that  there  is  actually  a  mean  systemic 
pressure,  i.e.  mider  normal  circumstances,  when  the  animal  is  in  a  hori- 
zontal position,  all  parts  of  the  system  are  slightly  distended.  Direct 
measurement  shows  that  this  mean  systemic  pressure  is  about  10  mm.  Hg. 
The  smallness  of  this  figure  shows  moreover  that  under  the  influence  of 
gravity  alone  the  pressure  will  be  easily  reduced  to  nothing  at  all  in  the 
upper  parts  of  the  body.  In  a  man  in  the  vertical  position,  in  the  absence 
of  the  nervous  reactive  mechanism  which  we  shall  consider  later  on,  the 


884  PHYSIOLOGY 

whole  of  the  blood  would  accumulate  in  the  abdomen  and  lower  parts  of 
the  body,  and  the  circulation  would  come  to  a  standstill.  On  the  other 
hand,  the  pressure  may  be  altered  in  any  part  of  the  vascular  system  in 
any  of  the  following  ways  : 

(1)  Alteration  of  capacity  of  the  total  system  either  by  contraction  of 
walls  of  the  vessels  or  by  pressure  on  them  from  without. 

(2)  Alteration  of  the  total  volume  of  the  circulating  fluid. 

Either  of  these  two  factors  would  affect  in  the  first  place  the  mean 
systemic  pressure.  The  distribution  of  pressure,  i.e.  the  relative  pressure 
in  the  arteries  and  veins,  will  be  determined  by 

(3)  Alteration  in  the  output  of  the  heart. 

(4)  Alteration  in  the  peripheral  resistance  and  therefore  in  the  ease  .with 
which  the  blood  can  escape  from  arterial  to  venous  side. 

In  any  change  either  in  arterial  or  venous  pressure  at  least  two  of  these 
factors  are  involved.  Every  constriction  of  arterioles  causes  not  only  an 
increase  in  the  peripheral  resistance  but  also  a  diminished  capacity  of  the 
whole  system,  so  that  the  arterial  pressure  is  raised  at  the  same  time  as 
the  mean  systemic  pressure.  Nearly  always  such  a  change  will  involve 
as  its  immediate  consequence  some  corresponding  alteration  in  the  heart- 
beat, so  that  at  least  three  factors  will  co-operate  in  the  production  of  the 
rise  or  fall  of  blood-pressure.  We  shall  have  occasion  to  deal  with  many 
examples  of  these  complex  conditions  when  we  are  discussing  the  reactions 
of  the  vascular  system  as  a  whole. 

THE  DEPENDENCE  OF  ARTERIAL  PRESSURE  ON  OUTPUT 

OF  HEART 

The  importance  of  the  heart-beat  in  determining  arterial  pressure  is 
connected  with  its  output  in  a  given  time.  The  arterial  pressure  is  due 
to  the  fact  that  the  heart  is  taking  up  fluid  from  the  venous  side  and 
pumping  it  into  the  arterial  side.  The  pressure  on  the  latter  side  must 
rise  so  long  as  the  rate  at  which  the  fluid  is  put  into  the  arterial  system 
by  the  heart  is  greater  than  that  by  which  it  escapes  through  the  peripheral 
resistance.     Arterial  pressure  therefore  is  a  resultant  of  the  two  effects  : 

(a)  The  amount  of  blood  entering  the  arterial  system  from  the  heart ; 

(6)  The  amount  of  blood  leaving  the  arterial  system  through  the 
peripheral  resistance. 

It  is  evident  that  the  pressure  will  be  altered  by  altering  either  of  the 
two  factors — peripheral  resistance  or  output  of  the  heart.  The  cardiac 
output  will  depend  on  the  amount  of  blood  contained  in  the  heart  at  the 
beginning  of  each  contraction,  on  the  strength  with  which  the  heart  beats, 
and  on  the  number  of  contractions  which  the  heart  gives  in  any  given 
period  of  time.  The  filling  of  the  heart  at  the  beginning  of  each  beat  is 
in  its  turn  dependent  on  the  amount  of  blood  which  is  available  to  fill  the 
cavities  and  therefore  on  the  pressure  in  the  great  veins.  Increased  fre- 
quency of  heart-beat  need  not  therefore  necessarily  increase  the  total 


THE  BLOOD -PRESSmE  885 

output  of  the  heart  into  the  arterial  system.  If  the  heart  is  beating  with 
optimum  rate  and  force  it  will  keep  the  venous  system,  at  any  rate  that 
part  nearest  the  heart,  practically  empty,  and  it  is  not  possible  for  it  to 
obtain  more  blood  to  put  into  the  arterial  side,  however  frequently  it 
may  beat.  There  will  be  an  optimum  frequency  of  the  heart-beat  which 
will  depend  on  the  state  of  filling  of  the  great  veins.  The  fuller  these  are 
the  more  rapidly  the  heart  may  beat  and  increase  the  total  Output.  On 
the  other  hand,  in  a  normal  animal  with  the  heart  beating  at  its  optimum 
rate  and  with  effective  contraction  of  its  muscular  walls,  while  slowing  the 
heart-rate  will  diminish  the  total  output  and  therefore  the  arterial  pressure, 
increase  in  the  frequency  of  the  beat  cannot  raise  the  arterial  pressure  to 
any  appreciable  extent,  though  the  heart  may  tend  to  wear  itself  out  by 
beating  at  a  greater  rate  than  the  optimum. 


SECTION   III 

THE  VELOCITY  OF  THE  BLOOD   AT  DIFFERENT 
PARTS  OF  THE  VASCULAR  SYSTEM 

When  fluid  is  flowing  through  a  tube  of  uniform  diameter,  the  amount  passing 
between  any  two  points  is  practically  in  proportion  to  the  difference  of 
pressure  between  these  two  points,  and  varies  inversely  as  the  resistance 
to  be  overcome.  If  the  tube  is  of  unequal  bore,  as  represented  in  Fig.  386, 
since  the  amount  of  fluid  passing  a  during  a  given  interval  of  time  must  be 
equal  to  the  amount  passing  6 — where  the  bed  of  the  stream  is  wider — the 
velocity  of  the  flow  must  be  smaller  at  h  than  at  a.     The  same  dependency 

of  velocity  on  the  total  bed  must 

apply  in  any  closed  system  of 

tubes.     Thus  in  a  closed  circuit 

(Fig.    385)    with    a    steady    flow 


J 


h  from  the  arterial  to  the  venous 

■^^-  ^^^'  side,  the  amount  of  fluid  leaving 

the  heart  and  passing  a  during  a  minute  must  be  exactly  equal  to  the  total 

amount  of  fluid  passing  from    arteries  to  veins  through  the  peripheral 

resistance  B. 

The  total  area  at  c  is  probably  one  thousand  times  that  of  the  aorta  at  a, 
and  we  should  expect  therefore  a  proportionate  slowing  of  the  blood-stream. 
As  a  matter  of  fact,  while  the  velocity  of  the  blood  in  the  aorta  of  a  large 
animal  may  be  taken  as  about  half  a  metre  per  second,  the  velocity  of  the 
blood  in  the  capillaries  is  about  half  a  milhmetre  per  second.  Moreover, 
since  the  total  cross-section  of  the  big  veins  near  the  heart  under  a  normal 
distending  pressure  is  about  twice  that  of  the  first  part  of  the  aorta,  the 
velocity  of  the  blood  in  the  great  veins  is  only  about  half  of  that  found  in  the 
aorta.  In  such  a  closed  circuit  increased  output  of  the  heart  will  increase  the 
average  velocity  round  the  system,  and  the  same  effect  may  be  produced  by 
diminution  of  the  peripheral  resistance. 

In  the  living  body  a  great  dilatation  of  the  arterioles,  causing  a  fall  of 
the  peripheral  resistance,  generally  increases  the  total  capacity  of  the  system. 
The  arterial  relaxation  therefore  not  only  gives  rise  to  an  easier  outflow  from 
arteries  to  veins  but  also  causes  a  diminished  dilatation  of  the  veins  and 
therefore  decreased  filUng  of  the  heart  during  diastole.     The  heart  output 

886 


VELOCITY  OF  BLOOD  IN  VASCULAR  SYSTEM  887 

is  therefore  also  lessened,  so  that  a  final  result  of  a  dilatation  of  the  arterioles 
may  be  a  diminished  instead  of  an  increased  velocity  throughout  the 
system. 

The  foregoing  discussion  of  the  factors  which  determine  the  average 
velocity  across  a  given  cross-section  of  the  whole  vascular  system  must  not  be 
applied  directly  to  the  changes  in  the  velocity  following  on  local  alterations 
in  the  resistance  presented  by  some  particular  vascular  area.  In  this  case 
the  local  changes  are  insufficient  to  affect  the  general  arterial  blood-pressure, 
and  the  effect  of  diminution  of  peripheral  resistance  is  to  furnish  a  short  cut 
for  a  small  portion  of  the  total  output  of  the  heart  from  the  ai-terial  to  the 
venous  side.  Thus  dilatation  of  the  vessels  of  the  submaxillary  gland,  while 
not  altering  the  general  blood-pressure  as  registered  in  the  carotid  artery, 
causes  the  blood-flow  through  the  gland  to  be  increased  six  to  eight  times, 
and  the  peripheral  resistance  in  the  gland  may  be  so  far  diminished  that  the 
blood  passes  through  the  capillaries  into  the  veins  without  losing  the  pulsa- 
tile force  imparted  to  it  by  each  heart-beat.  The  pressures  therefore  in 
arterioles,  capillaries,  and  veins  are  all  increased  by  this  local  vaso-dilatation. 
On  the  other  hand,  constriction  of  the  arterioles  of  any  given  part  will 
diminish  the  velocity  of  the  blood  through  this  part  and  also  the  pressure  in 
its  capillaries. 

The  larger  the  area  affected  by  the  change  in  the  peripheral  resistance, 
the  more  difficult  it  is  to  predict  a  priori  what  will  be  the  result  on  the 
velocity  of  the  blood  and  on  the  circulation  as  a  w^hole,  or  in  the  parts 
specially  affected.  Thus  section  of  one  splanchnic  nerve  in  the  dog  causes 
an  increased  flow  of  urine  from  the  kidney  on  the  same  side,  the  paralysis  of 
the  vessels  in  this  organ  causing  an  increased  flow  of  blood  through  it  and  an 
increased  pressure  in  its  capillaries.  Section  of  the  corresponding  nerve 
of  the  rabbit  may  cause  a  diminution  rather  than  an  increase  in  the  amount 
of  urine  secreted,  owing  to  the  fact  that  the  total  area  supphed  by  the 
splanchnic  nerve  is  much  greater  relatively  in  the  rabbit  than  in  the  dog. 
Thus  section  of  this  nerve  may  cause  such  a  \\^despread  dilatation  that  the 
blood-pressure  falls  ;  and  although  the  vessels  in  the  kidney  are  relaxed, 
the  arterial  pressure  is  not  sufficient  to  drive  through  these  relaxed  vessels  as 
much  blood  as  was  previously  driven  through  the  normally  contracted 
arterioles. 

METHODS  OF  MEASURING  THE  VELOCITY  OF  THE  BLOOD 

The  velocity  in  an  artery  is  measui'ed  by  placing  some  apparatus  in  the  path  of 
the  blood  without  intercepting  its  flow  ;  such  an  apparatus  inaj-  be  used  to  give  the 
quick  variations  in  the  velocity  which  occur  in  the  course  of  each  heart-beat,  or  the 
average  How  of  blood  t  hrough  the  cross-section  of  the  artery  in  a  given  space  of  t  i  me.  For 
the  latter  purpose  Ludwig's  Stromuhr,  or  current  clock  (Fig.  387),  has  been  most  used.  This 
instrument  consists  of  two  bulbs  of  equal  size,  a  and  b,  communicating  with  one  another 
above  ;  their  lower  ends  are  clamped  in  the  disc  c.  which  is  ]iierced  by  two  ojienings 
serving  to  connect  the  lower  orifices  of  the  bulbs  with  tlir  tubes  /,  /.  cemented  into  the 
lower  disc  ah. 

An  artery  such  as  the  carotid,  being  clamped  at  its  central  end  and  diviilcd.  a  is 
inserted  into  its  central  end.  and  J>  into  its  peripheral  cut  end.     The  tube  d  is  tilled  with 


PHYSIOLOGY 


oil  and  b  with  salt  solution  or  defibrinated  blood.     On  clamping  the  artery,  blood  flows 

into  a  and  drives  the  contained  oil  over  into  b,  the  contents  of  b  being  meanwhile  forced 
into  the  peripheral  end  of  the  artery.  When  blood  has  com- 
pletely filled  the  bulb  a,  the  two  bulbs  are  reversed,  and  the 
blood  now  entering  the  artery  displaces  the  oil  in  b,  and  forces 
the  blood  which  had  entered  a  on  into  the  peripheral  end  of 
the  artery.  Knowing  the  capacity  of  the  bulbs  and  the 
number  of  times  it  has  been  necessary  to  turn  them  in  the 
course,  say,  of  one  minute,  we  know  also  the  amount  of  blood 
which  has  passed  across  the  section  of  the  artery  under 
experiment. 

In  order  to  determine  from  this  volume  the  velocity  of  the 
blood  across  the  section,  i.e.  through  the  artery,  the  total 
volume  passing  in  the  minute  must  be  divided  by  the  cross- 
section.  This  will  give  the  velocity  per  minute.  Many  modifi- 
cations of  this  apparatus  have  been  devised.  A  simple  form 
of  cm-rent  measurer  is  shown  in  Fig.  388.  The  whole  apparatus 
is  constructed  of  glass.      The  tube   a  is   connected   with  the 

Fig.  387.     Diagram  of   central  end  of  a  cut  artery,  and  the  tube  p  with  the  peripheral 
Ludwig's  '  Stro7mihr.'     end.     The  blood  flows  into  B  and  fills  it.     As  soon  as  it  is  full 
and  its  level  rises 

over  the  level  of  the  bend  of  the  siphon  ^ ^ 

tube  s,  the  blood  is  rapidly  siphoned  ofi 

into  c  whence  it  flows  along  p  into  the 

peripheral  part  of  the  artery.     The  side 

tube  E  is  connected  with  a  mercury  or 

membrane  manometer.     Every  time  that 

B  is  emptied  into  c  a  depression   is  pro- 
duced  on  the  manometer  tracing,  which 

thus  records  not  only  the  average  pressm-e 

but  also  the  average  velocity  of  the  blood 

in  the  artery.      Each  instrument  has  to 

be  calibrated  in  order  to  know  how  much 

blood  passes  from  b  to  c  each  time  that 

siphonage  occurs. 

None  of  these  methods  give  any  infor- 
mation of  'any  rapid   changes  occurring 

in  the  velocity  of  the  blood,  e.g.  dm'ing  a 

single   pulse-wave.      For  this  purpose  we 

must  have  recourse  to  some  instrument 

such  as  Chauveau's  hsemadromograi^h  or 

Cybulski's  photohsematachometer.      The 

hcemadromograph  (Fig.  .389)  consists  of  a 

pendulum    which    is    hung    in    a    tube, 

through   which   the  blood  is  allowed  to 

flow,  placed  in  the  course  of  the  artery. 

The  deviation  of  this  pendulum  from  the 

vertical   will   be   in    proportion    to    the 

velocity  of  the  current,  and  if  its  upper 

end  be  connected,    as   in    the   diagram, 

with  a  tambour,  the  variations  in  velo- 
city   can    be   recorded    on   a    blackened 

surface  by  means  of  a  lever.     The  phofo- 

hcBmatachometer  is  based  on  an  interesting 

application  of  Pitot's  tubes.    If  a  current 

of  blood  be  directed  along  the  tube  ab  possessing  two  vertical  side  tubes   c    and   d 
the   pressure   at   c    will   be    greater    than    that   at   d,   since   at    c   the 


from  Artery 


to  Recorder 


FxG.  388.     A  simple  blood-current  measurer. 
(IsHiKAWA  and  Stakling.) 


(Fig.    390), 


VELOCITY  OF  BLOOD  IN  VASCULAR  SYSTEM 


889 


momentum  of  the  moving  mass  of  blood  is  added  to  the  lateral  pressure  of  the  fluid. 
A  tube  of  this  shape  is  connected  with  an  artery,  such  as  the  carotid,  and  the  tubes 


4 


pi 


Fig.  389.  Diagram  showing  the 
construction  of  Chauveau's 
hfemadromograph. 


Fig.  390.  Diagram  to  show  principle  of 
construction  of  Cybulski's  photo-hasmata- 
choraeter. 


h  and  h'  are  attached  at  the  points  c  and  d.  These  two  tubes  are  united  at  their  upper 
extremities.  In  this  case  so  long  as  the  blood  flows  from  a  to  h  the  fluid  in  /(  will  rise 
higher  than  in  /;.',  and  the  difference  in  height  of  the  fluid  in  the  two  tubes  will  be  pro- 


Fi(i.  391. 


Record  of  blood- velocity  in  the  carotid  artery 
of  the  rabbit.     (Cybulski.) 


portional  to  the  velocity  of  the  blood.  A  graphic  record  of  this  diftercnce  of  pressure 
is  obtained  by  allowing  a  narrow  beam  of  light  to  throw  an  inuige  of  the  menisci  of  the 
two  columns  of  fluid  through  a  slit  on  to  a  moving  photographic  plate.  Such  a  record 
is  given  in  Fig.  391.     The  width  of  the  black  space  at  any  point  is  proportional  to  the 


890 


PHYSIOLOGY 


velocity  of  the  blood  at  the  moment  at  which  this  part  of  the  record  was  being  taken. 
Of  course  this  instrument  has  to  be  calibrated  if  we  wish  to  determine  the  velocity  of 
the  blood  in  absolute  measure.  In  Fig.  391  the  velocity  at  the  points  1  and  1',  corre- 
sponding to  the  cardiac  systole,  was  248  mm.  per  second.  At  2  and  2',  corresponding 
to  the  dicrotic  elevation,  the  velocity  was  also  248  mm.  At  3  and  3',  towards  the  end 
of  diastole,  the  velocity  sank  to  127  mm. 

The  velocity  of  the  blood  in  the  capillaries  can  be  measured  by  direct  observation 
of  the  capillaries  under  the  microscope,  and  noting  the  time  it  takes  for  a  blood-corpuscle 
to  move  from  one  edge  of  the  field  to  the  other. 


THE    VELOCITY    IN    DIFFERENT    PARTS    OF    THE 
VASCULAR    SYSTEM 

During  systole  the  velocity  of  the  blood  in  any  part  of  the  arterial  system 
must  be  greater  than  during  diastole  ;   thus  in  the  carotid  of  the  horse  the 

following  figures  were  found  : 

Velocity  per  second 
During  systole        .  .  .  .  .         520  mm. 

During  diastole       .  .  .  .  .         150  mm. 

The  following  figures  have  been  obtained  from  experiments  on  dogs 
(Tigerstedt)  : 


Body 
weight 

Artery 

Volume 
per  second 

Linear 

velocity  per 

second 

Diameter 
of  artery 

B.P, 

Remarks 

kg. 

14-6 
14-1 

Crural. 

Crural. 
Carotid. 

CO. 

0-63 

1-69 
1-95 

mm. 
128 

275 
241 

mm. 
2-5 

2-8 
3-3 

mm.Hg. 

77 

88 
93 

Nerves  un- 
injured 
Nerves  cut 
Nerves  un- 
injured 

SECTION  IV 

THE   MECHANISM   OF  THE   HEART  PUMP 

In  the  mammal  the  two  sides  of  the  heart  are  only  in  communication  by 
means  of  the  blood-vessels  of  the  systemic  and  pulmonary  area.  Each 
side  consists  of  an  auricle  into  which  the  veins  open,  and  a  ventricle  which 
receives  the  blood  from  the  auricle  and  discharges  it  into  the  arterial  trunk — 
either  aorta  or  pulmonary  artery.  Since  the  auricles  have  to  act  merely  as 
a  receptacle  for  fart  of  the  blood  which  enters  during  the  relaxation  or 
diastole  of  the  heart,  their  cavities  are  smaller  than  those  of  the  ventricles, 
and  their  walls  are  thin,  corresponding  to  the  small  amount  of  work  thrown 
on  them  in  propelling  blood  into  the  relaxed  ventricle.  The  ventricles  have 
the  office  of  carrying  on  the  main  work  of  the  circulation  and  of  forcing  blood 
through  the  peripheral  resistance.  Their  walls  are  much  thicker  than  those 
of  the  auricles.  The  right  ventricle  has  a  wall  which  is  only  about  one- fourth 
the  thickness  of  the  left  ventricle,  in  conformity  with  the  much  heavier 
work  to  be  done  by  the  latter.  On  cutting  a  section  through  the  two  ven- 
tricles in  a  contracted  condition  the  thin  wall  of  the  right  ventricle  is  seen  to 
lie  in  the  form  of  a  crescent  round  the  circular  left  ventricle.  The  capacity 
of  both  ventricles  is  approximately  equal,  and  amounts  in  man  to  about 
1-40  c.c.  for  each  ventricle  when  the  heart  is  completely  relaxed. 

The  auricles  are  separated  from  the  ventricles  by  a  fibrotendinous  ring. 
From  this  ring  take  origin  most  of  the  muscular  fibres  of  the  heart  walls. 
The  muscular  fibres  of  the  auricles  run  in  both  circular  and  longitudinal 
directions,  the  circular  fibres  being  continued  round  both  auricles,  and  special 
rings  of  circular  fibres  surrounding  the  openings  of  the  great  veins.  From 
the  fibrotendinous  ring  between  the  auricle  and  the  left  ventricle  and  from 
the  sides  of  the  aorta  the  muscular  fibres  forming  the  superficial  layer  of  the 
ventricular  wall  pass  obliquely  downwards  to  the  left  towards  the  apex  of 
the  ventricle.  Here  they  loop  round  into  the  interior  of  the  ventricle  and 
pass  up  near  its  inner  surface  to  end  either  in  the  papillary  muscles  or  in  the 
auriculo-ventricular  ring  of  fibrous  tissue.  Between  these  two  layers  we 
find  a  third  inedian  layer  of  muscular  fibres  which  is  in  the  form  of  a  muscular 
cone.  The  fibres  of  this  layer  form  complete  loops  round  the  left  ventricle. 
The  middle  layer  is  connected  by  many  strands  of  muscular  fibres  with  both 
inner  and  outer  layers. 

Mall  divides  the  muscular  fibres  of  tlie  inniuiualian  heart  into  four  <i;rou])s,  two  super- 
ficial and  two  deep,  as  follows  : 

(1)  The  supcrjicial  bulbo-spiral  Jihres.     These  arise  from  the  conu.i  arfcrtosiis,  the 

891 


892 


PHYSIOLOGY 


left  side  of  the  aorta  and  the  left  side  of  the  auriculo-ventriciilar  ring,  and  take  an 
oblique  course  to  the  apex,  where  they  make  a  spiral  turn  (the  vortex)  and  reach  the 
interior  of  the  left  ventricle,  ending  for  the  most  part  in  the  intraventricular  septum 
and  the  papillary  muscles. 

(2)  The  superficial  sino-spiral  fibres  rise  on  the  dorsal  side  of  the  heart  from  the  right 
auriculo-ventricular  ring  and  run  obliquely  on  the  anterior  surface  of  the  right  ventricle 


Fig.  392.     View  of  the  heart  from  behind,  to  show  the  course  of  the  chief 
strands  of  muscle  fibres.     (Mall.) 
The  black  lines  represent  the  hulbo-spiral  fibres,  the  grey  lines  the  sino- 
spiral  fibres. 

to  the  apex,  where  they  also  turn  inwards,  forming  the  anterior  horn  of  the  '  vortex,' 
and  end  chieHy  in  the  papillary  muscles  of  the  right  ventricle. 

(3)  The  deep  hulho-spiral  fibres  form  a  complete  cylinder  around  the  left  ventricle, 
and  are  attached  chiefly  to  the  dorsal  side  of  the  aorta. 

(4)  The  deep  sino-spiral  fibres  are  attached  to  the  dorsal  aspect  of  the  left  auriculo- 
ventricular  ring,  whence  they  enter  the  right  ventricle  and  turn  upwards  towards  the 
base.  The  uppermost  of  these  fibres  form  circular  rings  round  the  conus  arteriosus  at 
the  base  of  the  pulmonary  artery. 

The  fact  that  the  muscular  fibres  are  continuous  over  both  auricles  and 
over  both  ventricles  respectively  ensures  the  practically  simultaneous  con- 
traction of  each  of  these  parts  of  the  heart.  Although  on  coarse  dissection 
there  seems  to  be  absolute  division  between  the  muscular  tissue  of  auricles 
and  ventricles,  it  has  been  shown  by  Kent,  His,  and  others  that  there  is 
continuity  of  muscular  tissue  between  the  two  parts  of  the  heart  by  a  special 


THE  MECHANISM  OF  THE  HEART  PUMP  893 

band  of  muscular  fibres, '  the  bundle  of  His,'  which  rises  in  the  wall  of  the 
right  auricle  and  passes  beneath  the  foramen  ovale  and  across  the  auriculo- 
ventricular  junction  into  the  inter-ventricular  septum.  The  exact  course 
of  these  fibres  and  their  significance  will  be  considered  later. 

The  normal  direction  of  the  blood-flow  through  the  heart  is  determined 
mainly  by  the  valves  which  guard  the  auriculo- ventricular  orifices  and  the 
openings  of  the  aorta  and  pulmonary  artery.     The  auriculo-ventricular 


Fig.  393.     Left  auricle  and  ventricle,  with  outer  side  cut  away  to  show  chief  points 
in  anatomy  of  heart.     (Tkstut.) 
1,  aorta  ;  2,  pidmonary  artery  ;  3,  ant.  coronary  vessels  ;  5,  5',  pulmonary  veins  ; 
G.  left  auricle  ;   7,  auricular  appendage  ;    10,  cavity  of  left  ventricle  ;    11,  12,  mitral 
valves  ;    13,  14,  papillary  muscles  ;    16,  arrow  pointing  to  aortic  orifice. 

valves  are  tubular  membranes  attached  round  the  entire  circumference  of 
the  auriculo-ventricular  ring.  They  are  composed  of  fibrous  and  elastic 
tissue,  covered  on  each  side  with  endocardium,  and  project  downwards  into 
the  cavities  of  the  ventricles.  On  each  side  the  membrane  is  divided  by 
deep  incisions  into  large  flaps,  three  in  number  on  the  right  side  (the  tricuspid 
valves)  and  two  in  number  on  the  left  side  (the  mitral  valves).  The  sail-like 
margins  of  these  valves  are  connected  by  thin  tendinous  cords  to  the  papil- 
lary muscles,  which  are  nipple- shaped  projections  of  the  muscular  walls  of 
the  ventricles.     By  this  means  the  edges  of  the  valves  are  kept  close  together 


894  PHYSIOLOGY 

and  prevented  from  eversioji  under  the  strong  pressure  exerted  by  the  con- 
tracting ventricle.  By  the  downward  pull  of  the  papillary  muscles  on  the 
valves  during  the  contraction  of  the  ventricles,  closure  is  rendered  more 
complete,  the  inner  surface  of  the  valves  being  apposed  over  a  considerable 
area.  The  action  of  the  valves  is  aided  by  the  contraction  of  the  fibres 
surrounding  the  base  of  the  heart,  so  that  the  auriculo-ventricular  orifice 
is  much  smaller  during  systole  than  during  diastole. 

From  a  purely  mechanical  standpoint  the  valves  guarding  the  arterial 
orifices  are  much  more  perfect  than  those  just  described,  which  depend  for 
their  efficiency  on  the  proper  contraction  of  the  ventricular  wall  and  of  the 
musculi  fafillares.  Each  orifice  is  provided  with  three  valves,  each  of  which 
is  semilunar  in  shape  and  attached  by  its  convex  borders  to  the  arterial  wall, 
and  presents  in  the  middle  of  its  free  border  a  small  fibro-cartilaginous 
nodule,  the  corpus  Arantii,  from  which  fine  elastic  fibres  pass  to  all  parts  of 
the  valve.  The  extreme  margin  of  the  valve,  the  lunula,  on  each  side  of  the 
corpus  Arantii  is  very  thin,  being  formed  of  little  more  than  the  endocardium. 
Whenever  the  pressure  in  the  arteries  is  greater  than  that  in  the  ventricles, 
these  valves  are  closed,  and  the  thin  margins  come  in  contact  with  similar 
portions  of  the  adjacent  valves,  so  preventing  the  reflux  of  a  single  drop  of 
blood.  The  borders  of  the  valves  under  these  circumstances  come  together 
in  the  form  of  a  star  composed  of  three  lines  at  angles  of  120°,  the  three 
corpora  Arantii  being  pressed  together  at  the  centre  of  the  star. 

No  valves  are  found  at  the  orifices  of  the  great  veins  into  the  auricles,  a 
reflux  of  blood  in  this  situation  during  contraction  of  the  heart  being 
limited  by  the  contraction  of  the  muscular  rings  round  the  veins,  which  always 
accompanies  the  auricular  contraction. 

The  heart  and  the  roots  of  the  great  vessels  lie  almost  free  in  a  special 
cavity,  the  wall  of  which  is  formed  by  a  tough  fibrous  membrane,  the 
pericardium.  This  is  attached  below  to  the  central  tendon  of  the  diaphragm, 
and  above  to  the  arterial  trunks.  It  is  lined  by  a  layer  of  endothehum 
continuous  with  a  similar  layer  covering  the  surface  of  the  heart.  The 
two  surfaces  are  kept  continually  moist  by  the  pericardial  fluid,  so  that  the 
heart  can  move  freely  within  the  pericardium  without  friction.  One  of  the 
chief  functions  of  the  pericardium  appears  to  be  to  check  an  excessive 
dilatation  of  the  heart  during  conditions  attended  by  a  great  rise  of  venous 
pressure. 

THE  SEQUENCE  OF  EVENTS  IN  THE  CARDIAC  CYCLE 

On  opening  the  chest  of  an  anaesthetised  animal,  while  artificial  respira- 
tion is  maintained,  the  heart  is  seen  contracting  rhythmically  within  the  peri- 
cardium. On  incising  this  sac  its  restraining  power  on  the  dilatation  of  the 
heart  is  shown  by  the  fact  that  during  diastole  the  wall  of  the  heart  bulges 
through  the  opening,  and  the  increased  diastolic  fiUing,  consequent  on  the 
removal  of  this  restraining  influence,  is  at  once  apparent,  if  in  any  way  the 
frequency  of  the  contractions  of  the  heart  be  diminished  so  as  to  prolong  the 
diastolic  period. 


THE  MECHANISM  OF  THE  HEART  PUMP  895 

Each  beat  of  the  heart  begins  by  a  simultaneous  contraction  of  both 
auricles  associated  with  a  retraction  of  the  auricular  appendages,  which 
become  pale  and  bloodless.  After  a  pause  of  not  more  than  a  tenth  of  a 
second  the  contraction  of  the  auricles  is  followed  by  that  of  the  ventricles, 
and  blood  is  thrown  out  into  the  large  arteries.  The  contraction  of  the  auricles 
lasts  about  a  tenth  of  a  second,  that  of  the  ventricles  about  three-tenths  of  a 
second.  The  period  of  relaxation  or  diastole  lasts  about  four-tenths  of  a 
second.  During  this  cycle  of  changes  the  following  events  are  taking  place 
within  the  heart : 

In  the  diastolic  period  the  aortic  valves  are  closed  and  the  arterial 
system  is  open  only  towards  the  capillaries.  In  consecjuence  of  the  high 
pressure  established  within  the  arteries  by  the  previous  heart-beats  the 
blood  flows  steadily  through  the  arterioles,  capillaries,  and  veins  into  the 
right  heart,  and  similarly  the  pressure  in  the  pulmonary  artery  causes  a 
partial  emptying  of  this  vessel  with  its  branches  through  the  pulmonary 
capillaries  into  the  left  heart.  The  flow  into  the  heart  is  assisted  by  the 
elastic  retraction  of  the  lungs,  which  causes  a  negative  pressure  in  the 
structures  between  them  and  the  chest  wall,  so  that  the  blood  is  sucked  from 
the  other  parts  of  the  body  towards  the  thorax.  During  diastole  there  is  a 
continuous  flow  of  blood  from  veins  into  auricles  and  from  auricles  into 
ventricles,  and  as  the  walls  of  both  these  cavities  are  relaxed  there  is  no 
impediment  to  the  inflow  of  the  blood  until  the  dilating  heart  begins  to 
stretch  the  pericardium. 

Under  normal  circumstances  the  diastole  comes  to  an  end  before  the 
restraining  influence  of  the  pericardium  can  be  effective.  The  contraction 
of  the  auricles  drives  their  contents  into  the  ventricles  and  so  still  further 
increases  their  distension,  no  resistance  being  offered  by  the  widely  dilated 
auriculo- ventricular  orifices  or  by  the  flaccid  wall  of  the  ventricles.  As  the 
blood  rushes  from  auricle  into  ventricle  through  the  funnel-shaped  opening 
of  the  membranous  tvibe  formed  by  the  valves,  eddies  are  set  up  in  the 
ventricle  tending  to  close  the  valves,  so  that  they  are  held,  as  the  resultant 
of  the  two  opposing  currents,  in  a  condition  midway  between  closure  and 
opening.  The  onset  of  the  ventricular  contraction  is  extremely  rapid. 
There  is  a  quick  rise  of  pressure  in  the  ventricle,  which  presses  together  the 
flaps  of  the  mitral  or  tricuspid  valves,  while  the  bases  of  these  valves  are 
approximated  by  the  contraction  of  the  circular  fibres  at  the  base  of  the 
ventricles.  As  the  heart  shortens  in  systole  the  papillary  muscles  also 
shorten,  so  that  the  valves  are  prevented  from  eversion  into  the  auricles, 
while  the  blood  is  pressed,  so  to  speak,  between  the  cone  of  the  ventricular 
wall  and  the  cone  formed  by  the  tubular  valves. 

The  outflow  of  blood  from  the  ventricles  does  not,  however,  commence 
immediately.  Whereas  at  the  beginning  of  systole  the  pressure  in  the 
ventricle  cavity  is  quite  small  (only  2  or  3  unn.  Hg),  there  is  a  pressure  in  the 
aorta  of  50  to  80  mm.  Hg.  Before  the  semilunar  valves  separating  the  lumen 
of  the  aorta  from  the  ventricular  cavity  can  be  opened,  the  pressure  in  the 
left  ventricle  must  rise  to  a  point  which  is  greater  than  that  in  the  aorta,  and 


896  PHYSIOLOGY 

similarly  on  the  right  side  of  the  heart.  As  soon  as  this  happens  the  valves 
open  and  the  outflow  of  blood  commences,  and  continues  so  long  as  the 
pressure  in  the  ventricles  is  higher  than  that  in  the  great  arteries.  Directly 
however,  the  ventricular  pressure  falls  below  the  arterial  pressure  the  valves 
must  close  and  the  output  of  blood  come  to  an  end. 

In  order  to  obtain  an  accurate  idea  of  the  exact  duration  of  each  of  these 
events  in  the  cardiac  cycle  it  is  necessary  to  study  the  changes  occurring  in  the 
pressure  within  the  auricles  and  ventricles  during  the  various  phases  of  the 
heart-beat. 

THE  ENDOCARDIAC  PRESSURE 

A  manometer  which  shall  register  accurately  the  changes  in  the  pressure 
within  the  heart  must  be  capable  of  responding  to  very  rapid  changes.  Thus 
in  the  left  ventricle  at  the  beginning  of  the  systole  there  may  be  a  rise  of 
130  mm.  Hg  in  -06  sec,  i.e.  2170  mm.  Hg  per  second.  In  a  heart  beating 
rapidly  and  forcibly  under  the  action  of  adrenalin,  the  rise  may  be  still  more 


Fig.  394.  Diagram  of  Marey's  cardiac  '  sound,'  consisting  of  a  long  tube  ab, 
terminating  at  one  end  in  the  ampulla  m,  which  is  covered  with  an  elastic 
membrane.  The  side-piece  c  serves  to  indicate  the  position  of  the  ampulla 
after  it  has  been  introduced  into  the  vessels. 

rapid,  e.g.  150  mm.  Hg  in  -025  sec.  A  mercurial  manometer  with  its  great 
inertia  would  be  quite  unequal  to  registering  such  rapid  changes  of  pressure 
and  would  moreover  tend  to  enter  into  oscillations  which  would  quite  deform 
the  curve.  We  require  an  instrument  with  very  small  weight  of  moving 
parts,  so  as  to  possess  small  inertia  and  be  capable  of  registering  a  rapid  rise 
of  pressure  without  entering  into  oscillations  of  its  own. 

Several  methods  have  been  adopted  for  this  purpose.  In  one  (Chauveau  and  Marey) 
a  cardiac  '  sound  '  (Fig.  394)  is  passed  down  the  jugular  vein  into  the  right  auricle  or 
ventricle,  or  down  the  carotid  artery  into  the  left  ventricle.     The  cardiac  sound  is  a 


FiQ.  395.     Marey's  tambour, 
a,  axis  of  lever  ;   h,  metal  tray  covered  with  rubber  membrane,  and  communi- 
cating by  tube  /  with  free  end  of  cardiac  sound. 

stiff  tube  having  an  elastic  bulb  or  ampulla  at  the  end  which  is  to  be  inserted  into  the 
heart.  The  bulb  is  supported  by  a  steel  frame,  so  that  it  is  not  completely  compressible 
by  external  pressure.  The  free  end  of  the  tube  is  connected  with  a  writing  tambour 
(Fig.  395),  a  small  round  metal  tray  covered  with  a  delicate  elastic  membrane.  To 
the  top  of  the  membrane  a  lever  is  attached  by  which  any  change  of  pressure  on  the 


THE  MECHANISM  OF  THE  HEART^PUMP  897 

ampulla  may  be  recorded  on  a  moving  smoked  surface.  The  large  size  of  these  sounds 
makes  it  difficult  to  use  them  on  any  animal  smaller  than  the  ass  or  horse.  In  smaller 
animals,  such  as  the  dog,  the  question  has  been  investigated  by  the  use  of  a  manometer 
such  as  that  of  Hiirthle.     In  this  instrument  (Fig.  396)  the  changes  of  pressure  are 


Fia.  396.     Diagram  to  show  construction  of  Hiirthle's  membrane  manometer. 

recorded  by  the  oscillations  of  a  thick  rubber  membrane  which  covers  a  very  small 
tambour.  The  tambour  is  filled  with  magnesium  sulphate  solution,  which  is  also  used 
to  fill  the  tube  connecting  with  the  heart.  This  tube  can  be  inserted  in  the  same  way 
as  Marey's  cardiac  sound. 

Even  Hiirthle's  instrmnent  is  inadequate  to  give  a  correct  representation  of  the  very 
rapid  changes  of  pressure  occurring  in  the  contracting  ventricle.  A  study  of  the  theory 
of  recording  instruments  by  Otto  Frank  has  enabled  him  to  lay  down  certain  funda- 
mental requirements  of  such  a  recording  instrument.  In  order  that  an  instrument 
may  reproduce  correctly  rapid  changes  of  pressm-e,  the  mass  moved  must  be  as  small  as 
possible  in  order  to  reduce  the  momentum,  and  therefore  the  tendency  to  overthrow  of  the 
instrument,  to  the  greatest  possible  extent.  Moreover,  the  movement  of  fluid  into  and 
out  of  the  instrument,  which  accompanies  each  change  of  pressiu-e,  must  occur  with 
the  smallest  possible  friction.  This  is  accomplished,  as  in  Hiii-thle's  instrument,  by 
using  a  very  small  tambour,  covered  with  a  strong  tightly  stretched  membrane  connected 
by  as  short  and  wide  a  tube  as  is  feasible,  with  the  heart  or  blood-vessel  where  it  is 
de5ired  to  register  changes  of  pressure.  A  lever  is  entirely  got  rid  of,  the  minute 
oscillations  of  the  membrane  being  recorded  by  means  of  a  beam  of  light  which  impinges 


D 

Fio.  397.     Diagram  of  Piper's  manometer. 

on  a  mirror  attached  to  the  rubber  membrane  and  reflected  on  to  a  moving  photographic 
surface.  In  Fig.  397  is  represented  the  construction  of  Piper's  manometer,  built  on 
the  principles  laid  down  by  Frank. 

>  It  consists  of  a  tube  armed  with  a  stilette.  A,  which  tits  it  accm'ately.  At  o  is  a  tap 
which,  when  opened,  will  permit  the  passage  of  the  stilette,  and  can  close  the  tube  en- 
tirely when  the  stilette  is  withdrawn.  About  2  cms.  above  the  lower  extremity  of  the 
tube  is  a  small  drum-like  enlargement,  closed  on  one  side  by  a  thick  membrane,  e. 
On  the  edge  of  this  membrane  is  fixed  by  means  of  shellac  a  minute  mirror,  F,  1  nmi.  in 
diameter.  With  the  stilette  protruding,  the  manometer  is  thrust  directly  into  the 
cavity  of  the  heart,  and  fixed  in  position  by  a  pm-se-string  suture  tlu:ough  the  super- 
ficial part  of  the  heart  muscle,  tied  tightly  round  the  end  of  the  manometer.  The  stilette 
is  then  withdrawn  and  the  tap  turned  off,  but  alterations  in  pressure  in  the  cavity  of  the 
heart  causes  minute  oscillations  of  the  menibrane,wluchcan  be  recorded  and  magnified  to 
any  desired  extent  by  means  of  a  beam  of  light  reflected  from  the  mirror  on  to  a  moving 
photographic  plate  or  paper.  The  advantage  of  this  optical  method  of  registration  is 
that  the  magnification  can  be  increased  to  any  extent  without  altering  the  mass  moved. 
The  '  figiu:e  of  merit '  of  this  manometer,  i.e.  its  own  period  of  vibration,  when  tilled  with 
fluid,  is  about  250  per  second  with  a  tliick  membrane,  so  that  it  canrecord  with  perfect 
accuracy  all  such  rapid  changes  of  pressure  as  may  occur  even  in  the  left  ventricle. 

29 


898  PHYSIOLOGY 

On  registering  the  endocardiac  pressure  by  the  optical  method  it  is 
found  that  the  curves  vary  in  form  according  to  the  condition  of  the  heart. 


Fig.  398.      Endocardiac  preissure  tracings,  taken  with  Piper's  manometer 

A,  Simultaneous  tracings  from  left  ventricle  and  left  auricle.      To  be  read  from  left 

to  right.    B  and  C  taken  from  left  ventricle,  C  at  a  faster  rate  of  recording  surface 

thanB.     'Jo  be  read  from  right  to  left.    Ki=  closure  of  A.V.  valves;  Pj  opening 

of  aortic  valves;   83,  elastic  oscillation  or  wave;  K2,  opening  of  A.  V.  valves. 

In  order  to  interpret  these  curves  we  must  utiHse  the  knowledge  obtained 
from  a  simultaneous  record  of  the  pressures  in  the  auricle  and  ventricle,  or 
in.  .the  ventricle  and  aorta.      Figm'e  398  represents  the  different  forms 


THE  MECHANISM  OF  THE  HEART  PUMP 


899 


of  curve  obtained  from  the  left  ventricle.  Very  often,  as  in  a,  the  curve 
is  not  unlike  a  single  muscle  twitch  or  the  curve  of  contraction  of  the  fi'og's 
heart  muscle.  Nearly  always  however  it  is  possible  to  see  on  the  upstroke 
one  or  two  elevations,  the  most  noticeable  being  the  elevation  marked 
Si-  This  can  be  shown  to  correspond  to  the  opening  of  the  aortic  valves. 
This  is  still  better  marked  in  b,  where  the  heart  was  beating  very  forcibly 
and  rapidly  under  the  influence  of  adrenalin,  and  is  also  very  exadent  in  c. 
In  some  cases,  as  in  a,  the  rise  of  pressure  occm's  distinctly  more  slowly 
after  Sj  than  before.  In  b  there  is  a  further  rapid  rise  of  pressure  after 
Sj  before  the  curve  begins  to  slope  away,  and  at  the  change  of  velocity  of 
rise,  there  is  a  second  wave  at  the  point  marked  S^.  This  is  also  marked  in  c. 
The  slope  of  the  curve  after  S^  or  Sg  varies  considerably  according  to  the 


Aorta 


l/entrLcle 
Auricle 


amount  of  blood  the  heart  is  sending  out.  In  c  the  intraventricular 
pressure  curve  runs  almost  horizontal  for  a  time  and  this  part  of  the  curve  is 
known  as  the  systoUc  plateau,  but,  as  is  evident  from  a,  a  plateau  in  the 
strict  sense  of  the  term  is  not  always  present.  At  the  end  of  the  '  plateau  ' 
the  pressure  rapidly  falls,  and  the  period  where  the  lines  thin  out,  i.e.  the 
point  at  which  the  fall  is  occurring  most  rapidly,  corresponds  to  the  closure 
of  the  aortic  valves. 

The  average  course  of  the  changes  of  pressure  in  the  heart  during  each 
beat  is  shown  diagrammatically  in  Fig.  399  (Piper).  The  cardiac  cycle 
begins  with  the  contraction  of  the  auricle  at  1  which  may  or  may  not  give 
rise  to  a  shght  rise  of  pressure  in  the  ventricles.  As  the  auricular  contraction 
dies  away,  the  ventricular  contraction  begins  at  2,  This  causes  a  very  rapid 
rise  of  pressure.     Almost  immediately  after  the  beginning  of  the  rise,  or 


900  PHYSIOLOGY 

sometimes  synchronously,  the  auriculo- ventricular  valves  close  at  the  point 
marked  3.  The  pressure  then  rises  rapidly  in  the  ventricular  cavity. 
Directly  it  exceeds  the  pressure  in  the  aorta,  the  aortic  valves  open  at  the 
point  marked  4,  and  the  aortic  pressure  thereafter  rises  with  the  ventricular 
pressure.  During  the  whole  duration  of  the  ventricular  contraction  the 
aortic  pressure  remains  somewhat  below  the  ventricular  pressure,  showing 
that  blood  is  flowing  continuously  from  ventricle  into  aorta.  The  rise  of 
pressure  in  the  aorta  may  be  at  first  rapid  and  then  slow  ofi  gradually. 
With  the  change  of  velocity  of  the  rise  of  pressure  vibrations  may  be  set  up 
at  5  especially  in  the  aorta  and  also,  but  to  a  less  extent,  in  the  ventricle. 
These  vibrations  are  however  often  absent.  At  the  end  of  the  plateau 
the  pressure  in  the  ventricle  falls  rapidly  as  this  organ  begins  to  relax.  Its 
pressure  therefore  falls  below  that  of  the  aorta  and  the  aortic  valves  close, 
the  closure  of  the  valves  being  followed  by  the  so-called  dicrotic  elevation 
or  incisure  at  7.  The  pressure  in  the  ventricles  then  continues  to  fall,  first 
rapidly  and  then  more  slowly,  until  it  reaches  the  fine  of  zero  pressure,  and 
remains  at  or  near  this  line  during  the  greater  part  of  diastole.  With  a  big 
inflow  there  may  be  a  shght  rise  towards  the  end  of  diastole  which  may  be 
accentuated  by  the  auricular  contraction.  If  the  chest  is  opened  the  pressure 
in  the  ventricle  never  sinks  below  zero  during  any  part  of  diastole.  The 
time  relations  of  these  events  naturally  varies  with  the  frequency  of  con- 
traction of  the  heart.  In  a  dog's  heart  beating  about  100  times  a  minute  the 
following  phases  in  the  ventricular  tracing  were  determined  by  Hiirthle. 

(1)  A  small  rise  of  pressure  due  to  contraction  of  the  auricles,  lasting 
about  '05  seconds. 

(2)  A  very  steep  ascent  rather  above  the  middle  of  which  the  aortic  valves 
open.  The  beginning  of  the  rise  is  generally  marked  by  a  sharp  secondary 
wave  or  by  a  sudden  change  in  the  direction  of  the  curve.  This  point  is 
about  -02  to  -04  seconds  after  the  beginning  of  the  ventricular  contraction. 

(3)  A  prolonged  stage,  lasting  about  two-tenths  of  a  second  during 
which  the  ventricle  is  contracting.  During  this  time  the  tracing  may  show 
a  flattened  top,  the  '  plateau,'  or  a  rounded  summit.  Kear  the  beginning 
of  this  plateau,  a  second  wave  may  make  its  appearance  if  the  rate  at  which 
the  pressure  rises  falls  off  suddenly.  This  second  wave  is  therefore  most 
marked  with  a  considerable  output,  and  a  heart  which  beats  forcibly  and 
rapidly. 

(4)  A  rapid  fall  due  to  the  relaxation  of  the  ventricular  muscle.  Near 
the  upper  part  of  this  fall  the  aortic  valves  close,  but  it  is  generally  difficult, 
without  comparison  with  the  simultaneous  aortic  pressure  curve  to  make  out 
the  exact  point  of  closure  on  the  ventricular  pressure  curve. 

(5)  A  period  lasting  about  two-tenths  of  a  second  during  which  the 
ventricle  remains  relaxed  and  the  pressure  is  approximately  zero,  in  some 
cases  rising  shghtly  towards  the  end.  The  period  of  outflow  of  blood  lasts 
from  the  moment  at  which  the  aortic  valves  open  to  the  moment  at  which 
in  the  relaxing  ventricle  the  pressure  falls  below  that  in  the  aorta  and  the 
aortic  valves  close.     It  therefore  corresponds  with  the  duration  of  that  part 


THE  MECHANISM  OF  THE  HEART  PUMP       901 

of  the  curve  which  has  been  called  the  '  plateau.'  The  majdmum  pressure 
attained  in  the  left  ventricle  naturally  depends  on  the  height  of  the  aortic 
pressure  and  is  always  greater  than  this.  Under  normal  conditions  in  the 
dog,  with  an  average  aortic  pressure  of  100  mm.  Hg.,  the  pressure  in  the 
ventricle  may  be  130  or  150  mm.  Hg.  The  difference  between  the  average 
pressure  in  the  aorta  and  the  maximum  pressure  attained  during  contraction 
of  the  ventricle  will  naturally  be  greater  the  larger  the  amount  of  blood 
which  is  thrown  out  at  each  contraction.  Thus  in  one  case  in  a  dog  of 
10  kilos,  with  an  average  aortic  pressure  of  100  mm.  Hg.,  the  maximum 
pressure  in  the  left  ventricle  was  145  mm.  Hg.  with  an  output  of  2040  c.c. 
per  minute,  and  115  mm.  Hg.  with  an  output  of  650  c.c.  per  minute.  On 
the  right  side  the  maximum  pressure  is  much  less,  corresponding  to  the  low 
resistance  of  the  pulmonary  system  of  blood-vessels.  Otherwise  the  general 
course  of  the  curves  is  very  similar  on  the  two  sides  of  the  heart.  The 
maximum  pressure  in  the  right  ventricle  may  be  taken  as  varying  between 
25  and  35  mm.  Hg.  under  ordinary  conditions. 

CHANGES  OF  PRESSURE  IN  THE  AURICLES 

Owing  to  the  absence  of  valves  between  the  right  auricle  and  the  venae 
cavffi,  changes  of  pressure  within  this  cavity  are  transmitted  along  the  veins. 
The  venous  pulsation  is  especially  marked  in  circumstances  which  give  rise 
to  high  venous  pressure,  so  that  the  veins  are  not  entirely  emptied  at  any 
part  of  the  cardiac  cycle.  The  most  superficial  observation  shows  that  the 
jugular  vein  pulsates  twice  for  each  heart-beat. 

The  exact  form  of  the  pressure  tracing  in  the  auricles  varies  considerably 
according  to  the  inflow  of  blood  and  the  state  of  filling  of  their  cavities.  A 
typical  tracing  with  a  moderate  inflow  of  blood  is  given  in  Fig.  398  A^  p.  898, 
and  in  this  figure  the  relations  of  the  different  elevations  in  the  auricular 
tracing  to  the  intraventricular  events  can  be  made  out.  A  somewhat 
different  curve  is  given  in  Fig.  400,  but  it  will  be  noted  that  the  essential 
features  of  the  curves  are  identical.  In  every  case  the  auricle  curve 
presents  the  following  features  : 

(1)  The  first  positive  wave  (pre-systolic  wave)  corresponding  to  the 
auricular  systole. 

(2)  The  second  positive  wave  l^  (first  systolic  wave)  occupying  the  begin- 
ning of  the  ventricular  systole.  This  is  caused  by  the  sharp  closure  of  the 
mitral  valve. 

(3)  A  third  positive  wave  (second  systolic  wave)  which  may  present 
secondary  undidations.  This  rise  of  pressure  is  due  to  the  gradual  filhng  of 
the  auricles  while  the  auriculo- ventricular  valves  are  still  shut. 

(4)  A  negative  wave  which  corresponds  to  the  '  post-systolic  vacuum  '  of 
Chauveau  and  Marey.  At  this  point  the  ventricle  is  entirely  relaxed  and 
the  auriculo-ventricular  valves  open,  so  allowing  the  blood  to  flow  freely  from 
the  auricle  into  the  ventricle.  This  negative  wave  is  not  always  well 
marked,  and  is  represented  only  by  a  series  of  small  undulations  in 
Fig.  398  A. 


902 


PHYSIOLOGY 


The  pressure  rises  in  the  left  auricle  somewhat  higher  than  in  the  right 
auricle.  In  the  latter  case  the  big  veins  act  as  a  supplementary  reservoir 
to  the  auricle,  so  that  in  no  period  of  the  cardiac  cycle  need  the  pressure  in 


Fig.  400.     Curve  of  pressures  in  left  auricle  of  cat.     (STKAtrB.) 
I,  II,  III  Ton  =  1st,  2nd,  and  3rd  heart  sounds. 

the  latter  chamber  rise  to  any  extent.     In  both  the  auricular  tracings  given 
the  heart  sounds  are  apparent  as  small  oscillations  in  the  curve. 

NEGATIVE  PRESSURE.  When  the  flow  of  blood  through  a  tap  is  suddenly 
interrupted,  the  momentum  of  the  fluid  tends  to  make  it  continue  its  movement  so  that 
a  diminution  of  pressiu-e  is  produced  in  the  rear  of  the  moving  column.  In  the  tracings 
obtained  by  means  of  the  older  instrrunents,  such  as  those  of  Hlirthle,  the  lever  at  the 
end  of  the  ventricular  systole  even  descended  below  the  base  line,  thus  suggesting 
that  for  a  short  period  of  time  there  was  actually  a  negative  pressure  in  the  ventricles. 
If  the  manometer  be  comiected  with  the  heart  by  a  tube  provided  with  a  valve  allowing 
the  movement  of  fluid  only  in  one  direction,  it  becomes  a  maximum  or  minimtmi  mano- 
meter according  to  the  direction  of  the  valve.  This  tube,  however,  increases  the  inertia 
of  the  whole  system,  so  that  the  use  of  the  minimum  manometer  tends  to  exaggerate 
the  apparent  negative  pressure.  According  to  some  statements  there  may  be  a  negative 
pressure  of  40  to  60  mm.  Hg.  in  the  ventricle  at  some  period  during  the  cardiac  cycle. 
Many  explanations  were  put  forward  to  account  for  this  negative  pressure,  but  they  are 
all  rendered  unnecessary  by  the  fact  revealed  by  more  perfect  graphic  methods  that  at 
no  period  in  the  cardiac  cycle  is  there  a  negative  pressiu'e  in  the  ventricles.  Naturally 
under  normal  conditions  the  pressm'e  in  the  chest  outside  the  heart  is  negative  owing 
to  the  elastic  retraction  of  the  lungs,  and  may  vary  from  —  3  to  —  30  mm.  Hg.,  according 
as  it  is  measiu-ed  during  normal  expiration  or  during  forced  inspiration.  This  negative 
I^ressure  may  be  transmitted  to  the  interior  of  the  heart,  but  the  pressiure  within  the 
ventricle  never  falls  below  the  piessm'e  obtaining  outside  the  ventricles. 


CHANGES  IN  FORM  OF  THE  HEART 
As  the  heart  walls  are  perfectly  flaccid  during  diastole,  the  shape  of  this 
organ  as  a  whole  will  depend  upon  the  position  in  which  the  heart  is  lying 
and  the  direction  of  its  support.  Thus  if  the  chest  and  the  pericardium  be 
opened  and  the  animal  be  in  the  supine  position,  the  heart  during  diastole  will 
be  flattened  from  before  backwards  as  a  result  of  the  simple  weight  of  its 
contents.     In  this  position  therefore  systole  will    be  accompanied  by  a 


THE  MECHANISM  OF  THE  HEART  PIBIP  903 

shortening  in  the  lateral  and  vertical  directions  and  a  lengthening  in  the 
sagittal  direction.  During  systole,  when  the  heart  becomes  tense  and  all  its 
fibres  are  firmly  contracted,  the  heart,  whatever  its  previous  condition, 
takes  the  form  of  a  truncated  cone.  Under  normal  circumstances  the  heart 
in  the  unopened  chest  lies  in  the  pericardium,  which  is  attached  above  to  the 
great  vessels  and  below  to  the  central  tendon  of  the  diaphragm.  It  is 
supported  laterally  by  the  lungs,  which,  however,  owing  to  their  elasticity, 
have  very  little  influence  on  its  shape  during  diastole. 

When  the  heart  is  freed  from  the  pericardium,  the  obhquity  of  its  fibres 
causes  the  apex  to  move  forwards  and  to  the  right  during  systole  ;  this 
movement  is  normally  prevented  by  the  attachment  of  the  pericardium  to  the 
central  tendon  of  the  diaphragm,  so  that  the  most  movable  part  of  the  heart 
comes  to  be  the  base.  If  three  needles  be  passed  through  the  chest  wall  so  that 
their  points  lie,  one  in  the  base,  one  about  the  centre  of  the  ventricles,  and 
one  in  the  apex  of  the  ventricles,  each  ventricular  systole  is  found  to  be 
accompanied  by  a  movement  of  the  needle  in  the  base  of  the  heart  down- 
wards, a  slighter  movement  in  the  same  direction  of  the  needle  in  the  middle 
of  the  ventricles,  and  practically  no  movement  at  all  of  the  needle  which  is 
thrust  into  the  apex.  During  systole  the  base  of  the  heart  moves  downwards 
towards  the  apex.  This  movement  is  determined  partly  by  the  shortening 
of  the  fibres  of  which  the  ventricular  wall  is  composed,  partly  by  the  lengthen- 
ing of  the  great  arteries  as  blood  is  forced  into  them  under  pressure  from  the 
ventricles. 

The  changes  in  the  shape  of  the  cavities  of  the  heart  during  contraction 
have  been  studied  in  the  stage  of  extreme  contraction  produced  by  heat 
rigour.  In  such  hearts  it  is  found  that  the  cavities  are  never  entirely 
obhterated,  though  the  right  ventricle  is  reduced  to  a  narrow  sht  ^Nidening  out 
slightly  in  the  neighbourhood  of  the  auriculo-ventricular  orifices,  while  in  the 
left  ventricle  a  distinct  cavity  is  left  between  the  mitral  valves  and  the  free 
ends  of  the  papillary  muscles.  During  normal  activity  it  is  probable  that  the 
emptying  of  the  cavities  rarely  proceeds  to  so  great  an  extent. 


THE  APEX  BEAT 

The  movement  of  the  heart  at  each  contraction  is  communicated  to  the 
chest  wallr  over  a  limited  area  of  which  it  may  be  felt  and  seen,  except  in  fat 
individuals.  The  region  where  the  pulsation  of  the  chest  wall  is  most  marked 
lies  in  the  fifth  intercostal  space,  a  little  to  the  median  side  of  the  left  nipple. 
The  pulsation  is  spoken  of  as  the  '  apex  beat,'  and  was  formerly  thought  to  be 
due  to  the  twisting  forward  of  the  apex  at  each  systole.  The  apex  of  the 
heart  is  really  situated  lower  down,  and,  as  we  have  already  seen,  so  long  as 
the  pericardium  is  intact  is  relatively  motionless.  During  diastole  the 
ventricles  form  a  flabby  flattened  cone  lying  against  the  chest  wall  and 
slightly  deformed  by  the  latter.  In  systole  the  ventricles  contract  forcibly 
on  the  contained  fluid  and  become  hard  and  rigid,  assuming  the  form  of 
a  rounded  cone.      This  sudden  recovery  of  shape  and  hardening  of  the 


904  PHYSIOLOGY 

ventricular  wall  pushes  out  the  part  of  the  chest  wall  in  immediate  proximity 
to  the  ventricles  and  so  gives  rise  to  the  '  apex  beat.' 

The  cardiac  impulse  may  be  registered  by  means  of  a  cardiograph. 
In  nearly  all  forms  of  this  instrument  a  button  resting  on  the  chest  wall 


Fig.  401.  A  cardiograph.  This  is  strapped  round  the  chest,  the  central  button  is 
applied  to  the  '  apex  beat,'  and  its  pressure  on  the  chest  wall  regulated  by 
means  of  ths  three  screws  at  the  sides.  The  tube  at  the  upper  part  of  the 
instrument  serves  to  connect  the  drum  of  the  cardiograph  with  a  registering 
tambour  such  as  that  shown  in  Fig.  395. 

transmits  the  movement  of  the  latter  to  a  tambour,  which  again  is  connected 
by  a  tube  to  a  registering  tambour.  One  such  instrument  is  shown  in  Fig. 
401. 

The  curves  so  obtained,  which  are  known  as  cardiograms,  may  vary 
considerably  in  the  same  subject  according  to  the  pressure  employed  and  the 
exact  spot  at  which  the  tambour  is  applied.  Their  interpretation  often 
presents  difficulties  owing  to  the  fact  that  their  form  is  conditioned  by  two 
factors,  viz.  (1)  the  actual  size  (antero- posterior  diameter)  of  the  ventricles, 


Fig.  402.     Cardiogram.     (Hxjrthle.) 

(2)  the  resistance  to  distortion  {i.e.  the  tension)  of  the  ventricular  wall ;  this 
factor  will  increase  in  importance  with  increasing  pressure  of  the  cardiograph 
button  on  the  chest  wall.  Fig.  402  represents  a  cardiographic  tracing  or  cardio- 
gram which  may  be  spoken  of  as  typical.  In  order  to  interpret  this  curve 
we  must  record  at  the  same  time  either  the  intraventricular  pressure  in 
animals  or  the  heart  sounds  in  man.  This  cardiogram  presents  considerable 
similarities  to  the  endocardiac  pressure  curve  ;  in  both  there  is  an  ascending 
limb,  a  plateau,  and  a  descending  limb,  and  in  many  cases  a  small  elevation 
occurs  at  the  beginning  of  a  curve  during  the  contraction  of  the  auricle. 
The  exact  point  at  which  the  auricular  passes  into  the  ventricular  contraction 


THE  MECHANISM  OF  THE  HEAET  PUMP 


905 


varies  from  case  to  case  and  may  be  altered  by  altering  the  degree  of  pressure 
put  on  the  recording  button.  In  the  first  figure  given  the  auricular  systole 
finishes  before  the  main  rise  of  the  lever  occurs.  In  many  cases,  however, 
the  elevation  due  to  the  auricular  systole  may  take  up  the  greater  part  of  the 
ascending  hmb  of  the  cm"ve,  as  in  Fig.  403. 

In  the  experiment  from  which  this  figure  was  taken  the  heart  sounds 
were  recorded  at  the  same  time  as  the  apex  beat.     It  will  be  seen  that  the 

1  .2 


Fig.  403.     Cardiogram  (b)  with'simultaneous  record  of  heart-sounds  (a), 

(Hi'RTHLE.) 

1,  position  of  fii'st  heart-sound  ;  2,  position  of  second  heart-sound. 

first  heart  sound,  corresponding  to  the  ventricular  systole,  begins,  not  at 
the  commencement  of  the  rise  of  the  cardiogram,  but  at  the  notch  near 
the  top  of  the  ascent.  The  first  part  of  the  ascent  is  therefore  caused  by  the 
increase  in  the  volume  of  the  ventricle,  due  to  the  sudden  contraction  of  the 
auricles,  the  ventricular  systole  being  marked  by  the  notch  near  the  top  of 
the  curve.  Owing  to  the  co-operation  of  the  volume  and  pressure  factors 
in  the  production  of  the  cardiogram,  the  curve  generally  begins  to  decHne 
with  the  diminution  in  volume  which  follows  the  sudden  opening  of  the  aortic 
valves.  Here  again,  however,  the  effect  will  vary  with  the  pressure  of  the 
button.  If  an  actual  deformation  of  the  ventricular  muscle  can  be  effected, 
as  in  thin  patients,  the  plateau  of  the  curve  may  last  during  the  whole  of  the 
cardiac  cycle.  Other  forms  of  curves  may  be  obtained  which  show  con- 
siderable deviation  from  the  endocardiac  pressure  tracing ;  these  are  spoken 
of  as  atypical,  and  are  generally  conditioned  by  a  faulty  position  of  the 
cardiograph,  the  button  being  applied  to  the  chest  wall  in  the  immediate 
vicinity  of  the  apex  beat  instead  of  to  the  apex  beat  itself. 


THE  HEART  SOUNDS 

If  we  apply  our  ear  to  the  front  of  a  person's  chest  (it  is  more  convenient 
to  use  the  stethoscope  for  the  purpose)  we  hear  two  distinct  sounds  accom- 
panying each  beat  of  the  heart,  followed  by  a  pause  corresponding  to  the 
diastole.  The  sounds  are  compared  to  the  syllables  lubh,  dup,  the  first  sound 
being  low-pitched  and  prolonged,  the  second  sound  high  and  sharp.  Thus 
the  heart  sounds  may  be  represented  :  lubb,  dup  (pause),  lubb,  dup  (pause). 

The  causation  of  the  second  sound  is  very  simple,  and  may  be  considered 
first.  It  is  heard  just  over  the  second  right  costal  cartilage,  i.e.  the  place 
where  the  aorta  lies  nearest  the  surface.     It  comes  at  the  end  of  the  systole, 

29* 


906  PHYSIOLOGY 

as  determined  by  the  hardening  of  the  apex  of  the  heart,  felt  as  the  apex  beat, 
and  can  be  shown  to  be  synchronous  with  the  closure  of  the  aortic  valves.  It 
is,  in  fact,  caused  by  the  sudden  shutting  and  stretching  of  these  valves  that 
occur  directly  the  heart  ceases  to  contract  and  to  force  the  blood  into  the 
aorta.  If  the  valves  be  hooked  back  in  an  animal  by  means  of  a  wire  passed 
down  a  carotid  artery,  the  second  sound  disappears  and  is  replaced  by  a 
murmur  caused  by  the  blood  rushing  back  into  the  ventricle  at  the  end  of  the 
systole.  The  same  disappearance  of  the  normal  second  sound  is  observed  in 
cases  where  the  valves  are  prevented  from  closing  by  diseased  conditions. 

The  pulmonary  and  aortic  valves  generally  close  simultaneously.  In 
some  cases,  however,  the  aortic  may  close  slightly  before  the  pulmonary, 
giving  rise  to  a  '  reduplicated  second  sound.'  The  pulmonary  element 
of  this  sound  is  best  heard  over  the  second  left  cartilage,  or  in  the  second  left 
intercostal  space. 

The  first  sound  has  probably  a  twofold  origin,  viz.  from  the  sudden  closure 
of  the  auriculo- ventricular  valves  and  from  the  contraction  of  the  thick 
muscular  wall  of  the  ventricle. 

If  the  veins  going  to  the  heart  be  clamped  so  that  the  heart  can  no  longer 
be  distended  with  blood  nor  the  valves  put  on  the  stretch,  the  first  sound 
is  altered  in  character,  but  not  abolished.  The  first  sound  may  indeed 
be  heard  on  listening  with  a  stethoscope  to  the  beat  of  an  excised  heart.  It 
is  said  that  two  notes  may  be  detected  in  the  first  sound — a  high  note  of 
short  duration  due  to  closure  of  the  valves,  and  a  low-pitched  note  due  to  the 
muscular  contraction.  The  muscular  element  of  the  first  sound  has  the 
same  pitch  as  the  sound  produced  by  contracting  voluntary  muscle,  and 
therefore  as  the  resonance-tone  of  the  ear.  This  consideration  prevents  our 
arguing  from  the  tone  that  a  cardiac  contraction  is  a  tetanus.  As  we  shall 
show  later  on,  each  ventricular  contraction  is  analogous  to  a  simple  muscle- 
twitch  and  not  to  a  tetanus. 

THE  THIRD  HEART  SOUND.  A  number  of  observers  have  described  a  third 
heart  sound  as  occurring  in  certain  individuals  during  the  diastole,  a  short  time  after 
the  second  sound.  It  is  softer  and  of  a  lower  pitch  than  the  second  sound,  and  is  heard 
most  distinctly  over  the  apex  beat.  It  is  probably  due  to  the  vibrations  set  up  in  the  fluid 
itself  or  in  the  auriculo-ventricular  valves  by  the  sudden  inrush  of  blood  from  auricles 
to  ventricles  at  the  beginning  of  the  diastole.  The  sound  is  shown  objectively  by  the 
vibrations  on  the  endocardiac  pressure  curve  given  in  Fig,  400  (Straub).  It  has  also 
been  registered  electrically  by  Einthoven. 

CARDIAC  MURMURS 
When  a  fluid  escapes  through  a  narrow  orifice  into  a  wider  space  vibrations 
are  set  up  in  the  fluid  and  may  be  transmitted  by  any  elastic  medium  to  the 
ear,  giving  rise  to  the  sensation  of  sound.  Such  a  sound  is  produced  when 
water  is  allowed  to  run  from  a  tap  into  a  vessel  of  water,  or  when  air  is  blown 
out  between  the  partially  closed  lips.  The  formation  of  such  vibrations 
forms,  indeed,  the  basis  for  the  construction  of  many  musical  instruments. 
The  same  sort  of  vibration  may  be  set  up  in  the  large  vessels  or  in  the  heart, 
whenever  the  blood  passes  rapidly  through  a  narrow  orifice  into  a  wider  space. 


THE  MECHANISM  OF  THE  HEART  PUMP       907 

In  the  normal  individual  sounds  produced  in  this  way  are  so  slight  that 
they  may  be  neglected  ;  under  abnormal  conditions,  as  after  diseases 
affecting  the  valvular  orifices  of  the  heart,  this  vibration  may  occur  during 
every  heart  cycle  and  be  heard  with  ease  on  applying  the  ear  to  the  chest. 
These  murmurs,  or  bruits  as  they  are  called,  are  of  paramount  importance  in 
enabhng  the  medical  man  to  form  a  judgment  as  to  the  condition  of  the 
different  valves  of  the  heart.  Thus  injury  to  an  aortic  valve,  so  as  to  allow 
of  leakage  during  diastole,  involves  the  squirting  of  a  small  amount  of  fluid 
under  high  pressure  from  the  aorta  into  the  relaxed  ventricle.  On  hstening 
to  the  chest  of  a  man  with  such  a  lesion  this  regurgitation  during  diastole  is 
heard  as  a  rushing  sound  occurring  in  the  place  of  or  continuing  the  second 
sound  up  to  the  beginning  of  the  next  first  sound  which  denotes  the  beginning 
of  systole. 

In  many  cases  the  disease  which  occasioned  the  inadecjuacy  of  the  valve 
is  followed  by  processes  of  repair  and  cicatrisation  in  which  the  valves  become 
puckered  and  contracted  and  perhaps  adherent,  so  that  the  orifices  can  never 
become  thoroughly  patent  or  thoroughly  closed.  Under  such  circumstances 
vibrations  will  be  set  up  in  the  cm-rent  of  blood  as  it  escapes  through  the 
narrow  orifice  into  the  aorta  during  systole,  and  on  listening  to  the  chest 
over  the  second  right  costal  cartilage  a  '  to  and  fro  '  bruit  is  heard  composed 
of  a  systolic  immediately  followed  by  a  diastoHc  murmur.  In  the  same  way 
incompetency  of  the  mitral  valve  or  dilatation  of  the  mitral  orifice,  in  con- 
sequence of  weakness  of  the  cardiac  muscle,  gives  rise  to  a  murmur  which 
lasts  during  the  whole  of  the  ventricular  contraction  and  is  therefore  systolic 
in  character.  Such  a  murmur  is  heard  best  over  the  apex  beat,  and  is  also 
transmitted  backwards  so  that  it  can  be  heard  on  listening  at  the  back  of 
the  patient.  A  narromng  of  the  mitral  orifice  in  consequence  of  contraction 
of  the  valves  will  set  up  a  resistance  to  the  flow  of  blood  from  left  auricle  to 
left  ventricle.  The  auricle  becomes  hypertrophied,  its  contraction  prolonged, 
and  the  escape  of  blood  through  the  contracted  orifices  gives  rise  to  a  murmur 
which  is  heard  on  listening  over  the  apex  beat  as  a  presystolic  bruit.  This 
bruit  is  easily  distinguished  from  a  systolic  murmur  by  noticing  that  it  runs 
up  to  and  ends  with  the  apex  beat,  whereas  a  systolic  murmur  does  not 
begin  until  the  elevation  of  the  apex  commences. 

Several  physiologists  have  succeeded  in  recording  heart  sounds  graphically.  Hiirthle's 
method  consists  in  an  ajjplication  of  the  microphone.  A  special  form  of  stethoscope  is 
so  arranged  that  by  its  means  the  vibrations  corresponding  to  the  heart  sounds  are 
transmitted  to  a  contact  between  silver  and  carbon.  Througli  this  contact  a  strong 
curi'ent  is  passing.  This  also  passes  through  an  electro-magnet,  which  attracts  an  iron 
disc  attached  to  the  membrane  of  a  Marey's  tambour.  Any  vibration  transn)itted  to 
the  carbon-silver  contact  alters  its  resistance,  and  so  the  strength  of  the  current  passing 
through  the  electro-magnet.  In  this  way  the  heart  sounds  can  alfect  tlie  pull  exerted 
by  the  elect ro-magnet  on  tlie  membrane  of  the  tambour,  and  tlie  change  in  the  volume 
of  the  contained  air  is  recorded  by  means  of  an  ordinary  registering  t;>mbour. 

Similar  results  have  been  obtained  by  Einthoven,  who  has  allowed  tlie  variations 
in  the  current  passing  through  the  microphone  to  be  recorded  directly  by  means  of  a 
very  delicate  capillary  or  string  elect  rometer. 


908 


PHYSIOLOGY 


TIME-RELATIONS 

The  time-relations  of  the  various  events  of  the  cardiac  cycle  are  indicated 
in  the  accompanying  diagram  (Fig.  404).  In  man  the  heart  beats  on  the 
average  about  seventy-two  times  in  the  minute,  so  that  each  cardiac  cycle — 
i.e.  systole  flus  diastole — can  be  regarded  as  occupying  0-8  sec.  During 
five-tenths  of  a  second  the  ventricles  are  relaxed  ;  during  the  first  four- tenths 
of  this  period,  which  corresponds  to  the  diastole  of  the  heart  as  a  whole,  blood 
is  flowing  in  a  steady  stream  from  the  veins  through  the  auricles  into  the 
ventricles,  so  that  the  heart  is  gradually  increasing  in  size.     The  systole  of  the 


Blood 
nto 


vent] 
from 


:  lowin| 
aurilcles  and 
icles 
veins. 


Systole 

of 
Aur- 
icles 


Systole 


Diastole. 


01       0  2       0  3       04       0  5       0  6        0  7       08       0  9       10  sees. 


Heajt  Sounds 


— —  aup 

Fig.  404. 


Lubb dup 

Diagram  of  events  constituting  a  cardiac  cycle. 


auricle  then  occurs  and  lasts  about  0*1  sec.  This  is  followed  by  the  ventricu- 
lar systole,  the  immediate  effect  of  which  is  to  close  the  auriculo- ventricular 
valves  on  both  sides  of  the  heart.  The  whole  ventricular  contraction 
lasts  0-3  sec,  ;  during  the  first  period  of  this  the  ventricle  is  getting 
up  pressure,  the  pressure  rapidly  rising  until  it  equals  the  aortic  pres- 
sure. This  period,  during  which  the  ventricle  is  simply  contracting 
isometrically  on  its  contents  without  any  flow  of  blood  occurring,  lasts 
between  -02  and  -04  sec,  and  is,  of  course,  longer  the  higher  the  pressure  in 
the  aorta.  Directly  the  intraventricular  pressure  rises  above  this  point  the 
aortic  valves  open  and  blood  is  driven  into  the  aorta.  The  outflow  of  blood 
continues  throughout  the  whole  of  the  ventricular  systole,  and  may  be  taken 
as  lasting  about  0-2  sec.  The  ventricle  then  suddenly  relaxes,  the  period  of 
relaxation  occupying  about  0-5  sec.  ;  the  '  plateau  '  of  the  endocardiac  pres- 
sure curve  on  the  average  lasts  about  0-18  sec,  and  according  to  the  condition 
of  the  heart  and  the  peripheral  resistance  may  present  a  gradual  ascent  or 
descent.  Directly  relaxation  commences  the  ventricular  pressure  falls 
below  the  aortic  pressure  or  the  puLmonary  pressure  and  the  semilunar  valves 
close,  giving  rise  to  the  second  sound.  Systole  is  now  at  an  end  and  the  dias- 
toHc  period  of  filling  recommences.  The  first  sound  is  synchronous  with 
commencement  of  the  ventricular  contraction,  and  the  same  event  is  signalled 
by  the  occurrence  of  the  apex  beat. 


THE  MECHANISM  OF  THE  HEAET  PUMP       909 

Although,  the  pulse  frequency  may  undergo  considerable  variations 
according  to  the  condition  of  the  individual,  being  higher  during  activity 
or  under  conditions  of  mental  excitement,  the  greater  part  of  the  difference 
in  duration  of  the  cardiac  cycle  thereby  induced  falls  upon  the  diastohc 
period.  Thus  to  take  \vide  limits  the  pulse-rate  may  vary  between  32  and 
124  beats  in  the  minute,  while  under  the  same  circumstances  the  period 
occupied  by  the  systole  only  varies  between  0-382  and  0-190  sec. — and  these, 
of  course,  are  extreme  limits.  Variation  therefore  in  the  time  occupied  by 
each  cardiac  cycle  is  determined  mainly  by  variation  in  the  time  occupied 
by  the  diastole. 

FILLING  OF  THE  HEART  IN  DIASTOLE 
Since  the  heart  is  perfectly  flaccid  during  diastole  it  is  unable  to  exert  any 
suction  force  on  the  blood  in  the  veins.  Its  filling  during  diastole  depends 
on  the  existence  of  a  positive  pressure  within  the  veins,  or  at  any  rate 
of  a  pressure  greater  than  that  in  the  auricles  and  ventricles ;  the  greater 
the  pressure  within  the  large  veins  the  more  rapidly  will  the  blood  enter 
the  heart  during  diastole  and  the  larger  the  amount  of  blood  in  this  viscus 
when  it  begins  its  contraction.  In  this  process  an  important  part  is 
played  by  the  mechanical  conditions  existing  in  the  thoracic  cavity.  Owing 
to  the  elasticity  of  the  lungs  and  the  fact  that  they  are  constantly 
tending  to  contract,  the  pressure  in  the  thorax  is  less  than  that  of  the 
external  atmosphere  by  the  amount  which  is  required  to  distend  the  lungs 
to  fill  the  cavity. 

At  the  end  of  expiration  this  difierence  amounts  to  about  5  mm.  Hg. 
rising  to  9  mm.  Hg.  at  the  end  of  inspiration  and  to  30  mm.  Hg.  at  the  end  of 
a  forced  inspiration.  On  the  other  hand,  the  veins  outside  the  thorax  are 
exposed  to  a  pressure  which  is  a  httle  above  that  of  the  atmosphere.  When 
the  thorax  is  at  rest  the  veins  and  auricles  are  therefore  expanded  and  the 
flow  of  blood  into  them  rendered  more  easy.  The  respiratory  movements, 
by  causing  aji  alternating  suction  on  the  walls  of  the  great  veins,  act  Hke  an 
accessory  pimip  and  cause  an  aspiration  of  blood  into  the  veins  of  the 
thorax  with  each  inspiration. 

It  is  evident  that  if  the  pressure  within  the  thorax  be  sufficiently  raised  so 
as  to  cause  a  positive  pressure  on  the  big  veins  and  auricles,  the  return  flow 
of  blood  to  the  heart  must  come  to  an  end.  Thus  during  extreme  muscular 
efforts  the  glottis  is  fixed  and  a  positive  pressure  is  produced  in  the  thorax. 
The  deficient  circulation  and  the  deficient  aeration  of  the  blood  thereby 
induced  are  showTi  by  the  engorgement  of  the  superficial  veins  and  the  blue- 
ness  of  the  surface.  Weber  showed  that  by  a  forcible  expiration,  with  the 
glottis  closed,  the  pulse  might  disappear  at  the  wrist  and  the  circulation  be 
brought  for  a  time  to  a  standstill,  so  that  even  loss  of  consciousness  might 
supervene. 

Since  the  heart  during  its  systole  diminishes  its  own  volume  by  the  expulsion  of 
blood  from  the  thorax,  it  becomes  smaller,  and  the  space  thus  provided  in  the  chest 
cavity  is  taken  up  by  an  expansion  of  the  veins,  auricles,  and  lungs.     To  this  systolic 


910  PHYSIOLOGY 

diminution  of  intrathoracic  pressure  is  due  the  '  cardiao-pneumalic  '  movements. 
These  are  recorded  by  attaching  one  nostril  to  a  delicate  tambour  by  means  of  a  tube, 
while  the  other  nostril  and  the  mouth  are  kept  closed.  If  a  carotid  pulse  tracing  be 
taken  at  the  same  time  it  will  be  found  that  there  is  a  fall  of  the  lever  attached  to  the 
nasal  cavity  synchronous  with  the  rise  of  the  pressure  in  the  arteries,  due  to  the  expulsion 
of  blood  from  the  heart. 

The  normal  filling  of  the  heart  during  diastole  can  be  prevented  by  any- 
thing which  hinders  its  expansion,  such  as  the  presence  of  fluid  in  the 
pericardial  cavity.  The  same  effect  may  be  produced  experimentally.  If 
oil  be  allowed  to  flow  into  the  pericardium  under  pressure,  when  the  pressure 
of  the  oil  rises  to  about  60  mm.  the  pressure  of  the  vena  cava  rises  to  a  height 
just  above  that  obtaining  in  the  pericardial  cavity.  On  increasing  the 
pressure,  a  point  is  finally  reached  at  which  no  more  blood  can  be  driven 
from  the  veins  to  the  heart,  so  that  the  arterial  blood-pressure  falls  to  zero 
and  death  ensues. 

In  order  to  maintain  the  arterial  pressure  it  is  necessary  that  the  amount 
of  blood  driven  into  the  arterial  system  by  the  contraction  of  the  left  ventricle 
should  be  exactly  equal  to  that  leaving  the  arteries  to  pass  into  the  capillaries 
during  the  period  which  elapses  between  each  systole. 

Over-filHng  of  the  heart  is  prevented  to  a  certain  extent  by  the  resistance 
of  its  walls.  The  danger  of  over-filling  is  therefore  most  marked  in  the  right 
ventricle.  An  important  part  is  played  moreover  by  the  pericardium  in  this 
regard.  Even  when  beating  normally,  the  heart  during  diastole  tends  to 
protrude  through  a  sht  made  in  the  pericardium,  and  Barnard  has  shown 
that  the  right  auriculo-ventricular  valve  ceases  to  be  entirely  efficient 
when  the  pericardium  has  been  freely  opened,  the  closure  of  this  valve  being 
dependent  on  the  support  aflorded  to  the  heart  by  the  pericardium. 

SYSTOLIC  OUTPUT  OF  THE   HEART 

The  amomit  of  blood  which  passes  through  the  whole  body  and  is  avail- 
able for  the  metabolic  exchanges  of  all  the  tissues  depends  on  the  amount  of 
blood  which  leaves  the  heart  each  minute.  The  height  of  the  arterial  pressure 
also  depends  on  the  relation  between  the  amount  of  blood  leaving  the  arterial 
system  by  the  capillaries  and  that  entering  from  the  heart.  The  determina- 
tion of  the  output  of  the  left  ventricle  is  therefore  one  of  the  most  important 
problems  in  physiology.  The  output  of  the  right  ventricle  must  be  equal 
to  that  from  the  left  ventricle,  otherwise  the  blood  would  accumulate  on 
one  or  other  side  of  the  heart  and  bring  the  circulation  to  a  standstill.  It 
is  therefore  immaterial  on  which  side  of  the  heart  the  output  be  determined. 

The  methods  which  have  been  devised  for  determining  the  cardiac 
output  fall  into  two  classes.  In  the  first  class  it  is  sought  to  determine 
the  total  volume  of  blood  leaving  the  right  or  left  ventricle  in  the  course 
of  a  given  time,  say  one  minute.  If  this  amount  be  divided  by  the  number 
of  heart-beats  in  the  same  time,  the  output  of  each  ventricle  per  beat  is  at 
once  obtained.  A  second  method  consists  in  the  determination  of  the 
volume  changes  in  the  ventricles  at  each  beat  of  the  heart.     During  diastole 


THE  MECHANISM  OF  THE  HEART  PITUP 


911 


the  ventricles  are  receiving  blood  and  increase  in  volume,  during  systole 
they  expel  blood  and  therefore  diminish  in  volume.  The  change  in  volume 
at  each  beat  gives  therefore  the  combined  output  of  right  and  left  ventricles 
and  must  be  divided  by  half  in  order  to  give  the  output  of  either  ventricle 
separately. 

METHODS  OF  DETERMINING  OUTPUT.      In  a  method  devised  by  the  author 

it  is  possible  to  deteiuiine  the  output  of  the  left  ventricle  under  all  manner  of  conditions 


Fig.  40.J.     Arrangement  of  apparatus  for  working  on  the  isolated 
mammalian  heart.     (Kxowi.tox  and  Starling.) 

and  to  vary  at  will  the  arterial  resistance,  the  venous  pressure,  the  filling  of  the  heart, 
or  the  tein])erature  of  the  blood-supply  to  the  heart.  The  arrangement  of  the  apparatus 
isshowniuFig.  40.').  Artihcial  respiration  being  maintained,  the  chest  isopencdunder 
an  ansesthetic.  The  arteries  coming  from  the  arch  of  the  aorta — inthecat.the  innomi- 
nate and  the  left  subclavian— are  thenligatured,  thus  cutting  off  the  whole  blood-supply 
to  the  brain,  so  that  the  anaesthetic  can  be  discontinued.  Cannula?  are  placed  in  the  inno- 
minate artery  and  the  superior  vena  cava.  The  cannula;  are  tilled  beforehand  with  a  solu- 
tion of  hiruelin  in  normal  salt  solution  so  as  to  prevent  clotting  of  the  blood  eluring 
the  experiment.  The  descending  aorta  is  closed  by  a  ligature.  The  only  path  left  for 
the  blood  is  by  the  ascending  aorta  and  the  camiula  CA  in  the  innominate  artery. 


912  PHYSIOLOGY 

The  arterial  cannula  communicates  by  a  T-tube  with  a  mercurial  manometer  M'  to 
record  the  mean  arterial  pressure,  and  passes  to  another  T-tube,  v,  one  limb  of  which 
projects  into  a  test-tube  B.  The  air  in  this  test-tube  will  be  compressed  with  a  rise 
of  pressure  and  will  serve  as  a  driving  force  for  the  blood  through  the  resistance.  It 
thus  takes  the  part  of  the  resilient  arterial  wall.  The  other  limb  of  the  T-tube  passes 
to  the  resistance  R.  This  consists  of  a  thin- walled  rubber  tube  {e.g.  a  rubber  finger- 
stall) which  passes  through  a  wide  glass  tube  provided  with  two  lateral  tubulures  w,  w. 
One  of  these  is  connected  with  a  mercurial  manometer  Jf  2  and  the  other  with  an  air 
reservoir  ^,  into  which  air  can  be  pumped  by  the  elastic  bellows  S.  When  air  is  in- 
jected into  the  outer  tube  the  tube  B  collapses,  and  will  remain  collapsed  until  the 
pressure  of  the  blood  within  it  is  equal  or  superior  to  the  pressure  in  the  air  surrounding 
it.  It  is  thus  possible  to  vary  at  will  the  resistance  to  the  outflow  of  the  blood  from 
the  arterial  side.  From  the  peripheral  end  of  B  the  blood  passes  at  a  low  pressure 
and  is  collected  in  a  vessel  N,  which  is  provided  with  a  siphon,  and  can  be  made  of 
such  dimensions  that  the  blood  is  siphoned  oS  as  soon  as  10,  20,  or  30  c.c.  have  collected 
in  the  vessel.  A  lateral  branch  on  the  siphon  tube  leads  by  a  rubber  tube  to  a  tambour 
D.  Every  time  that  siphonage  occurs  there  is  a  change  of  pressure  within  the  tambour 
which  can  be  registered  by  the  lever  on  a  blackened  smrface.  The  siphon  discharges 
the  blood  into  a  reservoir  F,  which  is  kept  immersed  in  a  vessel  of  water  maintained 
at  any  desired  temperature  by  some  source  of  heat.  From  the  spiral  below  F,  an 
india-rubber  tube  leads  to  a  cannula  GV,  which  is  placed  in  the  superior  vena  cava, 
all  the  branches  of  which  have  been  tied.  This  cannula  is  provided  with  a  thermometer 
to  show  the  temperature  of  the  blood  supplied  to  the  heart.  A  tube  placed  in  the 
inferior  vena  cava  and  coimected  with  a  water  manometer  shows  the  pressure  in  the 
right  auricle.  On  the  recording  surface  we  thus  have  a  record  of  the  arterial  pressure, 
of  the  output  of  the  whole  system,  as  recorded  by  the  tambour,  and  of  the  pressure 
within  the  right  auricle.  If  desired  the  simple  cm^rent  measurer  described  on  p.  888 
can  be  inserted  in  the  arterial  circuit  at  X,  so  as  to  give  immediately  the  output  of  the 
left  ventricle. 

This  method,  although  of  considerable  importance  in  giving  information  as  to  the 
conditions  which  determine  the  output  of  the  left  ventricle  and  the  maximum 
capacity  of  the  heart  as  a  pump,  tells  us  nothing  as  to  the  output  of  the  left  ventricle 
under  normal  conditions  in  the  intact  animal.  For  this  purpose  some  indirect  means 
must  be  adopted  which  can  be  used  on  the  intact  animal  and  if  possible  on  man  him- 
self, so  that  the  output  can  be  measured  under  different  conditions  of  rest  and  activity. 
Moreover,  the  output  as  measured  on  the  other  side  of  the  artificial  arterial  resistance 
represents  the  ventricular  output  minus  the  blood  flow  through  the  coronary  arteries. 
It  is  possible,  however,  to  insert  a  cannula  into  the  coronary  sinus,  and  so  to  measure 
the  blood-flow  through  the  heart  muscle.  The  coronary  circulation  must  be  added 
to  the  flow  through  the  arterial  resistance  in  order  to  arrive  at  the  correct  total  output 
of  the  left  ventricle.  The  two  chief  methods  for  the  determination  of  the  ventricular 
output  in  the  intact  animal  are  those  of  Zuntz  and  of  Krogh. 

ZUNTZ'S  METHOD.  This  is  based  on  a  comparison  of  the  differences  in  gases 
contained  in  the  arterial  and  venous  blood  and  the  actual  amount  of  oxygen  taken 
from  the  air  in  the  lungs.  Thus  in  one  case  he  found  that  in  a  horse  weighing 
.360  kilos  2733  c.c.  of  oxygen  were  taken  up  in  he  lungs  per  minute,  while  the  arterial 
blood  contained  10-33  per  cent,  more  oxygen  than  the  venous  blood.  Since  therefore 
every  100  c.c.  of  blood  that  passed  through  the  lungs  had  taken  up  10-33  c.c.  of 
oxygen,  and  2733  c.c.  had  been  taken  up  in  the  coiirse  of  a  minute,  it  is  evident  that 

100  X  2733 

10-33       =^M57c.c. 

of  blood  must  have  passed  through  the  lungs  in  the  time.  This  therefore  was  the  output 
of  blood  by  the  right  ventricle  in  a  minute  and  was  equivalent  to  -00122  of  the  body- 
weight  per  second. 

In  a  similar  experiment  on  a  dog  the  output  per  second  of  the  right  ventricle  was 
found  to  be  -00157  of  the  body-weight.     In  order  to  get  the  output  at  each  beat  it  will 


THE  MECHANISM  OF  THE  HEAET  PUMP       913 

be  necessary  to  divide  the  output  per  minute  by  the  number  of  heart-beats  in  the  same 
time.  From  the  results  of  determinations  made  in  this  way  Zuntz  concluded  that  the 
output  of  the  right  ventricle  in  man  at  each  beat  varies  between  50  and  100  c.c.  and 
may  be  taken  on  an  average  at  60  c.c. 

KROGH'S  METHOD.  In  Krogh's  method  an  endeavour  is  made  to  determine 
the  volume  of  blood  flowing  tlirough  the  lungs  in  a  given  time  by  determining  how 
much  nitrous  oxide  is  taken  up  from  a  mixtmre  of  nitrous  oxide  and  air,  with  which 
the  lungs  are  filled.  Nitrous  oxide  is  chosen  because  it  can  be  breathed  in  considerable 
proportions  without  injury,  and  is  itself  very  soluble  in  water  or  in  the  blood.  The 
estimation  is  carried  out  in  the  following  way.  A  small  recording  spirometer  is  filled 
with  about  4^  litres  of  a  gas  mixture  containing  10  to  25  per  cent.  N2O  and  20  to  25 
per  cent,  oxygen.  The  subject,  seated  in  a  chair  or  on  a  bicycle  ergometer,  expires  to 
the  greatest  possible  extent,  and  then  takes  a  deep  inspiration  from  the  spirometer. 
He  holds  his  breath  for  five  to  fifteen  seconds,  breathes  out  sharply  into  the  spirometer, 


4-10  , 


2-24 


28-/ sec 


Fig.  406.      (Krogh,) 

expiring  at  least  one  litre.  At  the  end  of  this  sharp  expiration,  a  sample  of  his  alveolar 
air  is  taken  by  comiecting  the  tube  from  his  face-piece  with  an  evacuated  glass  bulb, 
as  in  Haldane's  method  of  determining  alveolar  air.  The  breath  is  now  held  for  a 
period,  time  varying  between  six  and  twenty-five  seconds.  He  then  makes  a  final  sharp 
ample  expiration  into  the  spirometer,  a  sample  of  his  alveolar  air  being  taken  at  the 
end  of  this  expiration.  The  excursions  of  the  spirometer  indicate  exactly  what  volume 
of  air  he  has  breathed  in  and  breathed  out  at  each  part  of  the  experiment.  These  are 
recorded  on  a  travelling  siu-face,  so  that  the  duration  of  the  experiment  is  represented 
by  the  horizontal  distance  between  the  lines  showing  the  moments  of  sampling 
(Fig.  406). 

By  comparison  of  the  composition  of  ordinary  alveolar  air  with  the  alveolar  air  ob- 
tained after  the  first  sharp  expiration,  the  amount  of  residual  alveolar  air  is  determined, 
so  that  the  total  volume  of  gas  contained  in  the  lungs  at  each  part  of  the  experiment 
is  also  kno%vn.  Diu'ing  the  time  when  the  breath  is  being  held,  nitrous  oxide  is  being 
taken  up  in  solution  by  the  blood  as  it  passes  through  the  lungs,  its  solubility  being  such 
that  1  c.c.  of  blood,  if  exposed  to  an  atmosphere  of  pvu-e  nitrous  oxide  will  take  up 
0-43  c.c.  of  this  gas.  From  the  data  obtained  in  this  way,  the  amoimt'of  blood  passing 
through  the  limgs  diu'ing  the  period  between  the  two  expirations  can  be  calculated.  The 
following  record  of  one  experiment  may  serve  as  an  example.  The  volume  of  air  in 
the  lungs  at  the  begiiuiing  of  the  experiment  was  3 "25  litres  and  contained  12  per  cent, 
nitrous  oxide,  so  that  the  total  quantity  of  nitrous  oxide  in  the  air  of  the  lungs  was 
3250  c.c.  X  -^jfjj  =  390  c.c.  At  the  end  of  the  period  the  total  volume  of  air  in  tlie 
lungs  was  three  litres,  containing  only  10  per  cent,  nitrous  oxide,  so  that  the  lungs 
now  contained  only  300  c.c.  nitrous  oxide,  90  c.c.  nitrous  oxide  having  been  taken  up 
by  the  blood.     This  90  c.c.  was  taken  up  from  an  air  in  which  the  mean  pressure  of 

this  gas  was =  11  per  cent.     During  the  period  of  observation,  from  a  gas 

containing  at  atmospheric  pressure  11  per  cent,  of  nitrous  oxide,  each  c.c.  of  blood 

will  take  up  =  0-047  c.c.     In  order  to  take  up  90  c.c.  therefore  1-9  litres  of 

^        100 

blood  must  have  passed  through  the  lungs  during  the  time  of  the  observation.     The 


914 


PHYSIOLOGY 


experiment  lasted  twenty-eight  seconds.  The  amount  of  blood  passing  through  the 
lungs  per  minute  was  therefore  4-2  litres.  This  figure  represents  the  output  from  the 
right  ventricle  during  one  mimite,  and  if  the  pulse  rate  is  70  per  minute,  the  output 

per  beat  will  be  — — ^~  =  60  c.c.  per  beat.  The  figure  arrived  at  in  this  way  for  the 
^  70 

average  output  of  each  ventricle  in  man  during  rest,  thus  agrees  with  the  figure  obtained 
by  Zuntz.     The  output  of  both  ventricles  is,  of  course,  the  same. 

According  to  Krogh,  the  ventricular  output  per  minute  in  man  may  vary  from  2-8 
litres  to  21  litres  of  blood  per  minute.  The  latter  is  an  extreme  figure  and  was  obtained 
in  a  powerful  athelete  doing  hard  work.  In  the  case  of  Krogh  himself,  the  maximum 
output  was  about  12  litres  per  minute.  It  is  interesting  to  note  that  the  same  perform- 
ance may  be  obtained  from  a  dog's  heart  in  the  heart-lrmg  preparation,  allowing  for 
the  difference  in  size  between  the  hearts  of  the  dog  and  man  respectively. 

CARDIOMETRIC  METHOD,  Of  the  various  methods  which  have  been  devised  for 
recording  plethysmographically  the  changes  in  the  volume  of  the  heart  at  each  beat  (as 
first  carried  out  by  Roy),  the  simplest  is  that  devised  by  Henderson.  The  chest  and 
pericardium  being  opened,  a  glass  cardiometer,  of  the  shape  shown  in  Fig.  407,  is  slipped 


Fig.  407.     Henderson's  glass  cardiometer. 

over  the  heart.  This  cardiometer  consists  of  a  glass  sphere  with  a  wide  opening.  To 
the  margin  of  the  opening  is  tied  a  rubber  diaphragm  with  a  hole  in  it  which  accurately 
fits  the  heart  as  it  lies  in  the  auriculo-ventricular  groove.  The  tube  of  the  cardiometer  is 
connected  with  some  form  of  piston  recorder  or  a  tambour  with  a  slack  membrane. 
The  disadvantage  of  this  method  is  that  the  graphic  record  of  rapid  and  ample  changes 
in  volume  is  one  of  the  most  difficult  problems  in  experimental  physiology,  the  inertia 
and  friction  of  the  moving  piston  tending  to  deform  the  shape  of  the  ciu've  obtained. 
Straub  has  therefore  used  a  soap  bubble  as  the  volume  measurer,  photographing  its 
edge  and  using  the  record  as  an  index  to  the  change  in  volume.  It  is  possible,  how- 
ever, to  obtain  a  pistol  recorder  moving  sufficiently  freely  to  give  a  fairly  correct  re- 
production of  the  volume  changes  of  the  heart,  provided  that  these  do  not  occur  with 
too  great  rapidity.  It  has  been  suggested  by  Piper  to  convert  the  volume  changes 
into  small  pressure  changes,  and  to  record  these  latter  by  one  of  the  methods  described 
above. 

The  factors  which  determine  the  output  of  the  left  ventricle  are  best 
studied  in  the  heart  lung  preparation.  In  this  it  can  be  shown  that,  pro- 
vided the  venous  inflow  remains  constant,  the  output  is  also  constant  and 
is  unaffected  by  considerable  alterations  of  arterial  resistance  and  of  the 
rate  of  the  heart.  Thus  with  a  moderate  venous  inflow  the  output  remains 
constant  whether  we  maintain  the  average  arterial  pressure  at  60  mm.  Hg. 
or  at  160  mm.  Hg.  It  is  also  unaffected  by  altering  the  rate  of  the  heart 
from  80  beats  per  minute  up  to  160,  or  even  200,  beats  per  minute.     On 


THE  MECHANISM  OF  THE  HEART  PUMP       9lb 

the  other  hand,  the  output  is  at  once  altered  by  alterations  in  the  venous 
inflow  and,  as  already  stated,  can  be  altered  in  a  heart  weighing  50  gnis. 
from  a  few  c.c.  up  to  3000  c.c.  per  minute.  The  only  essential  in  this 
preparation  is  that  the  output  from  the  left  ventricle  shall  be  sufficient 
to  maintain  a  circulation  through  the  coronary  vessels  and  so  keep  the  active 
muscle  properly  supplied  with  blood. 

With  increasing  inflow  of  blood  into  the  heart  the  large  veins,  auricles, 
and  ventricles  naturally  become  more  filled  during  diastole,  and  during 
systole  of  the  ventricles,  when  the  auriculo- ventricular  valves  are  closed, 
the  blood  rushing  in  from  the  venous  system  must  accumulate  in  the  big 
veins  and  auricles  to  a  still  greater  extent.  The  venous  pressure  therefore 
rises  with  increased  venous  inflow.  In  so  far  then  as  venous  pressm'e  is 
an  index  of  venous  inflow,  we  may  say  that  the  output  of  the  heart  increases 
with,  the  venous  pressure  so  long  as  the  heart  is  functionally  capable  of 
deahng  with  the  blood  it  receives  during  diastole.  But  although  the 
ventricular  output  is  practically  independent  of  the  frequency  of  the  heart- 
beat and  a  constant  venous  inflow,  the  venous  pressure  tends  to  fall  as 
the  heart-beat  increases  in  rate.  The  optimum  venous  pressm'e  is  that 
which  fills  the  ventricle  during  its  diastole  to  the  maximum  extent  to 
which  it  is  able  to  respond.  As  the  rate  of  the  heart  increases  the  inflow 
of  blood  can  also  be  increased  without  causing  over  distension  of  the 
ventricles.  The  increase  of  heart  rate  therefore  is  an  important  factor 
in  enabling  this  organ  to  deal  with  the  maximum  amomit  of  blood.  Although 
increase  of  rate  does  not  alter  the  output  with  constant  venous  inflow,  it 
does  increase  the  maximum  amount  of  infloAving  blood  which  the  heart  is 
able  to  expel. 

We  thus  see  that  alterations  iu  the  vigour  of  the  circulation  depend  in 
the  first  instance  on  the  venous  circulation.  The  greater  the  volume  of  the 
blood  that  is  brought  up. to  the  heart  by  the  accessory  factors  of  the  cir- 
culation, the  greater  ^^•ill  be  the  output  of  this  organ.  The  changes  in  rate 
and  force  of  the  heart  which  accompany  its  increased  activity  and  increased 
output,  e.g.  during  exercise,  represent  merely  the  means  by  which  this  organ 
is  able  to  deal  in  the  most  advantageous  manner  with  the  increased  inflow. 

THE  WORK  OF  THE  HEART 
The  energy  of  the  ventricular  contraction  is  expended  in  two  ways  : 
first,  in  forcing  a  certain  amount  of  blood  into  the  already  distended 
aorta  against  the  resistance  presented  by  the  arterial  blood-pressure,  which 
itself  is  directly  conditioned  by  the  resistance  in  arterioles  and  capillaries  ; 
and  secondly,  in  imparting  a  certain  velocity  to  the  mass  of  blood  so  thrown 
out.  Thus  the  energy  of  the  muscular  contraction  is  converted  partly 
into  potential  energy  in  the  form  of  increased  distension  of  the  arterial  wall 
and  partly  into  the  kinetic  energy  represented  by  the  momentum  of  the 
moving  column  of  blood.  The  work  done  at  each  beat  may  be  calculated 
from  the  formula  :  ^j., 

W  =  QR  +  -j- 

-!7 


916  PHYSIOLOGY 

where  W  stands  for  work,  w  for  the  weight,  and  Q  for  the  quantity  (volume 
in  c.c.)  of  blood  expelled  at  each  contraction ;  E  is  the  average  arterial 
resistance  or  pressure  during  the  outflow  of  blood  from  the  heart,  and  V  is 
the  velocity  of  the  blood  at  the  root  of  the  aorta.     In  this  equation  QR.  is 

the  work  done  in  overcoming  the  resistance,*  and  — —  is  the  energy  expended 

in  imparting  a  certain  velocity  to  the  blood. 

If  we  take  60  c.c,  as  the  average  output  of  each  ventricle,  100  mm.  Hg. 
as  the  average  pressure  at  the  beginning  of  the  aorta,  and  500  mm.  per 
second  as  the  velocity  imparted  to  the  blood  thrown  into  the  aorta,  we  can 
calculate  the  work  done  by  the  human  heart  at  each  beat. 

QR  =  60  X  0-100 m.  X  13- 6  =  81  •  6  grammetres, 

or  roughly  80  grammetres.     On  the  other  hand,  the  expression 

wY-^      60  X  (0-5)2 


2g  2  X  9-8 


=  0*7  grammetres. 


It  is  evident  that  this  latter  factor  is  neghgible,  and  that  for  all  practical 
purposes  we  may  regard  the  work  of  the  heart  as  proportional  to  the  output 
multiphed  by  the  average  arterial  blood-pressure.  Taking  the  average 
pressure  in  the  pulmonary  artery  at  20  mm.  Hg.,  the  work  of  the  right 
ventricle  at  each  beat  would  amoimt  to  about  16  grammetres,  a  total  for 
the  two  ventricles  of  about  100  grammetres  per  beat,  which  is  equivalent 
to  about  10,000  kilogram  metres  in  twenty- four  hours  for  a  man  at  rest. 

This  work  is  done  by  a  contraction  of  the  muscle  fibres  surrounding  the  cavities 
of  the  ventricles.  It  is  important  to  remember  that  the  strain  or  tension  which  is 
thrown  on  these  fibres  and  which  resists  their  contraction  will  simply  be  determined  not 
by  the  blood-pressure  which  has  to  be  overcome,  but  also  by  the  size  of  the  ventricle 
cavities.  Since  the  pressure  in  a  fluid  acts  in  all  directions,  the  tension  caused  by  any 
given  pressure  on  the  walls  of  a  hollow  vessel  will  increase  with  the  diameter  of  the 
vessel.  Thus  if  we  take  a  sphere  with  a  radius  of  10  cm.  filled  with  fluid  at  a  pressure 
of  10  cm.  Hg.  there  will  be  a  pressure  on  each  square  centimetre  of  the  inner  surface 
of  the  sphere  of  136  grm.  The  total  distending  force,  i.e.  the  pressure  on  the  whole 
of  the  inner  wall  of  the  sphere,  will  be  equal  to  this  pressure  multiplied  by  the  area, 
i.e.  to  136  X  477^2  =  136  X  47r  X  100.  If  by  a  contraction  of  the  walls  the  radius  be 
reduced  to  5  cm.,  the  total  pressure  on  the  internal  surface  will  be  reduced  to 
136  X  47r  X  25,  i.e.  will  be  one  quarter  of  the  previous  amount.  Moreover  in  the  case 
of  the  heart,  with  increasing  distension  the  wall  becomes  thinner  and  the  number  of 
muscle  fibres  in  a  given  area  fewer,  so  that  the  larger  the  heart  the  more  strongly  will 
each  fibre  have  to  contract  in  order  to  produce  a  given  tension  in  the  contained  fluid. 
At  the  beginning  of  systole  the  distended  heart  must  therefore  contract  more  strongly 
than  at  the  end  of  the  systole,  in  order  to  raise  the  blood  it  contains  to  a  pressure 
sufficient  to  overcome  that  in  the  aorta. 


*  This  expression,  QR,  is  only  approximately  correct.  Supposing  the  pressvire  in 
the  aorta  at  the  beginning  of  systole  is  50  mm.  Hg.  and  at  the  end  of  systole  150  mm., 
the  work  could  not  be  deduced  accurately  from  the  average  pressure,  but  would  need  a 
simple  application  of  the  integral  calculus  for  its  determination.  The  expression 
employed  above  deviates  from  the  real  value  only  by  about  10  per  cent.,  and  is  therefore 
sufficiently  accurate  for  our  purpose. 


THE  MECHANISM  OF  THE  HEAET  PUMP       917 

It  is  evident  that  an  unrestricted  diastolic  filling  of  the  heart  is  not  of 
unqualified  advantage  to  this  organ.  If  during  diastole  the  heart  be  too 
forcibly  distended,  as  may  easily  occur  after  opening  the  pericardium,  or 
in  cases  of  enfeeblement  of  the  heart's  action  by  chloroform  poisoning  or 
otherwise,  the  muscle  fibres  of  the  heart  may  be  quite  unable  to  contract 
against  the  distending  force  represented  by  a  pressure  in  the  heart  equal 
to  that  in  the  aorta.  Under  such  conditions  we  may  have  sudden  heart 
failure,  which  can  only  be  reUeved  by  diminishing  the  diastolic  distension, 
as,  e.g.,  by  letting  blood  from  the  veins  opening  into  the  heart. 


SECTION  V 
THE  FLOW  OF  BLOOD  THROUGH  THE  ARTERIES 

THE  PULSE.  Owing  to  the  elasticity  and  distensibility  of  the  arterial  wall 
the  rhythmic  rise  of  pressure  corresponding  to  each  heart-beat  causes  an 
expansion,  which  can  be  felt  by  the  finger  placed  on  any  exposed  artery, 
such  as  the  radial,  and  is  spoken  of  as  the  pulse.  Just  as  the  blood-pressure 
diminishes  from  heart  to  periphery,  so  the  amplitude  of  the  pulse  decreases 
as  we  go  farther  away  from  the  heart. 

If  the  arterial  system  were  perfectly  rigid  the  increased  pressure  due 
to  the  forcing  of  the  blood  into  the  arterial  system  at  each  ventricular 
systole  would  occur  practically  simultaneously  at  every  point.  The  arteries 
are,  however,  elastic  and  distensible,  so  that  the  first  effect  of  the  flow  of 
blood  into  the  aorta  is  to  distend  the  section  of  the  aorta  nearest  to  the 
heart.  The  elastic  reaction  of  this  forces  a  portion  of  the  blood  into  the 
nearest  section,  so  that  the  increased  pressure  is  transmitted  from  segment 
to  segment  of  the  arteries  in  the  form  of  a  wave  at  the  velocity  of  about 
seven  metres  per  second. 

It  is  important  not  to  confuse  the  velocity  of  the  pulse- wave  with  that 
of  the  blood-flow ;  the  latter  is  never  greater  than  0-5  metre  per  second, 
and  is  very  much  less  than  this  in  the  smaller  arteries.  Perhaps  the  differ- 
ence between  the  two  quantities  may  be  made  clearer  by  illustration  : 
If  the  hindmost  of  a  row  of  billiard-balls  be  struck  sharply  with  a  cue  the 
foremost  ball  flies  off  and  the  others  stop  still ;  in  this  case  the  energy 
imparted  to  the  first  ball  by  the  stroke  has  been  transmitted  from  ball  to 
ball,  just  as  the  effect  of  the  ventricular  contraction  is  transmitted  from 
section  to  section  of  the  arterial  blood- stream.  If  the  balls  are  struck  so 
that  the  cue  continues  pressing  on  the  hindmost  after  the  stroke  is  delivered, 
the  front  ball  flies  off,  while  the  others  move  slowly  along  in  the  direction 
of  the  stroke.  In  the  arteries  this  continuous  pressure  is  furnished  by 
the  elastic  reaction  of  the  arterial  wall,  and  we  see  how  the  impact  of  the 
blood  may  travel  quickly  as  a  wave  of  increased  pressure  while  the  blood 
itself  is  moving  slowly  along,  impelled  by  the  reaction  of  the  arterial  wall. 

If  we  imagine  a  rigid  tube  ab  (Fig.  408)  provided  with  a  piston  at  the 
end  A,  and  filled  with  an  incompressible  fluid,  an  inward  movement  of  the 
piston  at  a  will  cause  a  simultaneous  outflow  of  fluid  at  the  end  b.  If  the 
end  B  is  closed  the  piston  at  A  cannot  be  moved  at  all.  Pressure  applied 
to  the  piston  will  raise  the  pressure  simultaneously  at  all  points  in  the 

918 


FLOW  OF  BLOOD  THROUGH  THE  ARTERIES 


919 


tube  AB.  The  increased  pressure  applied  at  a  is  therefore  transmitted 
with  practically  no  loss  of  time  to  all  parts  of  the  tube  ab.  This  immediate 
spread  of  the  wave  of  pressure  only  applies  to  an  incompressible  fluid 
within  a  rigid  tube.  If  the  fluid  were  compressible,  if  it  consisted,  €.(j.  of 
air,  a  sudden  movement  inwards  of  the  piston  at  a  would  not  be  felt  imme- 
diately at  B.  The  propagation  of  the  wave  of  pressure  from  a  to  b  would 
take  a  finite  period  of  time,  its  velocity  being  identical  with  that  of  the 
velocity  of  propagation  of  a  wave  of  sound  in  air,  i.e.  1100  feet  per  second. 


B 


Fig.  408. 


The  same  retarding  effect  will  be  produced  if  we  have  an  incompressible 
fluid  within  a  tube  whose  wall  is  distensible  and  elastic.  If  we  imagine 
(Fig.  409)  an  elastic  tube  bc  filled  and  distended  with  water  and  connected 
at  B  to  a  rigid  tube,  which  is  provided  with  a  piston,  the  first  effect  of  a 
rapid  movement  of  fluid  driven  in  by  the  piston  ^^dll  be  a  rise  of  pressure 
at  the  point  immediately  in  front  of  the  piston,  viz.  at  a.  The  wall  being 
distensible,  and  pressure  being  propagated  along  the  fluid  in  every  direction, 
the  rise  of  pressure  at  a  will  be  spent  partly  on  the  particles  of  fluid  in 


Fig.  409. 

front  of  it,  viz.  at  h,  but  also  on  the  walls  of  the  tube,  so  that  this  is  stretched 
and  the  cross-section  of  the  tube  enlarged.  The  distended  segment  at  a 
will  then  exert  a  pressure  on  the  contained  fluid,  driving  this  backwards 
and  forwards.  The  fluid  on  its  side  towards  the  piston  ^^^ll  tend  to  come 
to  a  stop,  while  that  towards  the  distal  end  of  the  tube  will  be  accelerated. 
The  distended  wall  therefore  returns  to  its  original  diameter,  and  the  next 
segment  at  h  is  stretched  in  its  turn,  so  that  a  wave  of  increased  pressure 
is  propagated  along  the  tube  in  the  direction  of  the  arrow. 

The  velocity  ^\^th  which  this  wave  is  propagated  depends  on  the  density 
of  the  fluid,  i.e.  its  inertia,  and  on  the  resistance  of  the  walls  of  the  tube 
to  distension,  since  this  will  determine  the  rapidity  of  its  recovery.  The 
velocity  of  propagation  of  the  wave  of  increased  pressure,  or  the  wave  of 
expansion  of  the  artery,  is  expressed  by  the  following  formula  : 


v  =  k\ 


gea 


920 


PHYSIOLOGY 


where  v  is  the  velocity  per  second, 

g,  the  acceleration  due  to  gravity, 
e,  the  elastic  coefficient  of  the  wall, 
a,  the  thickness  of  the  wall, 
d,  the  diameter  of  the  tube, 
D,  the  density  of  the  fluid, 
k,  a  constant. 


5ovWAAAAnAiA/V/\/\/\A/\  A 


Fig.  410.  Pulse-curves  described  by  a  series  of  sphygmographic  levers  placed 
at  intervals  of  20  cm.  from  each  other  along  an  elastic  tube,  into  which  fluid  is 
forced  by  the  sudden  stroke  of  a  pump.  The  pulse- valve  is  travelling  from 
left  to  right,  as  indicated  by  the  arrows  over  the  primary  (a)  and  secondary 
(6,  c)  pulse-waves.  The  dotted  vertical  lines  drawn  from  the  summit  of  the 
several  primary  waves  to  the  tuning-fork  curve  below,  each  complete  vibration 
of  which  occupies  tjV  sec,  allow  the  time  to  be  measured  which  is  taken  up  by  the 
wave  in  passing  along  20  cm.  of  the  tubing.  The  waves  (a')  are  waves  reflected 
from  the  closed  distal  end  of  the  tubing ;  this  is  indicated  by  the  direction  of 
the  arrows.  It  will  be  observed  that  in  the  more  distant  lever  (vi)  the  reflected 
wave,  having  but  a  slight  distance  to  travel,  becomes  fused  with  the  primary 
wave,  so  that  the  rise  of  pressure  in  VI  is  actually  greater  than  that  in  V. 
(From  Foster,  after  Marey.) 

If  the  end  c  of  the  tube  is  closed,   the  wave  of  a  positive  pressure  on 
arriving  at  B  will  be  reflected  back  as  a  positive  reflected  wave.      If  a 


Fig.  411. 


FLOW  OF  BLOOD  THROUGH  THE  ARTERIES  921 

tracing  be  taken  of  the  oscillations  or  variations  of  pressure  in  the  tube, 
two  waves  at  least  are  seen,  one  of  which  is  the  primary  wave  due  to  the 
movement  of  fluid  caused  by  the  piston  ;  the  other  is  the  secondary  wave 
reflected  back  from  the  periphery.  The  fact  that  the  secondary  wave  is 
a  reflected  one  is  shown  by  the  fact  that  the  nearer  to  the  peripheral  resist- 
ance the  pulse  is  recorded,  the  nearer  is  the  secondary  to  the  primary  wave, 
as  is  seen  in  Fig.  410. 

If  the  tube  bc  be  widely  opened  a  reflected  wave  is  also  observed,  but 
this  time  of  reversed  sign,  i.e.  the  wave  is  one  of  negative  pressure.  The 
production  of  this  wave  is 
dependent  on  the  momentum 
of  the  moving  column  of  fluid. 
If  in  the  tube  ab,  with  a  tap 
at  c  and  a  manometer  m 
(Fig.  411),  the  current  of  fluid 
be  suddenly  checked  by  turn- 
ing the  tap  c,  the  column  in      

front  of   the    tap,  having    a      

certain  momentum,  will  tend  ^ 
to  go  on  moving  and  therefore 
produce  a  suction  or  negative  pressure  behind  it.  When  a  wave  of  positive 
pressure  arrives  at  the  open  end  of  a  tube  there  is  a  sudden  increase  in 
the  velocity  of  output,  and  the  momentum  of  the  mass  of  fluid  which  is 
thrown  out  causes  a  similar  suction  or  negative  pressure,  which  travels  back 
the  whole  length  of  the  tube.  If  the  end  of  the  tube  is  only  partially 
closed,  every  primary  positive  wave  will  be  transformed  into  a  reflected 
one  which  is  partly  positive  and  partly  negative.  Since  both  these 
reflected  waves  travel  through  the  tube  with  the  same  velocity  and  will 
mutually  interfere,  the  result  may  be  either  a  positive  or  a  negative 
wave  or  nothing  at  all,  according  to  the  degree  of  constriction. 

In  a  branching  system  of  tubes,  such  as  the  arterial  system,  reflection 
of  waves  must  take  place  at  every  dividing  place.  All  the  conditions  for 
the  origin  of  reflected  waves  and  interference  of  such  waves  are  present 
in  the  arterial  system.  It  is  impossible  a  'priori,  however,  to  say  whether 
any  reflected  wave  will  form  a  marked  feature  on  the  pulse-tracing.  It  is 
possible  that  the  multitudinous  reflections  which  must  occur  in  every  part 
of  the  arterial  system  may  interfere  with  one  another  to  such  an  extent  that 
they  mutually  annul  each  other.  The  origin  of  any  secondary  wave  in 
the  pulse-tracing  must  therefore  be  determined  by  experiment. 

To  study  the  pulse  more  fully  it  is  necessary  to  obtain  a  graphic  record 
of  the  expansion  of  the  arteries,  or,  what  comes  to  the  same  thing,  of  the 
exact  changes  in  pressure  which  produce  this  expansion.  The  curve 
obtained  with  the  mercurial  manometer  shows  elevations  corresponding 
to  the  pulse  ;  but  the  instrument  is  far  too  sluggish  to  record  the  finer 
variations  of  pressure.  For  this  purpose  a  manometer  which  has  very 
little  inertia,  such  as  Hiirthle's  or  Piper's,  must  be  used.     The  expansion 


922 


PHYSIOLOGY 


of  the  artery  is  registered  by  means  of  a  lever,  which  may  be  made  to  rest 
more  or  less  heavily  upon  the  artery,  and  the  movements  of  which  are 
recorded  on  a  blackened  surface.  Such  an  instrument  is  called  a  sphygmo- 
graph.  Of  the  many  forms  of  sphymographs,  Marey's  or  Dudgeon's  is 
perhaps  the  most  convenient  for  chnical  purposes. 

The  principle  of  Marey's  sphygmograph  is  shown  in  Fig.  412.  The  button  b  is 
adjusted  so  as  to  press  on  the  radial  artery.  Its  movements  are  transmitted  to  a  lever 
m.     The  screw  on  this  works  on  a  small  cogged  wheel  at  o,  which  is  also  the  axis  of  the 


Fig.  412. 

writing  lever  I.  The  movements  of  the  button  b  thus  transmitted  to  a  point  near  the 
axis  of  I  are  reproduced  by  this  lever  highly  magnified,  and  as  such  are  recorded  on  a 
blackened  surface.     The  pressure  on  the  artery  can  be  adjusted  by  means  of  a  screw. 

Dudgeon's  sphygmograph  (Fig.  413)  is  rather  easier  to  use  than  Marey's,  and  is 
therefore  largely  employed  for  clinical  purposes.  It  is  provided  with  a  dial  by  which 
the  pressure  on  the  artery  can  be  graduated,  and  has  a  small  clockwork  arrangement 
for  moving  along  the  slip  of  smoked  paper  on  which  the  records  are  taken.     The 


Fig.   413.     Dudgeon's  sphygmograph,  showing  its  mode  of  application  to 

the  radial  artery. 

arrangement  of  the  levers  in  this  form  of  sphygmograph  is  shown  in  Fig.  414,  where  F 
is  the  (adjustable)  spring  bearing  by  its  button  p  on  the  artery.  The  up-and-down 
movements  of  p  are  transmitted  to  s,  being  much  magnified  and  converted  into  side- 
to-side  movements.  The  point  of  s  rests  on  the  blackened  surface  represented  in  section 
at  A,  and  scratches  on  this,  when  moving,  a  magnified  record  of  the  expansion  of  the 
artery  under  the  knob  p. 

In  all  these  sphygmographs,  even  the  most  perfect,  the  moving  parts  have  a  con- 
siderable amount  of  inertia,  so  that  the  curve  they  give  is  always  more  or  less  deformed. 
This  fact  must  be  borne  in  mind  when  comparing  the  pulse-curves  obtained  by  means 
of  a  sphygmograph  with  those  given  by  the  more  perfect  forms  of  manometer,  such  as 
Frank's  or  Piper's. 


FLOW  OF  BLOOD  THROUGH  THE  ARTERIES  923 

Either  form  of  sphygmograph  is  generally  applied  to  the  radial  artery, 
since  this  is  near  the  surface  and  is  supported  by  bone,  and  the  arm  is  well 
adapted  for  the  application  of  the  sphymograph.  The  pulse-curve  obtained 
by  means  of  a  sphymograph  varies  according  to  the  artery  employed  and 
the  force  with  which  the  lever  presses  on  the  artery,  but  all  the  curves 
present  the  same  general  features. 

The  velocity  of  the  pulse  can  be  measured  by  taking  simultaneous 
tracings  from  two  arteries  separated  by  some  distance  from  one  another, 
such,  as  the  femoral  artery  and  the  dorsalis  'pedis,  or  from  the  carotid  and 
radial  arteries.  In  a  healthy  individual 
the  velocity  varies  between  7  and  10 
metres  per  second.      The  more  rigid 
the  arteries  the  greater  will  be  the 
velocity,    so    that    the     velocity    of 
propagation  gradually  increases  wth 
advancing  age,  and  is  higher  in  the 
arteries     of    the     lower     extremities 
than  in  the  more  distensible  arteries 
of  the  arm. 

The  length  of  the  pulse-wave  can 
be  found  by  multiplying  the  velocity 
of  transmission  by  the  time  occupied 
by  the  wave  in  passing  any  given 
point.  The  duration  of  the  wave  at 
any  point  corresponds  to  the  time 
of  a  cardiac  cycle,  viz.  0-8  sec,  so 
that  if  the  velocity  of  transmission 
be  taken  as  7  metres  per  second,  the 
length  of  the  wave  is  about  5-6  metres. 

The  pulse-wave  thus  reaches  the  periphery  long  before  it  has  been  com- 
pleted in  the  aorta.  Fig.  415  represents  a  pulse-curve  taken  from  the  radial 
artery.  The  elevation  due  to  the  expansion  of  the  artery  is  rapid  and 
uninterrupted.  We  have  alreadv  explained  that  this  is  due  to  the  sudden 
pumping  of  blood  into  the  first  part  of  the  aorta,  whence  the  impulse  is 
transmitted  as  a  wave  along  the  arteries.  The  curve  descends  gradually 
till  the  next  beat  occurs,  since  the  elastic  reaction  of  the  arteries,  which 
tends  to  keep  up  the  pressure,  acts  more  constantly  and  steadily  than  the 
heart-beat.  On  this  descending  part  of  the  curve  occur  two  or  three 
secondary  elevations  :  h  is  the  primary  or  '  percussion  '  wave,  c  the  pre- 
dicrotic  or  '  tidal '  wave,  and  e  the  dicrotic  wave.  Elevations  may  occur 
on  the  curve  after  e  which  are  called  post-dicrotic  waves.  It  is  better  to 
class  the  elevations  before  the  dicrotic  notch  d  as  systolic  elevations,  and 
those  afterwards,  including  the  dicrotic  elevation  itself,  as  diastoUc. 

For  the  exact  understanding  of  these  elevations  it  is  necessary  to 
compare  the  pulse  tracings  taken  from  a  small  arteiy  with  the  variations 
in  pressure  which  occur  at  the  same    time  in  the  aorta  and  in  the  left 


Fig.  414.  Diagram  of  arrangement  of  re- 
cording lever  in  Dudgeon's  sphygmo- 
graph. 


Fig.  415.    Pulse-curve  from  radial  artery. 


924 

ventricle  (Fig.  416) 


PHYSIOLOGY 


We  are  enabled  in  this  way  to  dissociate  the  waves 
caused  by  the  ventricular  systole  from  those  which  have  their  origin  in 
the  arterial  system.  In  Fig.  416  is  given  somewhat  diagrammatically 
typical  tracings  of  the  intra-auricular,  intraventricular,  and  aortic  pressures 
during  one  heart-beat,  and  in  dotted  hues  is  represented  approximately 
the  sort  of  a  curve  which  would  be  given  by  a  sphymograph  applied  to  the 
aorta,  taking  into  account  the  greater  inertia  of  the  latter  instrument. 
The  auricular  systole  begins  at  the  ordinate  1.     It  gives  a  shght  rise  of 


Aorta 


I/entrlcle 
Auricle 


5  4  5 

Fig.  416. 

pressure  in  the  ventricle,  but  as  a  rule  is  not  transmitted  to  the  aorta, 
though  often  some  small  traces  of  it  can  be  seen.  As  the  auricular  con- 
traction is  dying  away,  the  ventricular  contraction  begins  at  2.  The  first 
effect  of  this  rise  of  pressure  is  to  close  the  auriculo-ventricular  valves, 
as  is  shown  by  the  elevation  at  3  in  the  auricular  curve,  and  the  shock 
of  the  closure  is  occasionally  transmitted  to  the  aorta.  The  pressure  in 
the  ventricles  then  rapidly  rises.  At  the  point  4  it  surpasses  the  pressure 
in  the  aorta  and  then  rapidly  rises  above  it.  Since  the  aortic  valves  offer 
no  resistance  to  the  flow  of  blood  from  ventricles  to  aorta,  they  must  open 
as  soon  as  the  intraventricular  exceeds  the  aortic  pressure,  and  this  is 
shown  by  the  rise  of  pressure  in  the  aorta  at  5.  The  shock  of  the  inrush 
of  blood  may  give  rise  to  a  distinct  secondary  wave  at  this  point.  The 
pressure  then  continues  for  a  time  to  rise  rapidly  both  in  the  ventricle  and 
in  the  aorta,  blood  flowing  from  the  heart  into  the  arterial  system.  As 
the  first  rush  of  blood  diminishes  and  as  the  blood  begins  to  escape  more 
rapidly  under  the  influence  of  the  rise  of  pressure  from  the  peripheral  end 
of  the  arterial  system,  the  rise  of  pressure  in  the  ventricle  and  aorta  slows 
off.  and  the  junction  between  these  two  periods  at  5,  where  the  rise  of 


FLOW  OF  BLOOD  THROUGH  THE  ARTERIES  925 

pressure  becomes  suddenly  slower,  may  be  marked  in  the  aortic  curve  by  one 
or  two  secondary  waves.  It  must  be  remembered  however  that  all  these 
secondary  waves  shown  on  the  aorta  at  4  and  5  may  be  absent,  the  one 
at  5  being  the  one  which  is  most  frequently  seen.  From  6  to  7  the  ventricle 
is  still  contracting  and  forcing  blood  into  the  aorta.  The  curve  of  pressure 
is  generally  rounded.  It  may  present  a  flat  top,  the  plateau,  or  the  top 
may  be  rounded  with  an  inchnation  to  fall  or  to  rise  (cf.  Fig.  398).  At  6 
the  ventricle  relaxes,  the  intraventricular  pressure  falls  rapidly,  and  at  7 
falls  below  the  aortic  pressure.  The  aortic  valves  must  now  close  since 
the  pressure  is  greater  on  their  aortic  side.  The  pressure  in  the  ventricle 
now  continues  to  fall  until  it  becomes  zero.  In  the  aorta  however  there 
is  a  sharp  elevation  immediately  after  7,  i.e.  immediately  after  the  closure 
of  the  aortic  valves.  This  is  known  as  the  dicrotic  elevation,  the  previous 
depression  being  the  dicrotic  notch.  It  is  at  this  point  that  the  second 
sound  of  the  heart  is  heard  and  is  evidently  due  to  the  vibrations  which 
are  represented  graphically  in  the  record  of  intra-aortic  pressure. 

There  are  several  factors  at  work  tending  to  produce  a  secondary  wave 
at  this  point.  With  the  sudden  cessation  of  the  inflow  of  blood  from  the 
ventricles  at  the  end  of  the  ventricular  contraction  a  negative  wave  must 
be  produced  at  the  beginning  of  the  aorta,  which,  transmitted  along  the 
arterial  system,  will  tend  to  produce  a  reflux  of  blood  towards  the  heart. 
The  movement  so  caused  is  reinforced  by  the  elastic  reaction  of  the  arterial 
wall  so  that  the  returning  blood  is  driven  up  against  the  aortic  valves, 
closing  them  tightly  and  putting  them  on  the  stretch.  Even  in  a  rigid 
tube  the  sudden  cessation  of  flow  causes  a  negative  wave,  followed  by  a 
positive  wave  in  the  opposite  direction  in  the  aorta  ;  this  positive  wave 
is  increased  by  the  elastic  reaction  of  the  stretched  aortic  valves.  The 
blood  is  driven  up  against  them  by  the  wave  of  positive  pressure  and  then 
rebounds,  hke  a  bilhard  ball  from  the  elastic  cushion,  and  gives  rise  to  the 
dicrotic  elevation.  That  the  dicrotic  elevation  is  for  the  most  part  a 
positive  wave  running  in  a  centrifugal  direction  is  shown  by  the  fact  that 
the  distance  between  it  and  the  primary  wave  does  not  alter  appreciably 
from  whatever  part  of  the  arterial  system  the  tracing  be  taken.  If  it  were 
a  reflected  wave  the  distance  between  it  and  the  primary  elevation  of  the 
pulse-curve  ought  to  be  less  the  nearer  the  periphery  the  pulse  tracing  is 
taken. 

The  predicrotic  waves  in  the  pulse  tracing  are  evidently  due  to  the 
instrimiental  exaggeration  of  the  wave  which  may  occasionally  be  seen 
even  in  a  perfect  pressure  tracing  at  5.  The  rapid  rise  of  pressure  in  the 
aorta  or  in  the  more  peripheral  artery,  which  follows  the  opening  of  the 
aortic  valves  sets  up  a  tendency  to  secondary  oscillations  at  this  point. 
The  greater  the  inertia  of  the  instrument,  the  greater  is  the  exaggeration 
of  these  waves.  As  is  shown  by  the  dotted  Une  in  Fig.  416,  the  lever  of 
the  sphygmograph  is  jerked  up,  so  that  it  practically  leaves  the  artery, 
and  then  falls  and  rebounds  again,  so  that  the  simple  rounded  top  becomes 
resolved  by  instrumental  error  into  a  curve  with  two  waves,  which  have 


926  PHYSIOLOGY 

been  called  the  percussion  wave  and  the  predicrotic  wave.  In  the  same 
way  the  inertia  of  the  instrument  will  tend  to  exaggerate  the  dicrotic 
elevation  and  possibly  to  give  rise  to  shght  postdicrotic  waves. 

The  general  form  of  the  pulse-curve  varies  with  changes  in  the  heart, 
in  the  arteries,  and  in  the  peripheral  resistance.  Thus  some  curves  may 
present  secondary  elevations  on  the  ascending  part,  and  are  called  anacrotic, 
w^hile  in  others  all  secondary  elevations  occur  on  the  descending  part. 
The  latter  type  is  called  catacrotic,  and  is  the  tracing  usually  obtained 
from  a  normal  radial  artery.  By  comparing  these  two  types  of  curves 
with  the  corresponding  intraventricular  pressures,  we  find  that  in  both 
cases  blood  is  flowing  into  the  aorta  during  the  whole  time  from  the  beginning 
of  the  primary  elevation  to  the  notch  just  before  the  dicrotic  elevation. 
This  is  shown  by  the  fact  that  the  intraventricular  pressure  is  all  this  time 
sHghtly  higher  than  the  aortic  pressure.  So  long  as  this  is  the  case  blood 
must  flow  from  ventricle  into  aorta.  (This  fact  proves  that  there  is  normally 
no  part  of  the  cardiac  cycle  during  which  the  ventricle  remains  contracted 
and  empty,  the  ventricle  in  all  cases  relaxing  before  it  has  completely 
emptied  itself  of  blood.) 

Now  it  is  easy  to  see  the  conditions  which  determine  whether  the  systolic 
plateau  shall  be  ascending  or  descending,  and  therefore  when  the  pulse 
shall  be  anacrotic  or  catacrotic.  If,  after  the  first  sudden  rise  of  pressure 
in  the  aorta,  the  blood  can  escape  more  rapidly  through  the  peripheral 
resistance  than  it  is  thrown  into  the  beginning  of  the  aorta,  the  '  systoHc 
plateau'  will  sink,  and  a  catacrotic  pulse  tracing  is  obtained.  If,  on  the 
other  hand,  the  peripheral  resistance  is  high,  or  an  extra  large  amount  of 
blood  be  thrown  into  the  aorta  at  each  stroke  of  the  heart  {e.g.  by  prolonga- 
tion of  the  diastole),  the  aortic  pressure  will  rise  so  long  as  blood  is  flowing 
in,  and  we  get  an  ascending  systohc  plateau  and  an  anacrotic  pulse.  Thus 
we  obtain  an  anacrotic  pulse  in  old  people  with  Bright's  disease,  in  whom 
the  peripheral  resistance  is  very  high,  and  also  in  animals  when  the  heart 
is  slowed  by  vagus  action. 

The  production  of  the  dicrotic  elevation  is  favoured  by  any  influence 
which  increases  the  elastic  resihency  of  the  arteries  or  causes  the  primary 
elevation  of  the  pulse  to  be  rapid  and  sharp.  Thus  it  is  much  more  pro- 
nounced in  young  people  than  in  old  people,  whose  arteries  have  become 
rigid.  When  the  peripheral  resistance  is  low  through  relaxation  of  the 
9,rterioles,  and  the  heart  is  beating  forcibly,  as  in  many  cases  of  fever  and 
also  to  some  extent  after  a  good  meal  with  alcohol,  the  dicrotic  elevation 
becomes  very  marked.  Under  such  circumstances  it  may  be  easily  felt 
with  the  finger  at  the  wrist,  and  in  many  cases  the  mistake  has  been  com- 
mitted of  taking  the  dicrotic  wave  for  a  normal  beat,  and  so  doubhng  the 
rate  of  the  pulse. 

OTTO  FRANK'S  WORK  ON  THE  PULSE.  In  the  account  given  above  of  the 
peculiarities  of  the  pulse-curve  in  different  parts  of  the  system  I  have  adopted  in  the 
main  the  views  of  Marey  and  Hiirthle,  which  have  been  generally  accepted  for  a  con- 
siderable time  and  have  influenced  most  of  the  clinical  work  on  this  subject.     According 


FLOW  OF  BLOOD  THROUGH  THE  ARTERIES 


927 


to  these  authors  all  the  secondary  waves  on  the  pulse-curve  are  central  in  origin,  and 
can  therefore  be  traced  with  slight  modification  on  the  curves  obtained  from  the  aorta, 
the  large  and  the  small  arteries.  Although  Marey  investigated  the  propagation  of 
reflected  waves  and  showed  their  presence  in  the  artificial  schema  of  the  circulation 
{vide  p.  920),  he  considered  that  they  could  not  contribute  to  the  production  of  the 
waves  on  the  pulse-curve,  owing  to  the  enormous  number  of  points  at  which  reflection 
might  occur,  so  that  the  different  reflected  waves  would  tend  mutually  to  annul  each 
other's  effects.  Moreover  the  distance  of  the  dicrotic  notch  from  the  primary  elevation 
was  found  to  be  nearly  the  same  at  different  parts  of  the  system,  pointing  to  a  propaga- 
tion of  this  wave  from  the  centre  to  the  circumference  of  the  arterial  system. 

Frank  points  out  that  the  effect  of  the  propagation  of  the  fairly  simple  wave  started 


Fig.  417,     Pulse-pressure  curves  taken  by  means  of  Frank's  manometer  (Frank), 
A,  B,  c,  aortic  pressure  curves  at  different  rates  of  the  heart ;    d  and  e,  aortic 
pressure  curve,  D,  compared  with  simultaneous  record  of  the  pressure  in  the  femoral 
artery  e. 

in  the  aorta  in  an  endless  system  of  elastic  tubes  would  be  to  diminisli  the  rapidity 
of  onset  of  each  vibration,  and  therefore  to  diminish  the  secondary  vibrations  on  the 
curve.  In  a  closed  elastic  system  of  tubes,  such  as  the  arterial  sj^stem,  there  will  be 
factors  at  work  analogous  in  many  respects  to  those  responsible  for  the  deformation 
of  the  curve  given  by  an  imperfect  manonieter.  These  will  be  of  two  kinds,  namely, 
(1)  oscillations  of  the  colunui  of  fluid  within  the  stretched  arterial  wall,  (2)  reflections 
of  waves  from  different  points  in  the  periphery.  These  reflections  we  should  expect , 
to  bo  evident  in  certain  cases.  Thus  in  the  carotid  there  should  be  a  reflected  wave 
from  the  circle  of  Willis  ;  in  the  descending  aorta,  from  the  bifurcation  of  tliis  vessel 
into  the  two  iliac  arteries.  As  a  result  the  pulse  in  the  peripheral  arteries,  such  as  the 
radial  or  femoral,  diverges  considerably  from  the  pulse  in  the  aorta.  In  the  figure 
(Fig,  417,  D  and  e)  the  primarj'rise  of  pressure  in  the  femoral  artery  is  even  higher  than  the 
primary  rise  in  the  aorta,  i.e.  the  primary  wave  must  be  augmented  here  by  a  reflected 
wave  from  the  peripherj-.  Frank  acknowledges  that  the  dicrotic  depression  in  tliis 
curve  is  due  to  the  propagation  of  the  wave  set  up  by  the  closure  of  the  aortic  valves  ; 


928  PHYSIOLOGY 

but  he  would  regard  the  more  pronounced  dicrotism  of  the  pulse,  of  which  examples 
have  been  given  earlier,  as  due  for  the  most  part  to  the  reflection  of  waves  from  the 
periphery. 

From  time  immemorial  the  physician  has  sought  by  feehng  the  pulse 
to  come  to  some  idea  as  to  the  condition  of  the  circulation.  A  number  of 
different  quahties  have  therefore  been  distinguished.  According  to  the 
number  of  beats  per  minute  the  pulse  is  distinguished  as  frequent  or  rare. 
The  size  of  the  pulse  has  reference  to  the  amplitude  of  excursions  of  each 
beat  and  the  pulse  is  distinguished  as  large  or  small.  The  velocity  of  the 
pulse  expresses  the  speed  with  which  the  excursion  is  accomphshed.  The 
quick  pulse  is  one  in  which  the  artery  presses  against  the  finger  suddenly 
and  then  disappears  suddenly,  while  in  the  slow  pulse  the  period  during 
which  pressure  can  be  felt  is  more  prolonged.  The  hardness  of  the  pulse 
is  determined  chiefly  by  the  blood-pressure.  If  the  pulse  is  compressible 
it  is  spoken  of  as  soft ;  if  it  can  only  be  obhterated  with  difficulty  it  is 
hard.  Certain  combinations  of  these  quahties  are  also  described.  Thus 
a  large  and  hard  pulse  is  spoken  of  as  strong,  a  weah  pulse  being  both  small 
and  soft.  A  small  hard  pulse  is  called  contracted.  If  the  rhythm  of  the 
heart-beat  is  irregular  the  pulse  is  also  irregular.  An  intermittent  pulse  is 
one  in  which  one  heart-beat  is  dropped  occasionally,  i.e.  once  in  every 
four  or  eight  beats,  and  may  be  due  to  the  interposition  of  a  ventricular 
contraction  which  is  too  weak  to  send  the  pulse  along  so  far  as  the  radial 
artery. 

Judgments  as  to  the  conditions  of  the  heart  and  circulation  from  the 
feeling  of  the  pulse  oscillations  must,  however,  be  made  with  extreme 
caution.  The  pulse-curve  may,  indeed,  give  approximate  information  as 
to  the  condition  of  things  in  the  heart.  Thus  the  period  between  the 
beginning  of  the  primary  elevation  and  the  dicrotic  notch  corresponds  to 
the  outflow  of  blood  from  ventricle  to  aorta.  A  large  pulse-curve  does  not 
necessarily  indicate  a  big  output,  since  the  expansion  of  the  artery  is 
determined  not  only  by  events  occurring  in  the  aorta  but  also  by  the  tonus 
of  the  artery  under  the  finger  and  the  resistance  in  the  peripheral  branches. 

Perhaps  the  best-marked  condition  of  the  pulse  is  that  known  as  the 
'  water-hammer '  pulse,  which  is  observed  in  cases  where  the  aortic  valves 
are  injured  or  diseased  so  as  to  allow  of  regurgitation  into  the  ventricle. 
The  systoHc  rise  of  pressure  in  the  arterial  system  is  followed  by  an  extremely 
rapid  fall,  so  that  towards  the  end  of  diastole  the  pressure  in  the  arteries 
may  be  insufficient  to  keep  the  arterial  system  filled.  Under  such  con- 
ditions, if  the  arm  be  held  above  the  head  and  the  wrist  of  the  patient 
be  grasped,  the  pulse  in  the  arteries  of  the  wrist  is  felt  as  a  smart  blow 
coinciding  with  each  beat  of  the  heart. 

THE  CIRCULATION  THROUGH  THE  CAPILLARIES 
The  capillary  circulation  is  most  easily  studied  by  examining  under 
the  microscope  the  tongue  of  the  frog  or  the  web  of  the  frog's  foot.     Under 
a  power  of  about  150   to   180   diameters   a   network  of  vessels   is  seen, 


FLOW  OF  BLOOD  THROUGH  THE  ARTERIES  929 

consisting  of  small  arteries,  capillaries,  and  veins.  The  direction  of  flow  in 
the  arteries  is  opposite  to  that  in  the  veins.  In  the  capillaries  the  flow 
is  from  arteries  to  veins,  though,  on  account  of  the  reticular  arrangement 
of  these  vessels,  the  direction  of  the  stream  through  them  is  not  quite 
constant  and  may  occasionally  be  reversed.  The  flow  of  blood  in  the 
arteries  is  rapid,  whereas  in  the  veins  it  is  generally  possible  to  distinguish 
the  individual  blood-corpuscles.  Through  the  capillaries  the  flow  is  very 
inconstant.  If  a  group  of  capillaries  be  watched  for  some  time  the  blood 
may  at  first  hurry  through  a  number  of  them  with  great  rapidity  ;  the 
flow  then  becomes  slower  and  then  may  quicken  up  to  a  moderate  pace 
again.  These  variations  in  the  capillary  flow  are  probably  associated 
with  spontaneous  alterations  in  the  condition  of  contraction  of  the  small 
arteries  supplpng  the  group  of  capillaries.  It  is  easy  to  observe  that  the 
arterial  flow  is  pulsatile,  the  pulsation  disappearing  in  the  capillaries  and 
veins.  Another  difierence  between  the  circulation  in  these  three  kinds 
of  vessels  is  to  be  found  in  the  condition  of  the  peripheral  zone.  In  the 
arteries  the  blood-stream  is  divided  into  two  parts,  the  peripheral  stream 
— about  -01  mm.  wide,  consisting  only  of  colourless  plasma  with  occasionally 
a  stray  leucocyte — and  an  axial  stream,  in  which  all  the  red  blood- corpuscles 
are  being  hurried  along.  In  the  veins  there  is  a  similar  peripheral  plas- 
matic zone,  but  here  we  find  regularly  scattered  leucocytes  which  travel 
rather  more  slowly  than  the  axial  stream  of  red  corpuscles.  The  formation 
of  this  axial  zone  is  purely  mechanical,  and  may  be  imitated  in  any  fluid 
containing  in  suspension  particles  whose  specific  gravity  is  somewhat 
higher  than  that  of  the  fluid.  In  the  capillaries  there  is  no  separation  of 
the  two  zones,  since  the  lumen  of  these  vessels  as  a  rule  allows  only  the 
passage  of  one  or  two  corpuscles  abreast,  so  that  they  are  everywhere  in 
contact  with  the  wall.  The  corpuscles  are  e\adently  elastic  structures, 
and  may  be  seen  to  bend  if  they  impinge  on  the  dividing  point  of  two 
capillaries  before  they  are  finally  swept  off  by  the  stream  into  one  or  the 
other. 

The  capillary  wall  is  composed  of  a  single  layer  of  elongated  flattened 
cells  which  present  little  resistance  to  the  passage  through  them  by  diffusion 
of  dissolved  substances,  such  as  sugar,  salts,  oxygen,  or  carbon  dioxide. 
In  this  way  the  tissue-cells  obtain  oxygen  from  the  red  blood-corpuscles 
and  nutriment  from  the  plasma,  and  give  off  to  the  circulating  blood  carbon 
dioxide  and  other  effete  substances  as  the  products  of  their  metabohsm. 
There  is  evidence  that  in  some  situations  the  cells  forming  the  capillary 
wall  may  be  contractile.  According  to  Strieker  and  others,  the  cell  substance 
is  arranged  in  strands  running  from  the  nuclei  around  the  capillary.  By 
the  contraction  of  these  strands  the  vessel  may  be  narrowed  to  obliteration. 
These  phenomena  have  been  observed  in  the  nictitating  membrane  of  the 
frog,  but  it  is  doubtful  how  far  they  may  be  extended  to  the  other  capillary 
systems  of  the  body.  If  the  contractile  power  is  at  all  universally  present, 
it  must  play  an  important  part  in  determining  the  amount  of  blood-flow 
through  the  capillaries  of  an  organ,  and  will  doubtless  be  largely  affected 

30 


930 


PHYSIOLOGY 


by  chemical  substances  produced  as  the  result  of  the  metabolism  of  the 

surrounding  tissues. 

The  average  length  of  a  capillary  is  between  0-4  and  0-7  mm.     The 

velocity  of  blood-flow  can  be  directly  determined  by  observing  under  the 

microscope  the  time  taken  by  any  given  corpuscle  to  travel  a  measured 
distance  on  the  microscope  stage.  The  mean  velo- 
city determined  in  this  way  varies  from  about  0-5 
to  0-8  mm.  per  second. 

The  blood-pressure  in  the  capillaries  may  be 
measured  approximately  by  applying  pressure  to 
the  outer  surface  of  the  skin  or  mucous  membrane 
and  noticing  the  point  at  which  blanching  of  the 
surface  is  produced. 


Fig.  418.  Apparatus  of 
von  Kries  for  measuring 
capillary  blood-pressure. 


In  von  Kries'  method  a  small  glass  plate,  from  2  to 
5  sq.  mm.  in  area,  is  placed  on  the  last  joint  of  the  finger. 
Attached  to  this  glass  plate  is  a  small  scale  pan  on  which 
weights  are  placed  until  the  pressure  is  just  sufficient  to 
blanch  the  underlying  skin.  In  using  this  method  the  cal- 
culation of  the  capillary  pressure  is  made  as  follows  : 
Supposing  that  the  size  of  the  glass  plate  is  4  sq.  mm.  and  1  grm.  in  the  scale  pan  is 
just  sufficient  to  cause  a  change  of  colour  in  the  skin,  then 

a  weight  of  1  grm.  -=  1  c.c.  HgO  =  1000  c.mm.  HgO 

is  present  on  an  area  of  4  sq.  mm.     The  height  of  the  column  of  water  supported  by 

.     ,       .       1000 

1  sq.  mm.  is  therefore =  250  mm.  H,0.     The  errors  of  this  method  are  consider- 

4  - 

able,  since  the  pressure  thus  determined  is  not  the  total  capillary  pressure,  but  this 

minus  the  pressure  in  the  tissue  spaces  on  the  outer  side  of  the  capillary  wall.     The 

result  will  therefore  vary  not  only  with  capillary  pressure  but  also  with  the  tension  of 

the  skin  and  the  amoimt  of  fluid  in  the  tissue  spaces. 

The  pressure  in  the  capillaries  as  found  by  this  method  necessarily  varies  with  the 

position  of  the  part  under  investigation,  i.e.  with  the  hydrostatic  pressure  of  the  column 

of  blood  between  it  and  the  heart.     The  following  figures  were  found  by  von  Kxies  : 

Finger :        Mm.  HgO  Distance  of  finger 

below  head 

328  . .  0  mm. 

329  . .  205  mm. 
513  . .  490  mm. 
738                       . .                             840  mm. 

Ear  :  20  mm.  Hg. 
Gums  of  Rabbits  :  33  mm.  Hg. 
Frog's  Web  (Roy) :   100-150  mm.  HjO. 
Capillary  venous  pressure  of  brain  (Hill) : 

(1)  Animal  in  horizontal  position  :   10  mm.  Hg. 

(2)  ,,       ,,     feet-down  position  :   zero  or  less. 

(3)  During  strychnine  convulsions  :  50  mm.  Hg. 

Owing  to  the  fact  that  a  varying  and  unknown  resistance — that  of  the 
arterioles — Ues  between  the  capillaries  and  the  arteries,  the  pressure  in 
the  capillaries  must  stand  in  much  closer  relationship  to  that  in  the  veins 
than  to  that  in  the  arteries.     One  cannot  therefore  argue  that  a  fall  of 


FLOW  OF  BLOOD  THROUGH  THE  ARTERIES  931 

arterial  pressure  necessarily  involves  a  fall  of  capillary  pressure  in  all  parts 
of  the  body.  We  can  only  judge  of  changes  in  the  capillary  pressure  by 
taking  simultaneously  the  pressures  in  both  the  afferent  and  efferent 
vessels.  If  these  both  rise  or  fall  together  we  may  be  certain  that  the 
capillary  pressure  also  rises  or  falls.  Where  the  arterial  and  venous 
pressures  move  in  opposite  directions  it  is  difficult  to  say  what  alterations, 
if  any,  will  be  produced  in  the  capillary  pressure. 

The  resistance  to  the  flow  of  blood  through  the  capillaries  is  determined 
by  the  internal  friction,  i.e.  the  viscosity  of  the  blood  ;  this  varies  in 
different  animals  between  three  and  five  times  that  of  water.  It  has  been 
calculated  that  the  fall  of  pressure  undergone  by  the  blood  in  passing 
through  any  given  capillary  area  is  only  about  20  to  60  mm.  of  blood,  and 
at  the  most  is  never  more  than  150  mm.  blood,  i.e.  about  10  mm.  Hg.  This 
bears  out  the  conclusion  to  which  we  have  already  come,  viz.  that  the 
chief  seat  of  the  resistance  in  the  vascular  system  is  the  arterioles,  and  it 
is  in  this  region  that  the  chief  fall  of  pressure  occurs. 


SECTION  VI 

THE  FLOW  OF  BLOOD  IN  THE  VEINS 

In  the  veins  there  is  a  constant  decrement  of  pressure  as  we  pass  from  the 
periphery  towards  the  heart.  This  decrement  of  pressure  is  the  conse- 
quence of  the  pumping  action  of  the  heart,  so  that  the  flow  through  the 
veins  must  be  ascribed  to  the  same  force  as  that  which  determines  the 
flow  through  the  arteries,  viz.  the  heart-beat.  Owing  to  the  fact  that  no 
appreciable  resistance  lies  between  the  veins  and  the  heart,  the  difference 
of  pressure  necessary  to  maintain  a  constant  flow  through  these  vessels 
is  very  small.  Thus  in  the  horizontal  position  the  pressure  in  the  femoral 
veins  may  be  from  5  to  10  mm.  Hg.,  and  in  the  inferior  vena  cava  from 
1  to  5  mm.  The  pressure  in  the  great  veins  near  the  heart  is  generally 
negative  owing  to  the  aspiration  of  the  thorax,  and  this  negative  pressure 
is  naturally  increased  during  inspiration.  Opening  the  thorax  therefore 
causes  a  rise  of  pressure  in  all  the  large  veins.  In  the  latter  the  pressure 
depends  chiefly  on  the  heart  activity,  being  lowered  by  vigorous  action 
of  the  heart  pump  and  raised  when  this  fails  in  any  way.  In  the  peri- 
pheral veins  the  pressure  is  more  dependent  on  the  flow  through  the 
corresponding  arteries.  If  an  artery  of  a  limb  be  Hgatured  the  pressure  in 
the  small  veins  of  the  limb  sinks  until  it  is  reduced  to  the  pressure  in  the 
nearest  large  trunk  in  which  a  flow  of  blood  continues. 

Each  cardiac  cycle  causes  variations  in  the  pressure  in  the  great  veins 
next  the  heart  in  two  ways  : 

(1)  By  the  transmission  along  the  veins  of  the  alterations  in  the  intra- 
auricular  pressure. 

(2)  By  the  diminution  in  the  volume  of  the  heart  in  consequence  of  the 
expulsion  of  its  blood  along  the  arteries  with  each  heart-beat. 

On  this  account  the  jugular  veins  show  pulsations  with  each  heart-beat 
which  are  somewhat  complex  in  character  and  resemble  closely  those 
occurring  in  the  auricle  {vide  p.  901).  In  Fig.  419  a  tracing  from  the 
wall  of  the  jugular  vein  is  given.  It  will  be  seen  that  each  heart-beat 
gives  rise  to  three  variations  in  pressure  within  the  veins.  These  three 
undulations  are  evidently  exactly  analogous  to  those  given  in  Fig.  400 
as  occurring  in  the  auricular  tracing.  We  should  therefore  regard  a  as  the 
auricular  contraction,  c  as  the  elevation  due  to  the  closure  of  the  auriculo- 
ventricular  valves,  v  as  the  elevation  due  to  the  accumulation  of  blood 
in  the  auricles  during  the  ventricular  systole.     The  curve  c  is  often  spoken 

932 


THE  FLOW  OF  BLOOD  IN  THE  VEINS  933 

of  as  the  carotid  elevation,  and  has  been  ascribed  by  Mackenzie  to  direct 
propagation  to  the  jugular  vein  from  the  underlying  carotid  artery.  He 
has  come  to  this  conclusion  because  he  has  not  found  it  in  tracings  of  the 
liver  pulse  in  cases  of  incompetent  tricuspid  valves.  There  is  no  doubt, 
however,  that  the  elevation  can  be  seen  on  tracings  from  the  inferior  vena 
cava.  The  explanation  of  its  absence  from  hver  tracings  is  probably  to 
be  ascribed  to  the  fact  that  the  great  mass  of  the  Hver  substance  is  miable 
to  transmit  the  very  rapid  oscillation  of  pressure  due  to  the  closure  of 
the  auriculo-ventricular  valves.     These  venous  pulsations  are  much  more 


ac 

V 


Ju^.V. 
Raul.  art. 


V' 


Fig.    419.     Venous   pulse-tracing   from   jugular   vein  comparod   with   the 
arterial  pvilse-tracing  from  the  radial  arterj'. 

marked  in  cases  of  heart  disease,  where  there  is  partial  failure  of  the  heart 
pump  and  overfilKng  of  the  venous  system,  often  combined  with  incom- 
petency of  the  auriculo-ventricular  valves. 

Besides  the  favourable  influences  exercised  on  the  circulation  through 
the  veins  by  the  aspiration  of  the  thorax  and  the  momentary  aspiration 
of  the  heart-beat  itself,  a  considerable  part  is  played  in  the  venous  circula- 
tion by  the  contraction  of  the  muscles  of  the  body  as  well  as  by  the  passive 
movements  of  different  parts.  The  adjuvant  effect  of  passive  or  active 
movement  on  the  circulation  through  the  veins  is  rendered  possible  by  the 
existence  in  these  vessels  of  valves,  which  are  semilunar  folds  of  the  intima 
projecting  into  their  lumen,  and  so  arranged  that  they  allow  the  passage 
of  blood  only  towards  the  heart.  Two  such  valves  are  as  a  rule  situated 
opposite  to  each  other.  Every  movement  of  a  hmb,  active  or  passive, 
causes  an  external  pressure  on  the  veins,  and  therefore  empties  them 
towards  the  heart.  Thus,  in  walking,  each  time  the  thigh  is  moved  back- 
wards the  femoral  vein  becomes  empty  and  collapses,  and  fills  again  as 
soon  as  the  leg  is  brought  forward  to  its  former  position  or  is  flexed  in  front 
of  the  body.  When  muscular  movements  become  general,  as  in  walking 
or  rumiing,  the  active  compression  of  the  veins  thus  brought  about  plays 
an  important  part  in  hurrying  the  blood  into  the  right  heart,  so  that  the 
output  of  this  organ  is  increased  and  the  arterial  blood-pressure  is  raised. 

Since  the  blood  in  the  vessels  is  subject  to  the  influence  of  gravity,  we 
should  expect  to  And  that  the  pressure  in  the  veins  of  the  foot  was  equal 
to  the  pressure  in  the  veins,  say,  of  the  hand  at  the  level  of  the  heart  'plus 
the  pressure  equivalent  to  the  column  of  blood  between  these  veins  and 


934  PHYSIOLOGY 

the  heart,  i.e.  about  a  metre  of  blood.  On  measuring  the  pressure  by 
von  Reckhnghausen's  or  by  Hill's  method  in  these  veins,  this  is  not  found 
to  be  the  case.  The  pressure,  indeed,  in  the  veins  of  the  foot  is  but  little 
higher  than  that  in  the  veins  of  the  hand.  Von  Recklinghausen  found 
that  after  subtracting  the  distance  between  the  foot  and  the  heart  the 
pressure  in  the  veins  was  negative  by  as  much  as  40  cm.  In  the  same 
way,  as  Hill  has  shown,  the  pressure  in  the  capillaries  of  the  foot  is  about 
the  same  as  in  the  capillaries  of  the  hand.  When  a  man  assumes  the 
upright  position  the  arteries  of  the  leg  and  foot  contract  until,  under  the 
combined  influence  of  the  heart's  contraction  and  gravity,  the  blood- 
supply  to  the  capillaries  is  only  sufficient  to  keep  the  pressure  in  these 
vessels  at  a  certain  moderate  height.  The  return  of  the  blood  from  the 
dependent  parts  cannot  be  ascribed  to  the  heart-beat  at  all,  but  is  due  to 
the  extrinsic  mechanism  of  circulation  through  the  veins,  i.e.  the  contrac- 
tions of  the  muscles  of  the  Umb  which  press  all  the  deep  and  superficial 
veins,  and  in  virtue  of  the  valves  force  the  blood  contained  therein  by 
Poupart's  ligament  into  the  abdomen.  The  fact  that  circulation  through 
the  legs  is  dependent  on  the  contractions  of  their  muscles  explains  why 
it  is  so  difficult  to  stand  still  for  any  length  of  time  without  moving,  and 
emphasises  the  need  of  moderate  exercise  for  the  maintenance  of  a  normal 
circulation. 


SECTION  VII 

THE  PULMONARY  CIRCULATION 

In  the  lungs  there  is  an  extensive  system  of  wide  capillaries  presenting 
very  little  resistance  to  the  flow  of  blood.  The  arterioles  are  wide  and  have 
only  a  slight  amount  of  muscular  fibre  in  their  walls,  so  that  a  slight  pressure 
suffices  to  drive  the  blood  from  the  right  to  the  left  heart.  The  determina- 
tion of  the  normal  average  pressure  in  the  pulmonary  artery  presents  con- 
siderable difficulties,  but  it  probably  does  not  exceed  15  to  20  mm.  Hg., 
i.e.  about  one-sixth  of  the  mean  aortic  pressure. 

The  capillaries  of  the  lungs  may  vary  passively  in  size  according  to  the 
condition  under  which  they  may  be  placed.  Thus,  whereas  at  the  height  of 
inspiration  the  blood  contained  in  the  lungs  is  about  one-twelfth  of  the 
whole  blood  in  the  body,  this  amount  is  diminished  during  expiration  to 
between  one-fifteenth  and  one-eighteenth,  and  by  forcible  artificial  inflation 
of  the  lungs  may  be  lessened  to  one-sixtieth.  These  changes  exercise  a 
considerable  effect  on  the  systemic  blood-pressure  and  are  largely  responsible 
for  the  respiratory  variations  observed  in  the  systemic  blood-pressure.  On 
the  other  hand,  the  distensibihty  of  the  lung  capillaries  may  play  an  impor- 
tant part  in  enabling  the  lungs  to  act,  so  to  speak,  as  a  reservoir  for  the  left 
side  of  the  heart.  If,  in  consequence  of  raised  arterial  pressure  or  other 
factor,  there  is  a  temporary  excess  of  output  on  the  right  side  that  cannot  be 
dealt  with  at  once  by  the  left  heart,  the  excess  is  taken  up  for  a  time  in  the 
lung  capillaries. 

Vaso-motor  fibres  to  the  lung- vessels  have  been  described  as  running  in 
the  anterior  roots  of  the  third,  fourth,  and  fifth  dorsal  nerves.  Their  action 
is,  however,  of  little  importance,  and  their  very  existence  is  questioned 
by  some  observers.  The  fact  that  injection  of  adrenalin  causes  some  vaso-con- 
striction  in  the  lungs,  points  to  the  presence  of  a  vaso-motor  sympathetic 
supply  to  those  organs. 

If  we  examine  a  tracing  of  the  arterial  blood-pressure,  we  notice  that  it 
presents  certain  periodic  oscillations  which  accompany  the  movements  of 
respiration.  With  each  inspiration  the  blood-pressure  rises ;  with  each 
expiration  it  falls.  The  synchronism  of  the  rise  and  fall  with  the  respiratory 
movements  is  not  exact,  since  the  rise  continues  for  a  short  time  after  the 
beginning  of  expiration  before  it  begins  to  fall,  and  the  fall  continues  right 
into  the  beginning  of  the  next  inspiration,  so  that  the  highest  point  of 
the  curve  occurs  at  the  beginning  of  expiration  and  the  lowest  point  at  the 

935 


936 


PHYSIOLOGY 


Bespimturj/  tracing 

Fig.  420.  Diagram  of  blood-pressure  curve, 
showing  effects  of  the  respiratory  movements 
on  blood-pressure  and  pulse-rate.  (The  effects 
are  purposely  exaggerated.) 


beginning  of  inspiration.  During  the  fall  which  accompanies  expiration  the 
heart-beats,  as  shown  in  the  diagram  (Fig.  420),  become  less  frequent,  and 
an  obvious  explanation  of  the  fall  of  pressure  would  be  to  ascribe  it  to  a 
reflex  inhibition  of  the  heart.  On  dividing  both  vagi,  this  difference  in 
the  pulse-rate  during  inspiration  and  expiration  disappears,  but  the  main 
features  of  the  blood-pressure  curve  remain  the  same  ;  so  that  we  must  look 
for  some  mechanical  explanation  of  the  respiratory  undulations. 

We  have  already  seen  that  under  normal  conditions  the  lungs  are  in  a 
state  of  over-distension,  and  that  in  consequence  of  this  condition  they  are 
constantly  tending  to  collapse,  and  are  therefore  exerting  a  pull  on  the  chest 

wall.  As  soon  as  we  admit  air 
into  the  pleural  cavity  by  per- 
forating the  chest  wall  the  lungs 
collapse.  The  force  with  which 
the  lungs  tend  to  collapse  amounts 
to  6  mm.  Hg.  at  the  end  of  a  quiet 
expiration,  so  we  say  that  in  the 
pleural  cavity  there  is  normally 
a  negative  pressure  of  6  mm.  Hg. 
As  the  chest  expands  in  inspira- 
tion it  drags  the  lungs  still  more 
open.  As  these  become  more 
distended  their  pull  on  the  chest  wall  becomes  greater,  and  hence  the 
negative  pressure  in  the  pleura  may  be  increased  during  forcible  inspira- 
tion to  30  mm.  Hg.  It  must  be  remembered  that  the  heart  and  great 
veins  and  arteries  are  in  the  thorax  separated  from  the  pleural  cavity  only 
by  a  thin  yielding  membrane,  so  that  they  are  practically  exposed  to  any 
pressure,  positive  or  negative,  which  may  exist  in  the  pleural  cavity.  Hence 
even  at  the  end  of  expiration  the  heart  and  large  vessels  are  subjected  to  a 
negative  pressure  of  6  mm.  Hg.  Outside  the  thorax  all  the  vessels  are 
exposed  to  a  positive  pressure,  conditioned  in  the  neck  by  the  elasticity  of 
the  tissues  and  in  the  abdomen  by  the  contractions  of  the  diaphragm  and 
abdominal  muscles. 

Blood,  like  any  other  fluid,  will  always  flow  from  a  point  of  higher  to 
a  point  of  lower  pressure.  There  must  thus  be  a  constant  aspiration  of  blood 
from  peripheral  parts  into  the  thorax.  This  aspiratory  force  will  not  in- 
fluence arteries  and  veins  ahke.  The  arteries,  having  thick,  comparatively 
non-distensible  walls,  will  be  very  little  affected  by  the  negative  pressure 
obtaining  in  the  thoracic  cavity,  whereas  the  thin-walled  distensible  veins 
will  be  largely  influenced  by  the  same  factor.  The  total  result  then  of  the 
negative  pressure  in  the  pleural  cavities  is  to  increase  the  flow  of  blood  from 
the  veins  into  the  heart  without  affecting  to  any  appreciable  degree  the 
outflow  of  blood  from  the  heart  into  the  arteries.  The  more  pronounced  the 
negative  pressure  in  the  thorax,  the  greater  will  be  the  amount  of  blood 
sucked  into  the  heart  from  the  veins.  During  inspiration  therefore  the 
heart  will  be  better  suppUed  with  blood  than  during  expiration,  and  this 


THE  PULMONAEY  CIRCULATION  937 

factor  in  itself  will  tend  to  raise  the  arterial  blood-pressure.  The  inspiratory 
descent  of  the  diaphragm  will  moreover  tend  to  increase  the  inflow  into  the 
heart  by  raising  the  positive  pressure  in  the  abdomen,  so  that  blood  is  pressed 
out  of  the  abdominal  veins  and  sucked  into  the  heart  and  the  thoracic 
veins. 

Another  important  factor  is  the  influence  of  the  respiratory  movements  on 
the  circulation  through  the  lungs.  In  trying  to  miderstand  this  influence  it 
must  be  remembered  that  the  pulmonary  capillaries  lie  in  a  certain  amount  of 
elastic  and  connective  tissue  and  are  separated,  on  the  one  side  by  the 
alveolar  epithelium  from  air  at  the  ordinary  atmospheric  pressure,  and  on  the 
other  by  the  pleural  endothehum  from  the  pleural  cavity,  where  the  pressure 
varies  from  6  to  30  mm.  Hg.  below  the  atmospheric  pressure.  We  may 
therefore  consider  the  pulmonary  capillaries  as  lying  between,  and  attached 
to,  two  concentric  elastic  bags.  Under  normal  conditions,  since  these  bags 
are  always  tending  to  collapse,  the  imier  one  must  be  pulhng  away  from  the 
outer  one,  and  the  outer  one  from  the  chest  wall.  Hence  there  must  be  a 
negative  pressure  in  the  tissues  between  these  two  bags — a  negative  pressure 
which  in  the  expiratory  condition  will  be  something  between  0  and  -  6  mm. 
Hg.,  and  in  the  inspiratory  condition  between  0  and  -  30  mm.  Hg.  If  we 
regard  the  average  pressure  within  the  pulmonary  capillaries  as  constant, 
these  capillaries  must  be  more  dilated  in  the  inspiratory  than  in  the  expiratory 
condition.  This  dilatation  of  the  pulmonary  capillaries  will  have  two 
effects.  Their  capacity  will  be  increased  and  the  resistance  they  present 
to  the  flow  of  blood  will  be  diminished. 

Let  us  now  consider  what  effect  these  changes  will  have  on  the  general 
arterial  blood-pressure.  We  will  assume  that  during  expiration  the  pul- 
monary vessels  have  a  capacity  of  25  c.c.  and  that  the  beat  of  the  right  heart 
is  forcing  through  them  10  c.c.  of  blood  per  second.  So  long  as  the  chest 
remains  in  the  expiratory  condition  10  c.c.  of  blood  will  be  floT\-ing  into  the 
left  heart  and  into  the  aorta,  so  that  the  systemic  blood-pressure  will  remain 
constant.  Now  let  us  suppose  that  an  inspiratory  enlargement  of  the  thorax 
takes  place,  the  negative  pressure  in  the  pleura  is  increased,  the  two  walls 
of  the  Imigs  are  pulled  farther  away  from  one  another,  and  there  is  a  general 
enlargement  of  the  pulmonary  capillaries.  We  will  assume  that  this  enlarge- 
ment increases  the  capacity  of  the  pulmonary  capillaries  from  25  to  30  c.c. 
Owing  to  this  increased  capacity,  the  first  5  c.c.  of  blood  which  flows  into  the 
lungs  after  the  beginning  of  inspiration  will  not  flow  out  through  the  pul- 
monary vein,  but  will  simply  serve  to  bring  the  capillaries  into  the  same  state 
of  distension  as  before.  Hence  at  the  beginning  of  inspiration  the  flow 
through  the  pulmonary  vein  will  be  diminished  ;  there  will  be  less  blood 
discharged  into  the  left  heart,  and  therefore  a  fall  in  systemic  pressure. 
As  soon,  however,  as  the  increased  capacity  of  the  pulmonarry  vessels  is 
made  up,  the  dilating  effect  of  the  inspiratory  movement  of  these  vessels 
Avail  aid  the  flow  through  the  lungs,  in  consequence  of  the  diminution  of 
resistance,  so  that  the  same  force  of  the  right  heart  which  drove  10  c.c.  of 
blood  per  second  through  the  former  resistance  during  expiration  vdW  now 

30* 


938  PHYSIOLOGY 

drive  more,  say  12  c.c.  of  blood.  There  is  thus  more  blood  entering  the 
left  heart,  and  therefore  a  rise  of  systemic  pressure  during  the  last  three- 
quarters  of  the  inspiratory  movement.  Expiration  will  have  exactly  the 
reverse  effect.  At  the  beginning  of  expiration  there  is  a  diminution  of 
capacity  in  the  pulmonary  vessels  from  30  to  25  c.c.  Hence  during  the  first 
second  of  expiration  the  outflow  of  blood  from  the  pulmonary  vein  into  the 
left  heart  will  be  17  c.c.  (12  c.c.  +  5  c.c).  After  this,  the  increased  resistance 
in  the  pulmonary  capillaries  in  consequence  of  their  constriction  will  come 
into  play,  and  the  flow  of  blood  through  them  will  fall  once  more  from  12  c.c. 
to  10  c.c.  Hence  at  the  beginning  of  expiration  the  inflow  of  blood  from 
the  pulmonary  vein  into  the  left  heart  is  greater  than  at  any  period.  The 
arterial  pressure  will  therefore  rise  to  its  greatest  height  at  the  beginning  of 
expiration,  and  will  fall  during  the  last  three-quarters  of  expiration,  but  will 
attain  its  minimum  only  at  the  beginning  of  the  next  inspiration. 

In  this  way  the  effect  of  the  respiratory  movements  on  the  systemic  blood- 
pressure  can  be  entirely  explained  by  the  influence  they  exert  on  the  lung- 
vessels  or  lesser  circulation.  On  the  other  hand,  Lewis  regards  the  peri- 
cardial pressure,  i.e.  the  direct  influence  of  the  thoracic  movements  on  the 
heart,  as  playing  a  much  more  important  part  than  changes  in  the  pulmonary 
circulation  in  the  production  of  the  respiratory  undulations  in  the  blood- 
pressure.  He  shows  moreover  that  in  man  the  effect  of  respiration  on 
arterial  blood-pressure  may  vary  according  to  the  type  of  respiratory 
movement,  a  deep  intercostal  inspiration  (not  prolonged)  causing  a  pure 
fall  of  pressure,  while  a  deep  diaphragmatic  inspiration  gives  a  pure  rise  of 
blood -pressure.  In  expiration  the  reverse  effects  hold.  He  concludes  that 
it  is  not  possible  to  make  any  general  statement  as  to  the  nature  of  the 
blood-pressure  response  to  a  particular  respiratory  act. 


SECTION   VIII 

THE  CAUSATION  OF  THE  HEART-BEAT 

If  the  heart  be  cut  out  of  the  body  of  a  cold-blooded  animal,  such  as  the 
frog  or  tortoise,  it  wall  continue  to  beat  with  the  normal  sequence  of  its 
different  chambers  for  hours,  or  even  days,  pro\"ided  that  it  be  kept  cool  and 
moist.  In  the  case  of  a  warm-blooded  animal  the  heart  is  similarly  capable 
of  continuing  its  rhj^thmic  contractions  for  some  little  time  after  excision. 
The  period  of  sur^^val  of  the  heart  is  less  in  warm-blooded  than  in  cold- 
blooded animals.  The  fact  that  in  both  cases  the  heart  will  continue  to  beat 
after  removal  from  all  its  connections  with  the  central  nervous  system,  and 
when  blood  is  no  longer  flowing  through  it,  shows  that  the  causation  of  the 
heart-beat  is  to  be  sought  in  the  walls  of  the  heart  itself. 

The  heart  wall  consists  of  a  muscular  tissue  resembhng  in  many  respects 
volmitary  muscle ;  hke  this,  it  presents  longitudinal  and  transverse  striations  ; 
like  this,  it  is  capable  of  contracting  in  response  to  direct  stimulation. 
Normally  voluntary  muscle  only  contracts  in  response  to  impulses  from  the 
central  nervous  system.  When  Remak  described  the  existence  of  collections 
of  ganglion-cells  in  the  sinus  venosus,  it  was  natural  that  "physiologists  should 
ascribe  to  these  collections  of  nerve-cells  the  same  automatic  rhythmic 
fimctions  that  had  been  found  by  Flourens  and  others  to  be  associated  with 
the  grey  matter  of  the  medulla  oblongata  in  connection  w4th  the  maintenance 
of  the  respiratory  movements. 

ANATOMY  OF  THE  FROG'S  HEART 

The  hearts  of  the  frog  and  of  the  tortoise  have  figured  so  largely  in  the  researches  on 
the  causation  of  the  heart-beat  that  it  may  be  profitable  to  mention  briefly  the  main 
points  of  their  anatomy. 

The  frog's  heart  consists  of  the  sinus  venosus,  which  receives  the  anterior  and 
l)osterior  venaj  cavte,  two  auricles,  one  ventricle,  and  the  bulbus  arteriosus,  which  opens 
into  the  two  aorta?.  The  venous  blood  from  the  body  flows  into  the  sinus  venosus  by 
the  three  vente  cavfe,  and  thence  into  the  right  auricle,  while  the  left  auricle  receives 
the  blood  from  the  lungs.  The  ventricle  thus  receives  mixed  arterial  and  venous  blood, 
the  arterial  blood  being  directed  by  the  spiral  valve  of  the  bulbus  aortae  so  as  to  flow 
chiefly  towards  the  head. 

The  muscular  fibres  of  the  heart  areless  highh- developed  thanthose  of  the  mammalian 
heart.  They  are  spindle-shaped,  and  only  dimly  cross-striated.  The  cross-striation 
becomes  more  distinctly  marked  as  we  proceed  from  sinus  to  ventricle,  the  sinus  muscle 
fibre  representing  the  most  primitive  condition.  There  is  complete  muscular  con- 
tinuity between  all  the  cavities  of  the  heart.     The  circular  ring  of  muscle  at  the  junction 

939 


940 


PHYSIOLOGY 


of  sinus  with  auricles  and  of  auricles  with  ventricles  presents  only  slight  traces  of  cross- 
striation  (Gaskell). 

The  heart  is  well  supplied  with  nerve  fibres  and  ganglion-cells.  The  two  vagi  enter 
the  sinus  venosus  and  branch  just  under  the  pericardium.  Here  they  become  con- 
nected with  a  collection  of  nerve-cells,  known  as  Remak's  ganglion.  From  the  sinus 
the  two  vagi,  now  called  septal  nerves,  pass  down  in  the  interauricular  septum,  one  in 
front  and  the  other  behind.  Near  the  auriculo -ventricular  groove  they  enter  two  col- 
lections of  ganglion-cells,  called  Bidder's  ganglia.  From  these  ganglia  non-meduUated 
fibres  are  distributed  to  surrounding  parts  of  the  auricle  and  to  the  whole  of  the  ventricle. 
In  the  upper  third  of  the  ventricle  occur  scattered  ganglion-cells  attached  to  the  nerve 
fibres.     These  are  quite  absent  in  the  lower  half  or  two -thirds. 

In  the  tortoise  (Fig.  422)  the  two  auricles  are  bound  together  by  a  flat  band  of 
tissue,  which  serves  also  to  connect  the  sinus  with  the  ventricle.     The  septum  between 


L.V.C.S     i-A 


Ventricle 


Fig.  421.  Diagram  of  frog's  heart.  (After 
Cyon.) 
V,  ventricle  ;  r.a,  l.a,  right  and  left  auricles 
(atrium) ;  s.v,  sinus  venosus  ;  p.v,  pulmonary 
veins  ;  l.v.c.s  and  B.v.c.s,  left  and  right  su- 
perior vena  cava  ;  v.c.i,  vena  cava  inferior ; 
Tr.A.  truncus  arteriosus. 


Cor  .v. 


Fig.  422.  Tortoise's  heart  (after 
Gaskell)  as  it  appears  when  sus- 
pended for  registering  the  auricu- 
lar and  ventricular  contractions. 
N,  nerve-trunk  with  fibres  con- 
necting Remak's  and  Bidder's 
ganglia ;  cor.  V,  coronary  vein. 


the  auricles  arises  from  the  central  line  of  this  junction  wall.  The  two  vagi  nerves 
pass  into  a  large  accumulation  of  ganglion-cells  in  the  sinus,  and  thence  along  the  basal 
wall  to  the  auriculo -ventricular  groove,  lying  just  under  the  pericardium.  In  the  groove 
they  pass  into  a  collection  of  ganglion-cells,  whence  fibres  are  given  off  to  both  auricles 
and  ventricle.  As  they  leave  the  sinus,  a  branch  is  always  given  off  by  the  right  nerve 
to  accompany  the  coronary  vein,  which  conveys  blood  from  the  ventricular  wall  to  the 
sinus.  Thus  the  nerves  of  the  tortoise's  heart  are  altogether  more  accessible  than  those 
of  the  frog's  heart.  In  other  points  the  tortoise's  heart  is  similar  to  the  frog's  heart, 
though  considerably  larger. 


THE  AUTOMATIC  CONTRACTION  OF  THE  FROG'S  HEART 
The  frog's  heart  in  the  body,  or  when  removed  from  the  body  intact, 
beats  regularly,  the  contraction  starting  in  the  sinus,  then  travelMng  to 
auricles,  ventricle,  and  bulbus.  If,  however,  the  heart  be  removed  by 
cutting  it  across  the  sino-auricular  junction,  or  if  the  auricles  be  functionally 
separated  from  the  sinus  by  a  hgature  round  this  junction  (Stannius's  liga- 
ture), the  auricles  and  ventricle  stop  in  an  uncontracted  condition  (diastole), 
while  the  sinus  goes  on  beating  regularly.  After  the  lapse  of  a  period  varying 
from  five  minutes  to  half  an  hour  the  detached  part  of  the  heart  begins  to 
beat,  at  first  slowly  and  then  more  rapidly,  but  never  attaining  the  rate  of  the 
sinus.  The  auricles  beat  first,  and  then  the  ventricle.  If  now  the  ventricle 
be  cut  away  by  an  incision  in  the  auriculo-ventricular  groove  from  the  auricles 
the  latter  go  on  beating ;  while  the  former,  after  a  few  beats  due  to  the 
excitation  of  the  incision,  stops  still,  and  only  after  a  considerable  time  may 
begin  again  to  contract  very  slowly. 


THE  CAUSATION  OF  THE  HEAET-BEAT  941 

On  the  other  hand,  a  ventricle- apex  preparation  (that  is  to  say,  the  lower 
two-thirds  of  the  ventricle  separated  functionally  from  the  rest  of  the  heart) 
never  beats  again  under  normal  circumstances.  To  single  stimuU  it  responds 
with  a  single  beat,  not  with  a  series  of  beats  as  the  whole  heart  does.  If  the 
lower  third  of  the  ventricle  be  separated  functionally  in  the  hving  frog  by 
crushing  the  ring  of  tissue  between  it  and  the  upper  third,  it  never  gives  a 
spontaneous  beat  again,  although  it  is  under  the  most  normal  conditions  pos- 
sible in  the  circumstances.  There  is  thus  a  descending  scale  of  automatic 
power  in  the  different  parts  of  the  frog's  heart — from  the  sinus,  where  it 
is  highest,  to  the  lower  parts  of  the  ventricle,  where  it  is  apparently 
absent.  From  this  fact  it  has  been  thought  that  the  automaticity  of  the 
frog's  heart  is  dependent  on  the  gangha  present  in  it.  The  contraction  was 
supposed  to  be  started  by  impulses  proceeding  from  the  sinus  gangUon. 
If  this  were  cut  off,  Bidder's  ganglia,  or  the  scattered  cells  in  the  upper 
third  of  the  ventricle,  could,  it  was  thought,  take  up  its  task  of  originating 
impulses.  The  muscle-cells  under  this  hypothesis  act  as  the  servants  of  the 
ganglion- cells,  just  as  the  voluntary  muscles  wait  on  the  commands  of  the 
cells  in  the  spinal  cord  and  brain. 

The  view  that  the  ganghon-cell  sends  out  rhythmic  impulses  had,  how- 
ever, to  be  discarded  when  it  was  discovered  that  the  muscle  forming  the 
lower  third  of  the  ventricle  either  of  the  frog  or  the  tortoise,  though  free  from 
ganglion-cells,  could  be  excited  by  various  means  to  rhythmic  contractions. 
Thus  it  could  be  set  into  rhythmic  action  when  supphed  with  salt  solution 
under  pressure,  through  a  perfusion  cannula,  or  when  excited  by  the  passage 
of  a  constant  current  or  of  weak  induction  shocks.  The  fact  that  the  heart 
muscle  responded  to  continuous  stimulation  by  a  rhythmic  discharge 
suggested  that  the  function  of  the  ganglion-cells  was  to  furnish  a  constant 
stimulation  to  the  muscle-cells  and  so  maintain  these  in  rh}i:hmic  acti\aty. 

The  theory  of  the  ganglionic  origin  of  the  cardiac  rhythm  was  seriously 
affected  by  a  series  of  researches  carried  out  by  Gaskell  and  by  Engelmann. 
The  arguments  against  the  '  neurogenic  '  hypothesis  may  be  summarised  as 
follows  : 

(a)  The  cardiac  muscle,  free  from  any  gangUon-cells  whatsoever,  can  be 
excited  by  various  means  to  rhythmic  contraction.  When,  in  the  living  frog, 
the  apex  of  the  ventricle  is  crushed  off  from  the  base  so  as  to  leave  only 
material  continuity  between  the  two  parts,  the  circulation  of  the  blood  is 
maintained  by  the  contraction  of  all  the  parts  of  the  heart  except  the  apex, 
which  never  resumes  its  activity.  If,  however,  the  intraventricular  pressure 
be  raised  by  clamping  the  aorta  the  apex  begins  to  beat  at  its  own  rhythm, 
which  is  independent  of  the  rhythm  of  the  rest  of  the  heart.  Moreover  a 
strip  can  be  cut  from  the  apex  of  the  tortoise's  ventricle  (Fig.  423),  free  from 
ganglion-cells,  which  on  keeping  in  a  moist  chamber  and  moistening  occasion- 
ally with  normal  salt  solution  enters  into  rhythmic  contractions. 

(b)  In  the  frog  it  is  possible  to  excise  the  inter-auricular  septum  with 
its  ganglia,  and  a  considerable  portion  of  the  ganglia  in  the  sinus  venosus  and 
at  the  base  of  the  ventricles,  without  interfering  in  any  way  with  the  cardiac 


942 


PHYSIOLOGY 


rhythm.  This  experiment  is  still  easier  to  carry  out  in  the  tortoise's  heart 
where  the  nerves  and  gangha  run  in  the  basal  portion  of  the  auricles.  This 
can  be  excised,  leaving  the  two  auricular  appendages  in  connection  with  the 
sinus  venosus  and  with  the  ventricles. 

(c)  The  heart  in  the  developing  chick  can  be  seen  beating  at  a  time  when 
it  is  quite  free  from  nerve-cells,  which  only  extend  into  it  at  a  later  date. 

{d)  Remak's  gangha  are  situated  at  the  point  where  the  two  vagus  nerves 
enter  the  heart,  and  under  the  microscope  can  be  seen  to  be  connected  with 
the  fibres  of  these  nerves.  We  have  now,  from  the  discovery  of  Langley  and 
Dickinson,  a  means  of  judging  of  the  action  of  gangfion-cells  in  the  drug 
nicotine,  which  first  stimulates  and  then  paralyses  nerve- cells  themselves 

or  the  synapses  between  the  cells 
and  the  nerve  fibres  in  connection 
with  them.  Direct  apphcation 
of  nicotine  to  the  heart,  after  a 
primary  period  of  slowing,  leaves 
the  heart-beat  practically  un- 
altered, the  normal  sequence  of 
beat  in  the  various  cavities  being 
unaffected.  After  the  apphcation 
of  the  drug,  however,  stimulation 
of  the  trunk  of  the  vagus  is  with- 
out effect,  though  slowing  or  stop- 
page of  the  heart  may  still  be 
produced  by  excitation  of  the 
post  ganglionic  nerve  fibres  of 
the  vagus  which  arise  from  the 
cells  of  Remak's  gangha.  These 
gangha  must  therefore  be  re- 
'garded  not  as  a  motor  centre  for 
the  heart,  but  merely  as  a  distri- 
buting-centre for  the  inhibitory 
fibres  of  the  vagus.  Since  tetani- 
sation  of  the  heart  with  weak  currents  also  causes  local  inhibition,  it  would 
seem  that  the  finer  nerve  fibres  ramifying  throughout  the  muscular  substance 
are,  to  a  large  extent  at  all  events,  inhibitory  in  their  function.  This  is 
confirmed  by  the  fact  that  atropine,  which  paralyses  the  inhibitory  fibres 
of  the  vagus,  also  abolishes  the  direct  inhibitory  effect  of  tetanisation  on  the 
heart  muscle.  Gaskell  and  Engelmann  therefore  came  to  the  conclusion 
that  the  source  of  the  cardiac  rhythm  was  to  be  found,  not  in  the  ganglia 
scattered  about  its  cavities,  but  in  the  muscular  cells  themselves. 

The  normal  sequence  of  events — i.e.  the  subordination  of  the  ventricle  to 
auricles  and  auricles  to  sinus,  so  that  the  beat  always  follows  in  the  order, 
sinus,  auricles,  ventricle,  bulbus — can  be  ascribed  to  the  difference  between  the 
natural  rhythms  of  these  different  cavities.  It  is  possible  to  record  the  con- 
tractions of  each  of  these  parts  of  the  heart  separately,  after  having  divided 


Fig.  423.  Tortoise's  heart  from  dorsal  surface. 
(Gaskell.) 
S,  sinus ;  J,  sino-auricular  junction ;  A,  auri- 
cles ;  C,  coronary  vein ;  V,  ventricle.  (The 
dotted  line  shows  how  a  strip  may  be  cut  from 
the  ventricle  apex.) 


THE  CAUSATION  OF  THE  HEART-BEAT 


943 


them,  either  functionally  by  crushing  the  intervening  tissue,  or  by  actual 
section.  Under  such  conditions  it  is  found  that  there  is  a  descending  scale 
of  rhythm  from  sinus  to  bulbus,  the  contractions  of  the  sinus  being  most 
frequent,  those  of  the  ventricle  and  bulbus  the  least  frequent.  Thus  it  is 
impossible  for  the  ventricle  to  beat  at  its  own  rhythm,  since  before  it  is  ready 
to  beat  again  after  performing  one  beat  it  receives  an  impulse  from  the 
auricles  causing  an  excited  beat.  That  the  normal  sequence  of  contractions 
is  dependent  simply  on  the  natural  rhythm  of  the  sinus  is  shown  by  the  fact 
that  by  exciting  the  ventricle  by  means  of  induction  shocks  repeated  at  a 
rhythm  shghtly  greater  than  that  of  the  sinus  it  is  possible  to  excite  a  reversed 
rhythm,  the  order  of  the  beat  being  now  ventricle,  auricles,  sinus  venosus. 

The  dependence  of  the  ven- 
tricular rhythm  on  the  beat  of  the 
sinus  may  be  shown  by  a  simple 
experiment.  The  ventricle  is  con- 
nected with  a  lever  suspended  by 
a  spring  so  as  to  record  its  con- 
tractions on  a  drum.  A  platinum 
loop  connected  with  a  galvanic 
battery  is  put  round  the  heart, 
either  round  the  sinus  or  round 
the  ventricle  (Fig.  •424).  When 
a  current  is  allowed  to  pass 
through  the  inner  loop  the  cor- 
responding part  of  the  heart  is 
warmed.  When  the  ventricle 
alone  is  warmed  the  beats  be- 
come larger,  but  the  rhythm  is 
unaltered.  On  lowering  the  loop 
so  as   to   warm  the    sinus,    the 

rhythm  of  the  whole  heart  is  quickened,  but  the  size  of  the  ventricular 
beats  is  unaffected.  The  different  rhythmic  power  of  these  parts  of  the 
heart  is  apparently  connected  with  the  histological  characters  of  the 
muscle  fibres  at  each  part.  The  lowly  differentiated  sinus  cell  has  well- 
marked  rhythmic  power  and  a  quick  rhythm  of  beat,  but  is  not  able  to 
exert  such  force  in  its  contraction.  The  more  highly  differentiated 
ventricle  cell  has  only  a  shght  rhythmic  power,  but  beats  forcibly  and 
is  a  good  servant  of  the  sinus. 


Fig.  424. 


THE  PROPAGATION  OF  THE  WAVE  OF  CONTRACTION 
The  normal  contraction  started  in  the  sinus  venosus  is  propagated  to  the 
auricles,  thence  to  the  ventricle,  and  thence  to  the  bulbus  aorta\  Between 
the  contractions  of  each  of  these  cavities  there  is  a  slight  pause,  whereas 
the  contraction  spreads  so  rapidly  over  each  cavity  that  all  parts,  say  of  the 
auricles  or  ventricle,  appear  to  contract  simultaneously.  It  is  obvious  that 
the  excitatory  wave  might  be  propagated  through  the  heart  from  one 


9M 


PHYSIOLOGY 


muscle-cell  to  another,  or  by  means  of  nerve  fibres,  wbich  would  excite  the 
muscular  tissue  of  each  cavity  to  contract. 

The  distinct  pause  which  intervenes  between  the  contractions  of  auricles 
and  ventricle  was  long  regarded  as  evidence  for  the  nervous  character  of  the 
contraction,  and  as  showing  the  operation  of  a  nerve-centre  in  the  co- 
ordination of  the  contractions  of  difierent  cavities.  A  contraction  wave 
may,  however,  be  started  at  any  part  of  the  heart  and  may  travel  from  this 
to  aU  other  parts.  Thus,  although  the  normal  direction  of  the  contractions 
is  from  sinus  to  ventricle,  it  is  possible,  by  stimulating  the  apex  of  the 
ventricle,  to  excite  contractions  in  the  reverse  order,  viz.  from  ventricle  to 
sinus.     Such  a  fact  is  at  variance  with  all  our  present  knowledge  of  excitation 


Tig.  425. 


Heart  of  tortoise  with  auricle  slit  up  so  as  to  cause  a  partial 
block.     (Gaskell.) 


of  motor  nerves.  Excitation  of  the  nerve  going  to  the  sartorius,  or  any  part 
of  the  nerve,  may  excite  contractions  of  all  the  fibres  of  which  the  muscle 
is  composed.  On  the  other  hand,  excitation  of  a  part  of  the  muscle  which 
is  free  from  nerve  fibres  causes  a  contraction  which  is  hmited  to  the  muscle 
fibres  directly  excited  and  does  not  extend  to  the  nerves.  If  motor  nerves 
arose  from  the  hypothetical  motor  ganghon  of  the  heart  and  passed  to  the 
ventricular  muscle,  one  would  not  expect  that  contraction  of  the  ventricular 
muscle  could  excite  these  nerves  and  so  cause  the  propagation  of  a  wave  of 
contraction  in  the  reverse  direction. 

That  the  propagation  cannot  be  due  to  any  nerve-trunks  running  from 
sinus  to  ventricle  is  shown  by  various  experiments  of  Engelmann  and 
Gaskell.  Thus,  if  the  auricle  is  sht  up  by  a  series  of  interdigitating  cuts,  the 
contraction  wave  starting  from  the  sinus  travels  along  the  auricular  muscle 
around  the  end  of  each  section,  and  finally,  on  arrival  at  the  ventricle, 
causes  a  contraction  of  this  cavity.  In  the  heart  of  the  tortoise  the  nerve- 
trunks  run,  not  in  the  interauricular  septum,  but  in  a  band  of  tissue  joining 


THE  CAUSATION  OF  THE  HEAKT-BEAT  945 

the  sinus  to  the  ventricles  ;  this  band  can  be  exercised  with  all  its  contained 
nerves  without  interfering  in  any  way  with  the  normal  sequence  of  contrac- 
tions. Moreover  the  pause  observed  between  the  contractions  of  auricles 
and  ventricles  has  been  shown  by  Gaskell  to  be  due  to  the  retardation  of  the 
excitatory  wave  which  occurs  in  its  propagation  through  the  muscular 
tissue  in  the  auriculo-ventricular  junction.  A  similar  retardation  of  the 
wave  can  be  produced  at  any  point  either  in  auricles  or  ventricle  by  diminish- 
ing the  conducting  muscular  tissue  to  a  sufficiently  small  extent.  Thus, 
if  the  auricle  of  the  tortoise  be  divided  as  in  the  diagram  (Fig.  425),  it  will 
be  noticed  that  the  sinus  first  contracts,  then  the  auricular  half  As ;  a 
distinct  pause  then  occurs  while  the  contractile  process  is  passing  over  the 
'  bridge,'  and  finally  Av  contracts,  followed  by  the 
ventricle.  The  apparent  pause  between  the  contrac- 
tion of  the  auricles  and  ventricle  is  due  therefore  to 
a  partial  '  block '  at  the  auriculo-ventricular  junc- 
tion. If  the  block  be  increased  in  the  experiment 
just  quoted,  as,  for  instance,  by  allowing  the  bridge 
of  tissue  to  dry  or  by  making  it  still  narrower,  it  may 
be  found  that  only  one  out  of  every  two  contractions 
passes  across  the  bridge  (Fig.  426),  and  the  slightest 
increase  in  the  resistance  to  the  propagation  of  the    ^^^:    '^^9\    Contraction 

r     j:    r>  Qf  auricles  and  ventn- 

wave  may  lead  to  the  block  becoming  complete.  On  cles  of  tortoise  heart, 
moistening  the  bridge  again  every  contraction  may       J^^  grolTe^'h^^^Uen 

be   seen  to  pass.  clamped  so  as  to  pro- 

By  the  methylene-blue  method  it  is  possible  to       fSrwing  ^  onJy'  elery 
demonstrate  a  close  network  of  non-medullated  fibres       second  contraction  to 
surrounding  all  the  muscle-cells  of  the  heart.     It  is       ^^^^'    ^  askell.j 
obvious  that  the  experiment  just  quoted  would  not 

exclude  the  possibihty  of  propagation  occurring  through  such  a  nerve 
network.  The  properties  of  the  network  would  have  to  difier  from  those 
of  any  of  the  nerve  tissues  with  which  we  are  acquainted  ;  whereas  we  know 
that  under  certain  circumstances  impulses  may  be  transmitted  fi'om  fibre  to 
fibre  even  in  striated  muscle,  and  such  a  mode  of  propagation  is  the  most 
obvious  explanation  of  the  phenomena  observed  in  the  heart. 

If  the  auricles  be  soaked  for  some  time  in  distilled  water  they  enter  into 
a  condition  of  what  is  known  as  water-rigor  {Wasserstarre).  In  this  con 
dition  they  are  incapable  of  contracting,  but  can  still  propagate  the  wave^from 
sinus  to  ventricle.  This  experiment  has  been  regarded  as  a  demonstration 
of  the  part  taken  by  nerve  fibres  in  the  propagation  of  the  wave,  but  such 
an  explanation  is  not  necessary,  since  a  similar  condition  of  water-rigor  in  a 
voluntary  muscle  fibre  has  been  shown  to  allow  the  passage  of  an  excitatory 
wave  through  the  affected  part  to  the  normal  portion  of  the  muscle,  which 
then  responds  by  a  contraction. 

A  series  of  interesting  researches  by  Carlson  on  the  mechanism  of  the  heart-beat  in 
the  king-crab  Limulus  have  been  thought  to  throw  light  on  the  vexed  question  of  the 
automatism  of  the  vertebrate  heart. 


946 


PHYSIOLOGY 


In  Limulus  the  heart  forms  a  segmented  tube  of  ordinary  striated  muscular  fibres. 
In  large  specimens  the  tube  may  be  from  10  to  15  cm.  long  and  2  to  2  J  cm.  broad. 
Like  the  hearts  of  most  other  invertebrates  and  of  all  vertebrates,  it  has  a  local  system 
of  ganglion-cells,  but  so  situated  that  they  can  be  cut  away  entirely  from  the  muscular 
portions  of  the  organ.  The  arrangement  of  the  cardiac  nervous  system  in  Limulus  is 
shown  in  Fig.  427. 

The  ganglion-cells  are  collected  chiefly  in  a  dorsal  nerve  ganglion  cord  which  runs 
almost  the  whole  length  of  the  heart.     From  this  cord  non-medullated  nerve  fibres  pass 


i2;:22=sd^^,^££2s. 


Fig.   427.     Heart  of  Limulus  from  dorsal  surface.     (Carlson.) 
mnc,  median  nerve-cord  ;  In,  lateral  nerve-trunks. 

directly  into  the  substance  of  the  heart,  and  also  send  branches  to  two  lateral  nerve- 
trunks,  by  which  fibres  are  distributed  to  all  parts  of  the  heart. 

The  heart  normally  contracts  about  forty  times  per  minute.  Each  contraction 
affects  all  parts  practically  simultaneously,  though  in  the  dying  heart  the  posterior 
portions  apparently  contract  slightly  before  the  anterior,  and  may  continue  to  contract 
after  the  anterior  end  has  come  to  a  standstill. 

Division  of  the  muscular  tissue  leaving  the  nerve-strands  intact  does  not  alter  in 
any  way  the  synchronism  of  contraction  of  the  two  ends  of  the  heart.  Division  of  the 
nervous  cord  into  two  parts,  the  section  being  carried  between  the  posterior  third  and 
anterior  two-thirds,  causes  complete  lack  of  co-ordination  between  the  two  ends  ;  both 
ends  of  the  heart  continue  to  contract,  but  at  different  rhythms.     Extirpation  of  the 


Fig.  428.     '  Nerve-muscle  preparation  '  of  heart  of  Limulus  consisting  of  the  muscle 
of  the  two  anterior  segments,  with  the  two  lateral  nerves.     (Carlson.) 

nerve-cord  abolishes  spontaneous  contractions.  If  the  anterior  half  of  the  dorsal 
ganglionic  cord  be  excised,  all  parts  of  the  heart  will  continue  to  contract  in  unison. 
If  now  the  lateral  nerve-trunks  be  divided,  the  anterior  half  of  the  heart  ceases  to  con- 
tract, showing  that  it  was  being  excited  by  impulses  arising  in  the  posterior  part  of  the 
ganglionic  cord.  It  is  possible  therefore  to  make  a  nerve-muscle  preparation  of  the 
anterior  part  of  the  heart,  consisting  of  the  muscle  of  the  first  two  segments  with  a 
longer  stretch  of  the  lateral  nerves  (Fig.  428).  Stimulation  of  the  lateral  nerves  with 
a  single  shock  causes  a  single  beat  of  the  anterior  segments  ;  tetanising  shocks  cause  a 
continued  contraction  of  the  muscle  preparation. 

There  seems  to  be  no  doubt  that  in  this  animal  the  beat  of  the  heart  is  originated 
and  co-ordinated  by  the  action  of  the  local  ganglionic  centres.  Moreover  Carlson  has 
shown  that  the  inhibitory  nerve  to  the  heart  acts,  not  by  direct  influence  on  the  muscle 
fibres,  but  by  an  inhibition  of  the  automatic  activity  of  the  ganglionic  cells,  thus  con- 


THE  CAUSATION  OF  THE  HEART-BEAT  947 

firming  for  this  special  case  the  general  view  of  inhibition  long  ago  put  forward  by 
Morat,  but  not  now  generally  accepted. 

The  heart  muscle  docs  not  show  a  refractory  period,  but  on  direct  stimulation  with 
repeated  shocks  there  may  be  a  summation  of  contractions,  which  maj'  fuse  to  a  com- 
plete tetanus.  The  question  naturally  arises  how  far  the  heart  of  Limulus  is  to  be 
regarded  as  a  special  case,  or  how  far  we  may  transfer  results  gained  from  experience 
on  this  heart  to  those  of  other  hearts  in  which  a  perfect  separation  between  ganglion- 
cells  and  muscle  fibres  is  not  so  easily  attainable.  Carlson  has  sought  to  show  the 
applicability  of  his  results  to  the  explanation  of  the  cardiac  mechanism  in  vertebrates 
by  a  series  of  observations  on  other  invertebrates'  hearts,  where  the  muscular  and 
nervous  tissues  are  not  so  easily  dissociable.  Such  hearts  present  phenomena  very 
analogous  to  those  of  the  frog's  heart.  According  to  him  the  phenomenon  of  the  re- 
fractory period,  the  '  all  or  none  '  law  of  contraction,  and  the  absence  of  tetanus  in  the 
heart  of  the  frog  is  due,  not  to  the  peculiar  functions  of  the  muscle  fibres,  but  to  the 
fact  that  in  all  our  experiments  we  are  affecting  muscular  and  nervous  tissues 
simultaneousl^^ 

In  the  absence  of  more  perfect  knowledge  of  the  properties  of  the  nerve-nets  which 
surround  involuntary  and  cardiac  muscle  fibres  a  decision  of  the  point  is  not  yet  possible. 
The  muscle  and  nerve  fibres  of  Limulus  show,  however,  important  differences  from  the 
cardiac  muscle  of  the  frog  in  their  reaction  to  chemical  stimuli.  Acceptation  of  the 
neiu"ogenic  theory  would  necessitate  the  prediction  of  a  type  of  nervous  tissue  endowed 
with  properties  for  which  we  have  no  analogy  in  any  of  the  nerve  tissues  which  have 
been  the  subject  of  exact  investigation,  whereas  the  myogenic  theory  only  ascribes  to 
the  muscle-cells  of  the  heart  properties  which  are  the  common  attribute  of  all  protoplasm 
or  are  displayed  in  a  less  marked  degree  by  the  ordinarj^  skeletal  muscle  fibres.  It 
would,  at  any  rate,  be  premature  to  transfer  unreservedly  all  the  results  obtained  on  the 
heart  of  the  Limulus,  the  muscle  fibres  of  which  have  the  structure  and  behavioiu"  of 
skeletal  muscle  fibres,  to  the  explanation  of  the  phenomena  exhibited  by  the  hearts  of 
vertebrates. 

THE  HEART-BEAT  AS  A  WAVE  OF  CONTRACTION 

It  the  beat  of  the  frog's  ventricle,  or  a  strip  of  mammalian  ventricle,  be 
recorded,  the  curve  obtained  resembles  closely  the  twitch  of  a  voluntary 
muscle  produced  in  response  to  a  single  excitation.  Whereas,  however,  a 
single  contraction  with  the  subsequent  relaxation  of  voluntary  nuiscle  only 
lasts  about  one-tenth  of  a  second,  the  contraction  of  the  mammahan  ventri- 
cular muscle  lasts  three-tenths  of  a  second,  of  the  frog's  ventricle  about 
half  a  second,  and  of  the  tortoise  ventricle  about  two  seconds.*  In  the  heart, 
as  in  a  voluntary  muscle  fibre,  the  contractile  process  originates  at  the 
stimulated  point  and  travels  thence  to  all  other  points. 

The  progress  of  the  excitatory  wave  is  well  seen  if  a  record  be  taken  of  the 
electrical  changes  resulting  in  the  frog's  heart  from  a  single  stinnilation.  If 
the  two  ends  of  a  strip  of  ventricular  muscle  be  connected  with  the  two 
terminals  of  a  capillary  electrometer,  stimulation  at  one  end  causes  a  diphasic 
variation,  showing  that  the  excitatory  process  starts  at  the  stimulated  end 
and  travels  to  the  other  eiid  of  the  heart.  Thus  if  the  acid  of  the  electro- 
meter be  connected  with  the  base  of  the  ventricle  and  the  mercury  of  the 
capillary  be  connected  with  the  apex,  stimulation  at  the  base  causes  a  wave 
passing  from  base  to  apex.     Directly  after  the  stimulation  therefore  the  base 

*  The  duration  of  the  contraction  depends  on  the  temperature.  The  figures  given 
are  for  the  mammalian  heart  at  37°  C.  and  for  the  amphibian  heart  at  about  15°  C. 


948 


PHYSIOLOGY 


becomes  negative  and  the  column  of  mercury  moves  towards  the  acid ; 
a  moment  later  the  contraction  extends  to  the  apex.  All  parts  of  the 
heart  are  now  in  a  similar  condition  of  excitation  :  there  is  no  difference  of 
potential  between  the  two  terminals  and  the  mercury  comes  back  quickly 
to  the  base  hne.  Relaxation,  hke  contraction,  starts  first  at  the  base 
and  proceeds  thence  to  the  apex.  There  is  thus  a  small  period  during 
which  the  apex  is  still  contracted  while  the  base  is  relaxed  and  the  apex 
is  therefore  negative  to  the  base.  This  terminal  negativity  of  the  apex 
is  shown  on  the  capillary  electrometer  by  the  excursion  of  the  colunm 
of  mercury  away  from  the  point  of  the  capillary  (cp.  Fig.  87,  p.  230). 


Fig.  429.     Electrometer  record  of  variation  of  spontaneously  beating  tortoise 

heart.     (Gotch.) 

Analogous  effects  are  obtained  on  leading  off  the  spontaneously 
beating  heart  in  the  frog  or  tortoise  (Fig.  429).  The  conditions  are, 
however,  rather  more  complex,  and  the  most  usual  variation,  as  Gotch 
has  shown,  is  triphasic.  In  its  most  primitive  form  the  vertebrate  heart 
is  composed  of  a  simple  tube  in  which  a  contraction  starts  at  the  venous 
end  and  is  propagated  in  a  wave-hke  manner  along  the  tube  to  the 
arterial  end.  In  the  higher  vertebrates  the  heart  at  its  first  appear- 
ance has  the  same  tubular  form,  but  the  simple  tube  very  rapidly 
becomes  modified,  partly  by  twisting  on  itself,  partly  by  the  outgrowth 
of  the  dorsal  or  the  ventral  wall  of  the  tube  to  form  the  cavities  of  the 
auricle  and  ventricle.  Gotch  suggests  that  the  excitatory  process  follows 
the  course  of  the  original  tube  and  that  the  typical  form  of  the  curve 
is  due  to  the  base  becoming  excited  twice,  first  at  the  part  in  con- 
tinuity with  the  auricle,  and,  secondly,  when  the  wave  sweeps  up  to 
the  bulbus  aortse.  But  it  is  possible  that  in  the  cold-blooded,  as  in 
the  mammahan,  heart  there   may   be  a  special  conducting  tissue  which 


THE  CAUSATION  OF  THE  HEAKT-BEAT  949 

leads   the  excitatory   process   to  many   different    parts  of  the  ventricle 
almost  simultaneously. 

There  is  no  doubt  that  the  ventricular  systole  is  comparable  with  a 
simple  muscular  twatch  and  cannot  be  regarded  as  the  summation  of  several 
contractions.  Since  the  excitatory  process  extends  in  the  form  of  a  wave 
not  only  to  all  parts  of  the  same  cavity  but  to  all  parts  of  the  heart,  it  is 
evident  that  the  musculature  of  the  heart  is  to  be  compared,  not  with  skeletal 
muscle  composed  of  many  fibres,  but  to  a  single  muscle  fibre  in  which  all 
parts  are  in  functional  continuity. 

THE  BEAT  OF  THE  MAMMALIAN  HEART 
The  mammalian  heart,  like  the  heart  of  cold-blooded  animals,  will  beat 
for  some  time  after  it  has  been  cut  out  of  the  body,  and  a  perfectly  rhythmic 
activity  may  be  maintained  for  hours  by  feeding  the  heart  from  the  coronary 
arteries  either  \^dth  defibrinated  blood  or  ^^^th  oxygenated  Ringer's  solution, 
with  or  without  the  addition  of  glucose. 

Ganglion-cells  are  found  in  the  mammalian  heart  around  the  openings  of  the  great 
veins,  along  the  border  of  the  interauricular  septum,  in  the  groove  between  auricles 
and  ventricles,  and  in  the  basal  parts  of  the  ventricles. 

The  ventricles  of  mammals  are  endowed  with  a  greater  rhythmic  power 
thaii  the  corresponding  cavities  in  the  frog  and  tortoise.  It  is  possible  to 
sever  or  crush  all  the  nervous  and  muscular  connections  between  auricles  and 
ventricles  without  destroying  their  mechanical  connection  by  means  of  fibrous 
tissue.  Such  a  procedure  does  not,  even  for  a  moment,  stop  the  contractions 
of  the  ventricles,  which  go  on  beating  at  a  rh}'i:hm  which  is  independent  of  and 
slower  than  that  of  the  auricles.  Porter  has  shown  that  a  mere  fragment 
of  the  ventricular  wall,  perfectly  free  from  ganglion-cells,  may  maintain 
rhythmic  contractions  for  some  hours  if  fed  by  an  artificial  circulation  through 
a  branch  of  the  coronary  artery.  We  may  therefore  conclude  that  in  the 
mammalian,  as  in  the  amphibian,  heart  the  cause  of  the  rh}i:hm  is  to  be 
sought  in  the  properties  of  the  muscle  fibres  themselves,  and  that  every  part 
of  the  heart-muscle  possesses  the  power  of  rhythmic  activity,  the  normal 
sequence  of  the  beats  being  determined  by  the  greater  frequency  of  the 
natural  rhythm  of  the  venous  end  of  the  heart. 

In  the  mammalian,  as  in  the  amphibian,  heart  the  excitatory  condition 
started  at  one  point  in  the  muscle  spreads  through  the  muscle  in  all  directions, 
and  the  process  of  conduction  of  excitation  seems  to  be  independent  of  nerve 
fibres.  The  excitatory  process  may  be  conducted  not  only  in  the  ordinary 
direction  from  auricles  to  ventricles,  but  also  from  ventricles  to  auricles. 
If  the  ventricles  be  excited  at  a  rhythm  of  higher  frequency  than  the  natural 
beat  which  is  starting  at  the  venous  end  of  the  heart,  we  may  obtain  a 
reversed  rhythm  in  which  the  order  of  the  beats  is  ventricles — auricles. 
It  is  difficult  to  conceive  of  an  arrangement  of  neurons  which  would  propa- 
gate impulses  impartially  from  auricles  to  ventricles  or  from  ventricles  to 
auricles.  Such  a  condition  would  seem  to  be  in  contradiction  to  the  law 
of  forward  direction  which  obtains  throughout  the  nervous  system.     On  the 


950 


PHYSIOLOGY 


other  hand  the  phenomena  are  easily  explained  on  the  assumption  that  the 
whole  of  the  musculature  of  the  heart  acts  in  many  respects  as  a  single 
muscle  fibre,  along  which  an  excitatory  process  may  be  propagated  in  any 
direction.  But  in  the  adult  mammahan  heart,  on  superficial  dissection, 
the  muscle  fibres  both  of  auricles  and  ventricles  are  seen  to  arise  from  a  fibro- 
cartilaginous ring  surrounding  the  auriculo- ventricular  junction,  leaving 
apparently  no  muscular  continuity  between  the  two  cavities.  On  this 
account  it  was  thought  for  many  years  that  the  propagation  of  the  contrac- 
tion from  auricles  to  ventricles  must 
occur  by  means  of  nerve  fibres,  and 
it  was  only  with  the  discovery  by 
His  of  a  distinct  band  of  modified 
muscle  fibres,  passing  from  the  auri- 
cles to  the  ventricles,  the  '  auriculo- 
ventricular  bundle,'  that  an  anato- 
mical basis  was  furnished  for  the 
physiological  behaviour  of  the  heart. 
The  heart  is  developed  from  a  mus- 
cular tube  in  which  at  the  beginning 
we  must  assume  muscular  continuity 
throughout.  The  primitive  vertebrate 
heart  is  formed  by  a  modification  of 
this  muscular  tube.  In  this  heart,  as 
Keith  has  shown,  we  may  distinguish 
five  chambers,  namely,  the  sinus 
venosus,  the  auricular  canal,  the 
auricle,  the  ventricle  and  the  bulbus 
(Fig.  430).  The  musculature  of  these 
chambers  is  continuous  throughout. 
In  the  adult  heart,  e.g.  of  man,  the 
anatomical  relations  of  the  different 
cavities  have  become  considerably 
modified  in  the  course  of  develop- 
ment. The  sinus  venosus,  i.e.  the 
part  where  in  the  lower  vertebrates  the  contraction  wave  takes  its 
origin,  is  now  represented  merely  by  the  termination  of  the  superior 
vena  cava  and  of  the  coronary  sinus  in  the  right  auricle.  These  two 
veins  are  derived  from  the  right  and  left  ducts  of  Cuvier  in  the  embryo. 
The  sinus  venosus  is  also  represented  by  a  small  amount  of  tissue  under- 
ling the  tcenia  terminalis  of  the  right  auricle,  as  well  as  by  the  remains 
of  the  Eustachian  and  venous  valves.  The  auricular  canal  gives  rise 
to  the  auricular  septum  and  to  the  auricular  ring  surrounding  the  auricu- 
lar-ventricular orifice,  and  in  some  hearts  it  is  prolonged  into  the  ventricle 
as  the  intraventricular  or  invaginated  part  of  the  auricular  canal.  In  the 
adult  heart  two  accumulations  of  more  primitive  tissue  are  found  in  the 
region  corresponding  to  the  sinus  venosus  of  the  embryo  which  are  known 


Fig.  430.  A  generalised  type  of 
vertebrate  heart.  (Keith.) 
a,  sinus  venosus ;  b,  auricular  canal  ; 
c,  auricle ;  d,  ventricle  ;  e,  bulbus  cordis  ; 
/,  aorta  ;  1-1,  sino-auricular  junction  and 
venous  valves  ;  2-2,  canalo-auricular  junc- 
tion ;  3-3,  annular  part  of  auricle ;  4-4,  in- 
vaginated part  of  auricle  ;  5,  bulbo-ventri- 
cular  junction. 


THE  CAUSATION  OF  THE  HEART-BEAT  951 

as  the  sino-auricular  node  and  the  auriculo-ventricular  node.  The  sino- 
aiiricular  node  (Fig.  431)  Ues  in  the  groove  between  the  superior  vena  cava 
and  the  right  auricle.  The  auriculo-ventricular  node  Ues  at  the  base  of 
the  auricular  septum  on  the  right  side,  below  and  to  the  right  of  the  opening 
of  the  coronary  sinus.  From  this  point  a  bundle  of  muscular  fibres  (the 
bundle  of  His  or  the  auriculo-ventricular  or  A.V.  bundle)  runs  along  the  top 
of  the  interventricular  septum  just  below  its  membranous  part  and  then 


Superior  Vena  Cava 


Aorta 


InteriorVenet 

Cava 


Papillap' 
JHuscle 


Fig.  431. 


divides  into  the  right  and  left  septal  divisions,  which  pass  do^^■ll  in  each  ven- 
tricle on  the  interventricular  septmn  into  the  papillary  muscle  arising  from 
the  septum.  Each  half  of  the  bundle  gives  off  several  branches  which  break 
up  more  and  more,  fijially  forming  a  reticulated  sheet  of  tissue  over  the 
greater  part  of  the  interior  of  the  ventricles  just  below  the  endocardimn. 
The  fibres  composing  this  tissue  are  more  primitive  in  character  than  the 
rest  of  the  cardiac  musculature  and  have  long  been  distinguished  as  the 
'  fibres  of  Purkinje.'  In  them  the  fibrillation  is  confined  to  the  periphery  of 
the  muscle  cell.  They  are  distinguished  by  a  high  glycogen  content.  They 
may  be  regarded  as  a  part  of  the  muscular  wall  of  the  heart  specially  differen- 
tiated for  the  rapid  conduction  of  the  excitatory  process  to  all  parts  of  the 
ventricles  (Figs.  432  and  433). 

Numerous  nerve  fibres  and  ganglion-cells  are  found  to  accompany  the  muscle  fibres 
of  the  auriculo-ventricular  bundle.  We  have,  however,  no  reasons  for  regarding  the 
uisrvons  structures  as  concerned  in  the  propagation  of  the  excitatory  wave. 


952 


PHYSIOLOGY 

bundle  forms  the  only  continuous  muscular 


The  auriculo-ventricular 
tissue  between  the  auricles  and  ventricles,  and  destruction  of  it  causes  com- 
plete abohtion  of  the  normal  sequence  of  beat  between  auricles  and  ventricles. 


s.bv^' 


Fig.  432.  Left  ventricle  laid  open  to  display  the  interventricular  septum  on 
which  the  course  of  the  left  division  of  auriculo-ventricular  bundle  and  its 
ramifications  are  shown  in  black.     (After  Tawaba.) 


--i^' 

^^^ 

^^^L 

^0^^ 

g^ffi 

aue|=jafe€S^^ 

^^^ 

^^^^2 

He 

mA 

^^m 

K 

^^ 

\a 

^nr 

s^aJ"^ 

IB 

m 

Fig.  433.     Fibres  of  Purkinje,  from  the  subendocardial  network.     (Taw aba.) 

By  leading  off  different  parts  of  the  heart  to  the  string  galvanometer  it  is 
possible  to  determine  the  time  relations  of  the  excitatory  process.  ^  It  is 
then  found  that  the  mass  of  Purkinje  tissue,  known  as  the  sino- auricular 
node,  is  the  starting-point  of  the  excitatory  process  concerned  in  each  heart- 
beat. It  is  therefore  spoken  of  as  the  '  pace-maker  '  o£  the  heart.  At  each 
beat  a  contraction  starts  at  the  sino- auricular  node,  spreads  a  short  way  up 


THE  CAUSATION  OF  THE  HEART-BEAT  953 

the  great  veins,  and  along  the  auricular  muscle  in  all  directions.  When  it 
arrives  at  the  auriculo-ventricular  node,  the  impulse  is  carried  on  to  the 
ventricles  along  the  auriculo-ventricular  bundle,  spreading  along  the  branches 
of  this  bundle  to  almost  all  parts  of  the  ventricular  muscle.  Although 
normally  the  sino-auricular  node  initiates  each  heart-beat,  this  node  can  be 
put  out  of  action  by  injury  or  coohng  without  stopping  the  rhythmic 
sequence  of  the  heart-beat,  the  office  of  pace-maker  being  now  taken  up  by 
the  auriculo-ventricular  node.  A  speciahsation  of  function  accompanies 
the  differentiation  in  structure  which  we  find  in  the  auriculo-ventricular 
bundle  and  its  branches.  Lewis  has  showTi  that  the  conduction  of  the 
excitatory  process  along  the  auriculo-ventricular  bmidle  of  the  Purkinje 
tissue  occurs  about  ten  times  as  fast  as  the  conduction  through  the  ordinary 
muscular  tissue  of  the  heart,  the  rates  being  about  5000  mm.  and  500  mm. 
per  second  respectively.  Although  all  parts  of  the  ventricles  receive  the 
impulse  to  contraction  almost  simultaneously,  the  contraction  wave,  as 
judged  by  the  electrical  changes,  is  found  to  commence  slightly  earher  at  two 
points,  namely,  on  the  anterior  surface  near  the  apex  to  the  right  of  the 
groove  separating  right  and  left  ventricles,  and  at  the  extreme  apex  of  the 
heart  where  the  endocardiac  tissue  comes  very  close  to  the  surface.  On 
the  other  hand,  the  conus  arteriosus  is  the  last  part  of  the  heart  to  begin 
contracting. 

The  limitation  of  the  muscular  continuity  to  a  single  narrow  bundle  which  is  en- 
dowed with  greatly  increased  conducting  powers,  and  ends  in  a  network  of  tissue 
endowed  with  similar  powers,  is  e^^dently  designed  (to  use  an  old-fasliioned  but 
convenient  word)  to  ensure  that  all  parts  of  the  ventricles  contract  practically 
simultaneously.  If  this  were  not  the  case  the  sudden  contraction  of  the  muscle  fibres 
near  the  base  of  the  ventricles  would  simply  bulge  out  the  still  uncontracted  portion 
near  the  apex,  and  there  would  be  a  risk  of  injury  or  even  ruptui'e  of  the  uncontracted 
part  of  the  ventricle  under  the  stress  of  the  pressure  produced  by  the  contracting  part. 
On  the  other  hand,  if  all  parts  of  the  heart  were  endowed  with  a  similar  rapid  power  of 
conduction,  any  part  slightly  more  excitable  or  irritated  than  the  rest,  might  serve  as 
a  centre  for  emitting  excitatory  waves  which  would  interfere  with  those  transmitted 
from  the  auricles,  and  the  tendency  to  heart  delirium  would  be  enormously  increased. 

THE  HUMAN  ELECTROCARDIOGRAM 
The  passage  of  the  excitatory  wave  over  the  different  heart  cavities  is 
associated  with  corresponding  electrical  changes  resulting  in  differences  of 
potential.  If  we  lead  oft'  any  two  parts  of  the  heart's  surface  to  a  string 
galvanometer  or  capillary  electrometer,  we  obtain  movements  which  are 
caused  partly  by  changes  occurring  in  the  muscle  just  underlying  the  elec- 
trode, partly  by  changes  occurring  at  a  distance  and  transmitted  by  the  inter- 
vening muscle  acting  simply  as  a  moist  conductor.  These  two  kinds  of 
effect  may  be  alluded  to  as  direct  and  indirect.  If  we  lead  off,  not  from  the 
heart  itself,  but  from  neighbouring  tissues  in  contact  with  the  heart,  we 
shall  still  obtain  the  indirect  effect  of  the  electrical  changes  at  each  heart- 
beat, and  these  can  be  obtained,  as  Waller  has  shown,  when  the  intact 
animal  is  led  off  to  the  electrometer  or  galvanometer  by  his  limbs.  In  an 
animal  such  as  the  dog  the  two  fore  Umbs  may  form  one  lead  and  the  two 


954  PHYSIOLOGY 

hind  limbs  the  other.  In  man,  when  the  heart  hes  asymmetrically,  it  is 
usual  to  lead  off  the  right  arm,  and  left  arm,  the  right  arm  and  left  leg,  or  the 
left  arm  and  left  leg,  the  hand  or  foot  being  immersed  in  salt  water  con- 
nected to  the  galvanometer  by  a  zinc  electrode  contained  in  a  porous  pot  full 


Fig.  434.     Electrocardiogram  of  man,  obtained  by  leading  off  from  the  two  hands 
to  a  string  galvanometer. 

c  is  the  carotid  pulse  tracing.     The  different  parts  of  the  curve  are  designated 
by  the  letters  p,  Q,  B,  s,  T,  first  applied  to  them  by  Einthoven. 

of  saturated  zinc  sulphate  solution.     By  this  means  an  electrocardiogram 
is  obtained  similar  to  that  shown  in  Fig.  434. 

In  view  of  the  mechanism  of  the  propagation  of  the  excitatory  wave 
in  the  ventricle  we  should  not  expect  the  cardiogram  obtained  in  this 
indirect  fashion  to  be  easy  of  interpretation,  at  any  rate  so  far  as  regards 
the  course  of  the  wave  through  the  ventricular  muscle.     Such  an  electro- 


Had.art. 


Fig.  435.  Simultaneous  tracings  of  the  jugular  venous  pulse  and  the  radial  arterial 
pulse,  from  a  case  in  which  the  A.V.  bundle  was  destroyed  by  disease.  The 
contractions  of  the  auricles  are  marked  by  the  a  waves  on  the  venous  pulse. 
They  are  more  rapid  than  and  quite  independent  of  the  ventricular  con- 
tractions.    (Mackenzie.) 

cardiogram  however  is  of  considerable  use  clinically,  especially  for  the 
determination  of  the  relation  between  the  auricular  and  the  ventricular  con- 
tractions. The  different  points  in  a  typical  tracing,  such  as  that  contained 
in  the  figure,  are  designated  by  the  letters  P,  Q,  R,  s,  t,  which  were  first 
apphed  to  them  by  Einthoven  and  are  retained  because  they  do  not  involve 
any  theoretical  interpretation  of  the  curves.  Of  these  p  is  certainly  due  to 
the  auricular  contraction  and  Q  marks  the  beginning  of  the  ventricular 
contraction.     The  A.V.  interval  is  given  by  the  distance  between  p  and  q, 


THE  CAUSATION  OF  THE  HEART-BEAT  955 

the  total  duration  of  the  excitatory  condition  in  the  ventricle  by  the  distance 
between  q  and  t. 

The  fibres  of  the  auriculo-ventricular  bundle  may  be  destroyed  by  disease.  In 
such  cases  we  get  a  series  of  phenomena  known  under  the  name  of  Stokes-Adams's 
disease,  the  main  characteristic  of  which  is  the  slow  contractions  of  the  ventricle,  accom- 
panied by  a  rapid  venous  pulse  at  a  rhythm  entirely  independent  of  the  ventricular 
pulse.  The  automatic  activities  of  auricle  and  ventricle  are  in  fact  dissociated  (Fig.  435). 
At  certain  intervals,  or  at  certain  stages  of  the  disease,  the  fibres  of  the  bundle  may 
present  only  a  partial  block,  so  that  the  ventricle  responds  once  to  every  second  con- 
traction of  the  auricle.  The  existence  of  this  disease  is  shown  at  once  on  the  electro- 
cardiogram by  the  dissociation  of  the  normal  relation  between  the  auricular  and  ven- 
tricular variations.     It  may  be  also  sho\vn  by  a  study  of  the  venous  pulse  (Fig.  435). 

THE  PHYSIOLOGICAL    PROPERTIES    OF    THE    CARDIAC   MUSCLE 
THE  RESPONSE  OF  HEART-MUSCLE  TO   DIRECT  EXCITATION 

When  a  skeletal  muscle  is  directly  stimulated  with  induction  shocks  of 
varying  strength,  within  narrow  limits  the  height  of  the  contraction  is 
proportional  to  the  strength  of  the  stimulus.  If  the  frog's  ventricle,  rendered 
motionless  by  a  Stannius  ligature,  be  stimulated  with  a  single  induction 
shock,  if  it  responds  at  all  it  will  respond  with  a  maximal  contraction,  no 
change  in  the  extent  of  the  contraction  being  obtainable,  however  the  stimu- 
lus may  be  increased.  There  is  thus  no  proportionality  in  the  heart  between 
strength  of  stimulus  and  height  of  contraction.  The  heart,  if  it  contracts 
at  all,  always  contracts  to  its  utmost,  the  height  of  the  contraction  being 
dependent,  not  on  the  strength  of  stimulus,  but  on  other  conditions  affecting 
the  muscle  at  the  time  of  its  response. 

Although  much  stress  has  been  laid  on  this  supposed  difference  between 
heart-muscle  and  voluntary  muscle,  a  renewed  investigation  of  the  response 
of  the  latter  to  graded  stimuh  by  Gotch  and  by  Keith  Lucas  tends  to  show 
that  the  distinction  is  not  so  fundamental.  According  to  these  observers  the 
fact  that  the  response  to  a  minimal  stimulus  in  skeletal  muscle  is  smaller  than 
the  response  to  a  maximal  stimulus  is  simply  owing  to  the  fact  that  in  the 
former  case  only  a  small  proportion  of  the  muscle  fibres  is  active  and  that 
increasing  the  strength  of  the  stimulus  merely  increases  the  number  of  fibres 
thrown  into  contraction.  According  to  this  view  therefore  a  maximal  con- 
traction of  skeletal  muscle  would  be  one  involving  all  the  fibres.  In  the 
heart-muscle  all  the  muscle  fibres  are  functionally  continuous,  so  that  a  stimu- 
lus, if  it  excites  at  all,  must  excite  all  the  fibres,  and  every  contraction  must 
be  analogous  to  the  maximal  contraction  of  a  skeletal  muscle.  The  existence 
of  the  '  all  or  none  '  law  in  any  contractile  tissue  would  be  therefore  dependent 
on  the  existence  of  functional  continuity  between  all  the  contractile  elements 
of  the  tissue. 

In  the  retractor  penis  of  the  dog  it  is  possible  to  get  graded  contractions 
with  graded  strength  of  stimuli,  and  in  this  case  it  is  easy  to  observe  that 
with  increasing  strength  of  stimulus  a  greater  extent  of  the  muscle  is  thrown 
into  the  contractile  state.  Closely  connected  with  this  manner  of  response 
is  the  fact  that  in  heart-muscle,  under  normal  circumstances,  it  is  not  possible 


956 


PHYSIOLOGY 


Fig.  436.  Group  of  pul- 
sations showing '  stair- 
case '  character. 


to  get  summation  of  contractions  by  putting  in  a  stimulus,  however  strong, 
before  the  muscle  has  returned  to  rest.  If,  however,  the  propagation  of  the 
first  contraction  throughout  the  heart-muscle  be  retarded  or  prevented  by  a 
partial  death  of  the  tissue,  or  by  stimulus  of  the  vagus  nerve,  it  is  possible, 
as  Frank  has  shown,  to  obtain  an  apparent  summation  of  two  stimuH,  i.e. 
a  curve  in  which  the  second  contraction  is  superposed  on  and  rises  higher 
than  the  first.  Such  a  result,  on  the  explanation  given  above,  would  be  due 
to  a  phenomenon  of  '  block  '  Hmiting  the  propagation  of  the  first  contractile 
wave,  and  yielding  more  to  the  second,  though  this  is  not  the  explanation 
given  by  the  original  observer. 

SUMMATION  OF  STIMULI 

If  an  isolated  frog's  ventricle  which  is  not  beating  be  stimulated  with 
inadequate  shocks,  it  may  be  found,  on  repeating  these  shocks  at  short 
intervals  of  time,  that  they  become  adequate  and  cause  a  contraction  of  the 
ventricle.  A  stimulus  therefore  which  is  subminimal 
may  nevertheless  cause  some  change  in  the  heart- 
muscle,  so  that  the  latter  responds  more  readily  to 
subsequent  stimuli. 

A  similar  improving  effect  of  previous  stimulation 
on  the  condition  of  the  heart-muscle  may  be  observed 
on  the  contractions  themselves.  Thus  in  a  Stannius 
preparation,  if  the  ventricle  be  excited  with  single  induction  shocks,  once 
in  every  ten  seconds,  the  first  four  or  five  contractions  form  an  ascending 
series,  each  contraction  being  rather  higher  than  the  preceding  one.  This 
is  often  spoken  of  as  the  '  staircase  phenomenon  '  (Fig.  436). 

THE  REFRACTORY  PERIOD 

At  each  contraction  of  the  heart-muscle  there  is  a  sudden  decomposition 
of  contractile  material  which,  so  far  at  least  as  concerns  the  incidence  of  an 
external  stimulus,  is  maximal,  i.e.  complete.  Directly  this  has  occurred  a 
process  of  assimilation  or  re-formation  of  contractile  material  begins.  This  lasts 
throughout  the  diastolic  period,  and  the  store  of  contractile  material  is  at  its 
maximum  just  before  the  next  contraction.  A  mechanical  analogy  is  furnished 
by  a  bucket  into  which  a  stream  of  water  is  constantly  flowing,  and  which  tips 
up  automatically  and  empties  out  its  contents  as  soon  as  the  water  reaches 
a  certain  height.  It  is  evident  that  the  power  of  the  heart-muscle  to  contract 
in  response  to  a  stimulus  (its  '  irritability ')  must  be  at  a  minimum  imme- 
diately after  the  automatic  discharge  or  decomposition  has  taken  place,  and 
will  continually  increase  from  this  point  as  the  store  of  contractile  material 
grows,  until  it  arrives  at  such  a  height  that  the  explosive  discharge  occurs 
spontaneously.  Hence  in  each  cardiac  cycle  there  is  a  period,  known  as  the 
refractory  period,  in  which  stimuli  applied  to  the  heart  have  no  effect.  This 
will  be  followed  by  a  period  in  which  a  stimulus  is  followed  by  an  extra 
contraction,  but  with  a  prolonged  latent  period.  Just  before  the  next 
spontaneous  contraction  the  irritability  is  at  its  height,  and  the  heart-muscle 


THE  CAUSATION  OF  THE  HEAET-BEAT 


957 


responds  with  a  contraction  to  a  minimal  stimulus.     These  facts  are  well 
shown  in  Fig.  437. 

When  a  tracing  is  being  taken  from  part  of  the  heart,  e.g.  the  ventricle, 
which  is  beating  rhythmically  in  consequence  of  a  stimulus  communicated 
to  it  from  some  other  part,  such  as  the  sinus  venosus,  an  extra  contraction  is 


Fit;.  437.  Tracings  of  spontaneous  contractions  of  frog's  ventricle,  to  show  refractory 
period.  In  each  series  the  surface  of  the  ventricle  was  stimulated  by  an  induction 
shock  at  E.  as  indicated  by  the  tracing  of  the  signal.  In  1, 2  and'3,  this  stimulus 
had  absolutely  no  effect,  since  it  fell  during  the  refractory  period.  In  4,  ;">.  6,  7 
the  effect  of  the  shock  was  to  interpolate  an  extra  contraction  in  the  series,  the 
latent  period  (shaded  part)  gradually  diminishing  from  4  to  7  (diastolic  rise  of 
irritability).  In  8  the  irritabilitj^  of  the  preparation  was  already  considerable, 
and  the  latent  period  inappreciable.  The  '  compensatory  pause '  after  the 
extra  beat  is  also  well  shown  in  4,  5,  6,  7,  8.     (Marey.) 


followed  by  a  '  compensatory  pause,'  and  in  certain  cases  the  first  contraction 
following  the  pause  is  considerably  augmented.  This  is  due  to  the  fact  that 
one  of  the  impulses  arriving  from  the  sinus  arrives  at  the  ventricles  during 
the  refractory  period  ensuing  on  the  application  of  the  artificial  stimulus  ; 
hence  it  produces  no  effect  and  the  ventricle  has  to  wait  for  the  arrival  of  the 
next  succeeding  excitatory  wave  from  the  sinus  before  it  gives  its  next  beat. 
Hence  the  compensatory  pause  does  not  occur  when  we  are  testing  the  effects 
of  artificial  stimuli  on  the  sinus  venosus. 


958  PHYSIOLOGY 

On  account  of  the  refractory  period  which  ensues  on  the  commencement 
of  the  contractile  process  on  heart  muscle,  it  is  impossible  to  throw  the 
muscle  into  a  tetanus,  since  all  the  stimuh  which  fall  during  systole  are 
entirely  inefEective.  By  using  very  strong  stimuh  it  is  possible  to  intercalate 
extra  contractions  before  the  heart  has  returned  to  the  base  hne,  i.e.  before 
diastole  is  complete.  So  that  in  this  way  one  may  obtain  almost  a  continuous 
contraction,  presenting,  however,  waves  on  its  summit,  which  differs  from 
the  tetanus  of  skeletal  muscle  in  the  fact  that  its  height  is  no  greater  than 
the  height  of  a  single  contraction. 

Only  when  the  functional  continuity  of  the  heart-muscle  is  impaired 
by  the  '  block  '  effect  of  vagal  stimulation  or  the  administration  of  muscarine 
is  it  possible  to  obtain  phenomena  even  superficially  analogous  to  the  summa- 
tion of  contractions  in  skeletal  muscle.* 

FACTORS  MODIFYING  THE  ACTIVITY  OF  CARDIAC  MUSCLE 
INFLUENCE  OF  TENSION  AND  DISTENSION 
When  we  examine  the  behaviour  of  a  heart  isolated  from  the  central  nervous 
system  and  from  the  rest  of  the  body,  as,  for  instance,  in  the  heart-lung 
preparation  {vide  p.  911)  we  find  that  it  has  a  marvellous  power  of  adaptation, 
i.e.  of  regulating  its  activity  according  to  the  mechanical  demands  which  are 
made  upon  it.  Thus  while  we  may  maintain  the  venous  inflow  constant  so 
that  the  heart  is  sending  out  a  litre  of  blood  per  minute,  it  makes  no  difference 
to  the  output  of  the  heart  whether  the  average  arterial  pressure,  and  there- 
fore the  resistance  to  the  outflow  of  blood,  be  maintained  at  80  or  160  mm. 
Hg.,  although  in  the  latter  case  the  heart  must  do  exactly  twice  as  much 
work  in  order  to  maintain  the  outflow  at  the  same  level.  In  the  same  way 
we  may  maintain  the  arterial  pressure  constant  and  alter  the  venous  inflow 
and  we  find  that  within  very  wide  hmits  the  heart  is  able  to  expel  against  the 
arterial  resistance  the  whole  of  the  blood  which  flows  into  it  from  the  veins. 
In  this  way  we  can  alter  the  output  of  a  small  heart  of  50  gms.  from  300  to 
3000  c.c.  per  minute.  As  we  should  expect,  this  variation  in  the  work 
done  by  the  heart  is  associated  with  corresponding  variations  in  the  chemical 
changes  which  occur  at  each  heart-beat.  Evans  has  shown  that  the 
respiratory  exchanges  of  the  heart  increase  'pari  passu  with  the  work  it  is  said 
to  do.  Careful  investigation  of  the  volume  and  pressure  changes  of  the 
heart  under  varying  conditions  of  arterial  resistance  and  venous  filling 
enables  us  to  throw  some  light  on  the  mechanism  of  this  power  of  adaptation. 
Let  us  take  first  the  changes  in  volume  as  recorded  by  the  cardiometer. 
A  heart  is  contracting  100  times  per  minute  and  forcing  out  at  each  beat 
10  c.c.  of  blood  into  the  aorta  against  an  average  pressure  of  80  mm.  Hg., 
with  systolic  and  diastolic  pressures  respectively  of  100  and  60  mm.  Hg.  In 
order  that  the  left  ventricle  may  force  10  c.c.  of  blood  against  this  resistance, 

*  According  to  Mines  the  effect  of  vagus  excitation  in  enabling  the  production  of 
summation  is  due  to  the  shortening  of  the  refractory  period  which  results  from  vagal 
stimulation. 


THE  CAUSATION  OF  THE  HEART-BEAT  959 

the  pressure  in  its  interior  must  rise  at  each  heart-beat  above  the  maximum 
systolic  pressure  in  the  aorta,  e.g.  to  110  mm.  Hg.  The  aortic  valves  w411 
open  as  soon  as  the  pressure  rises  above  60  mm.  Hg.  The  arterial  resistance 
is  now  increased  so  as  to  raise  the  average  pressure  to  120  mm.  Hg.  The 
heart  now  may  raise  the  pressure  in  its  interior  to  120  mm.  Hg.  This  will 
be  higher  than  the  diastolic  pressure 
in  the  aorta  and  a  certain  amount 
of  blood  will  escape,  but  the  outflow 
of  blood  will  cease  as  soon  as  the 
pressure  in  the  aorta  is  equal  to 
that  in  the  ventricle.  Diastole  will 
then  occur,  the  ventricle  will  relax 
before  it  has  emptied  out  10  c.c.  of 
blood.  Let  us  assume  it  has  forced 
out  3  c.c.  of  blood — it  will  then 
contain  an  excess  of  7  c.c.  of  blood 
at  the  end  of  diastole.  Meanwhile 
the  venous  inflow  is  proceeding  at 
the  same  rate  as  before  so  that  at 
the  end  of  diastole  it  has  7  c.c.  more 
blood  than  it  had  at  the  end  of 
the  previous  beat,  i.e.  its  diastolic 
volume  will  be  increased  and  the 
heart  will  be  dilated.  At  the  in- 
creased beat  we  find  that  the  con- 
traction of  the  ventricle  is  much 
more  forcible.  The  maximum  pres- 
sure now  rises  to  130  mm.  Hg.  and 

8  c.c.  of  blood  are  sent  out  into 
the  aorta.  At  the  end  of  this  beat 
the  heart  will  be  still  fuller  than 
before,    containing    an    excess    of 

9  c.c.  of  blood.  The  third  beat 
is  still  more  forcible,  the  intra- 
ventricular pressure  rising  to  a 
maximum   of    140    mm.   Hg.,  ard 

10  c.c.  of  blood  are  expelled.  After  this  the  heart  goes  on  beating  regularly 
expelling  10  c.c.  of  blood  at  each  beat,  i.e.  the  same  amount  as  it  receives 
from  the  veins,  and  the  arterial  pressure  is  maintained  constant  at  an  average 
of  120  mm.  Hg.  But  the  heart  remains  more  dilated  than  it  was  previously 
since  it  contains  an  excess  of  9  c.c.  of  blood.  If  now  the  arterial  resistance 
be  suddenly  reduced  to  its  previous  amount,  the  first  beat  after  the  change 
may  send  out  17  c.c.  of  blood,  the  second  beat  12  c.c.  of  blood  and  the  third 
beat  10  c.c.  as  before.  We  see  therefore  that  the  energy  set  free  at  each 
contraction  of  the  heart  is  increased  by  increasing  the  volume  of  the  heart, 
but  increased  volume  of  the  heart  means  increased  length  of  the  muscular 


Fig.  4.38.  Effect  or  increased  arterial  pros- 
sure  on  the  volume  changes  of  the  heart, 
with  a  stead}'  inflow  of  l.l-t  c.e.  blood  per 
10  seconds. 

C.  cardiometer  curve.  B.P.  arterial  blood- 
pressure.  V.P.  pressure  in  the  inferior 
vena  cava.  The  lines  100  and  80  show  the 
height  of  the  blood- pressure  in  mm.  Hg. 


960 


PHYSIOLOGY 


fibres  composing  its  wall,  so  we  arrive  at  a  statement  similar  to  that  made 
previously  for  voluntary  muscles,  namely,  that  the  energy  of  contraction  is 
a  function  of  the  length  of  the  muscle  fibres,  i.e.  to  the  extent  of  active  surface 
involved.  This  reaction  of  the  heart  to  increasing  distension  has  long  been 
known  but  was  ascribed  to  the  excitatory  influence  of  tension  on  the  muscle 
fibres.  It  is  evident  that  in  a  resting  heart  increasing  distension  of  its 
cavities  will  tend  to  stretch  its  muscle  fibres  and  therefore  to  exert  a  tension 


vpjjjMlipjjJj^^ 


Fig.  439.     Effect  of  alterations  in  venous  supply  on  volume  of  heart.     Heart,  67  gms. 

Arterial  Venous  Output  of  heart 

pressure  pressure  in  10  sees. 

A    ...         124         ..  95         ..         86 

B    .  .  .         130         ..         145         ..       140 

C     .  .  .         124         ..  55         ..         33 

The  curved  line  at  the  side  represents  the  value  of  the  cardiometer  excursions 

in  capacity  of  ventricles  in  c.c. 

on  them.  By  an  accurate  record  of  the  pressure  changes  within  the  con- 
tracting ventricle  under  varying  conditions  it  is  possible  however  to  exclude 
the  tension  on  the  fibres  as  the  determining  factor.  In  a  heart  beating 
regularly  the  inflow  of  blood  is  proceeding  during  diastole,  during  the  relaxa- 
tion of  the  ventricles,  i.e.  the  muscles  are  giving  before  the  inflowing  blood. 
The  latter  is  therefore  able  to  distend  the  heart  without  exercising  more  than 
a  minimal  pressure  on  its  walls  and  it  is  found  that  the  pressure  in  the  ven- 
tricles may  be  approximately  zero  at  the  end  of  diastole  whether  the  heart 
is  contracting  against  a  resistance  of  80  mm.  Hg.  or  a  resistance  of  120  mm. 


THE  CAUSATION  OF  THE  HEART-BEAT  961 

Hg.,  or  whether  it  is  receiving  5  c.c.  or  10  c.c.  during  the  period  of  diastole. 
With  a  bigger  outflow  or  a  bigger  resistance  the  energy  of  contraction  is 
increased,  although  the  tension  on  the  heart  wall  at  the  beginning  of  the 
contraction  is  not  altered.  The  only  condition  then  which  always  changes 
pari  passu  with  the  energy  of  contraction  is  the  distension  of  the  heart 
cavities,  i.e.  the  length  of  its  muscle  fibres,  and  we  are  therefore  justified 
in  regarding  this  last  factor  as  the  one  which  determines  the  energy  of  the 
response  of  the  muscle  to  excitation.  Naturally  if  the  distension  increased 
beyond  a  certain  extent  it  would  be  associated  wdth  increased  tension  on  the 
muscle  fibres.  But  the  changes  of  initial  tension  and  excitatory  response 
are  not  proportional.  It  is  evident  that  the  capacity  of  the  heart  for  adapting 
itself  to  changes  in  mechanical  demands  made  upon  it  will  be  limited  by  the 
inability  of  the  heart  to  dilate  further,  as  is  probably  the  case  in  the  intact 
animal,  where  its  dilatation  is  Hmited  by  the  pericardium,  or  by  the  mechani- 
cal disadvantage  at  which  the  further  dilated  heart  acts.  The  more  the 
heart  attains  a  globular  form,  the  greater  the  mechanical  disadvantage  of 
the  muscle  fibres  in  raising  the  pressure  in  the  interior  of  the  ventricles  {vide 
p.  916)  so  that  by  continually  increasing  the  demands  on  the  heart  we  shall 
finally  arrive  at  a  stage  at  which  this  organ  is  unable  to  deal  with  the  blood 
which  is  applied  to  it  and  rapidly  fails  to  expel  any  of  its  contents. 

The  physiological  condition  of  the  heart  is  measured  by  the  maximum 
pressure  which  it  is  able  to  produce  in  its  cavities  when  it  contracts,  starting 
from  a  certain  initial  size  or  length  of  fibres.  As  the  heart  becomes  fatigued 
this  pressure  falls  so  that  the  heart  must  dilate  in  order  that  each  contraction 
shall  produce  the  same  maximum  pressure  as  before.  Fatigue  of  the  heart  is 
shown  therefore,  not  by  failure  of  it  to  do  its  work,  but  by  the  fact  that 
it  can  only  do  its  work  when  it  is  undergoing  considerable  dilatation. 
Dilatation  is  therefore  a  measure  of  fatigue.  What  is  often  spoken  of  as  the 
tonus  of  the  heart  is  really  synonymous  with  physiological  condition.  A 
heart  in  good  condition  has  a  high  tonus.  It  empties  itself  almost  completely 
at  each  beat  even  when  receiving  a  considerable  quantity  of  blood  during 
diastole.  A  heart  with  a  low  tonus  is  in  the  condition  of  a  fatigued  heart. 
It  is  widely  dilated  and  when  it  has  finished  contracting  still  contains  a  large 
amount  of  residual  blood. 

This  property  of  the  cardiac  muscle  is  responsible  for  the  power  of 
'  compensation  '  possessed  by  a  diseased  heart.  We  may  take  as  an  example 
the  destruction  of  one  aortic  valve,  a  lesion  which  can  be  produced  experi- 
mentally in  a  dog.  In  this  case,  immediately  after  the  lesion  is  established, 
no  additional  resistance  is  offered  to  the  expulsion  of  the  blood,  and  the  ven- 
tricle will  send  the  normal  amount  into  the  aorta.  During  the  succeeding 
diastole  the  blood  at  a  high  pressure  in  the  aorta  will  leak  back  into  the 
ventricle  through  the  damaged  valve.  The  arterial  pressure  therefore  falls 
rapidly,  and  the  ventricle  receives  blood  from  two  sides,  i.e.  by  regurgitation 
through  the  aortic  valves,  and  in  the  normal  way  from  the  auricles  and  veins. 
At  the  end  of  diastole  the  ventricle  is  therefore  overfilled.  Increased 
stretching  of  its  fibres,  however,  has  the  effect  of  exciting  an  increased  con- 

31 


962  PHYSIOLOGY 

traction,  and  the  heart  at  its  next  systole  throws  out  not  only  the  normal 
quantity  of  blood  but  also  that  which  it  has  received  back  from  the  aorta. 
The  arterial  system  thus  receives  at  each  beat  the  normal  quantity  of  blood 
plus  the  amount  which  leaks  back  into  the  ventricle  after  each  systole  ; 
so  that  the  amount  of  blood  remaining  in  the  aorta  and  available  for  passage 
on  to  the  capillaries  is  the  same  as  in  the  normal  animal.  On  this  account, 
after  a  lesion  of  the  aortic  valves  has  been  established,  the  average  of  the 
arterial  pressure  remains  the  same  as  before,  although  the  oscillations  of 
pressure  with  each  heart-beat  are  increased  in  extent.  The  augmented 
output  by  the  ventricles  naturally  involves  increased  work  on  the  part  of  their 
muscular  walls,  which  react  in  the  same  way  as  skeletal  muscle  does  to 
increased  work,  i.e.  by  hypertrophy ;  the  final  efiect  therefore  is  a  heart 
bigger  than  normal,  with  hypertrophied  and  thickened  walls,  but  capable 
of  maintaining  an  adequate  circulation  throughout  all  parts  of  the  body ; 
in  other  words,  in  the  healthy  animal  complete  compensation  has  taken 
place. 

THE  INFLUENCE  OF  TEMPERATURE   ON    THE   HEART   RATE 
The  frequency  of  the  heart  varies  directly  with  the  temperature.     The 
higher  the  temperature  the  greater  the  frequency.     At  40°  C.  the  contrac- 
tion of  the  mammalian  heart  may  be  four  times  as  frequent  as  at  25°  C. 

\ 


Fig.  440.  Tracing  of  contractions  of  a  frog's  heart  (by  Ringer),  showing  effect 
of  adding  a  trace  of  CaCl2  to  the  NaCl  solution  used  previously  for  perfusion. 
The  arrow  marks  the  point  at  which  the  addition  was  made. 

INFLUENCE    OF    THE    CHEMICAL    COMPOSITION    OF    THE 
SURROUNDING  MEDIUM  ON  THE  HEART-MUSCLE 

The  tissues  of  the  heart,  hke  all  other  cells  of  the  body,  require  for  the 
normal  display  of  their  functions  a  definite  osmotic  environment,  i.e.  a 
certain  molecular  concentration  of  the  fluid  with  which  they  are  bathed. 
This  is  equivalent  to  a  0-65  per  cent,  sodium  chloride  solution  for  the  frog's 
heart,  and  to  a  0-9  per  cent,  solution  for  the  mammalian  heart.  As  Ringer 
first  showed,  the  nature  of  the  neutral  salt  employed  for  making  up  the 
normal  solution  is  all-important  to  the  heart-muscle.  Thus  a  strip  of 
muscle  from  the  apex  of  the  tortoise's  ventricle  as  a  rule  does  not  beat  spon- 
taneously. If,  however,  it  be  immersed  in  a  0-7  per  cent,  solution  of  sodium 
chloride  it  begins  to  beat  rhythmically  after  a  short  latent  period.  The 
contractions  soon  reach  a  maximum  and  then  gradually  die  away.  Sodium 
chloride  therefore  acts  as  a  stimulus  to  contraction,  but  is  unable  to  main- 
tain the  beats  for  any  considerable  length  of  time.  The  strip  of  muscle 
ceases  contracting  in  a  condition  of  relaxation.  On  now  adding  to  the 
solution  a  trace  of  calcium  chloride  or  calcium  sulphate,  the  contractions 


THE  CAUSATION  OF  THE  HEART-BEAT  963 

begin  again  (Fig.  440).  Now,  however,  the  relaxations  after  each  contrac- 
tion become  more  and  more  incomplete,  until  finally  the  heart  stops  in  a 
tonically  contracted  condition.  If  now  a  trace  of  potassium  chloride  or 
phosphate  be  added  the  contractions  begin  again  and  may  last  for  many 
hours,  although  the  solution  contains  nothing  which  can  furnish  energy 
to  the  contracting  muscle.  It  has  been  suggested  that  the  rhythmic  con- 
tractions of  the  heart-muscle  may  be  the  result  of  the  constant  chemical 
stimulus  of  the  inorganic  salts  present  in  the  blood-plasma,  sodium  acting 
as  a  stimulus  to  contraction,  while  the  calcium  salts  are  necessary  for  the 
maintenance  of  the  systolic  tone,  and  the  potassium  salts  for  the  occurrence 
of  relaxation. 

The  exact  significance  of  these  different  salts  for  the  functions  of  cardiac 
and  other  forms  of  muscular  tissue,  though  they  have  been  the  subject  of 
many  detailed  investigations,  must  be  still  regarded  as  an  open  question. 


Fig.  441.     A  frog's  heart  poisoned  by  excess  of  calcium  salts,  recovers  its  spontaneous 
rhythm  on  adding  a  trace  of  KCl  to  the  perfusion  fluid.     (Ringer.) 

The  fluids  containing  the  three  salts  mentioned  above  in  slightly  varying 
proportions  are  commonly  used  to  maintain  the  beat  in  an  excised  heart 
either  of  a  cold-  or  of  a  warm-blooded  animal.  In  the  case  of  the  latter  it 
is  necessary  to  keep  the  fluid  saturated  with  oxygen.  According  to  Locke 
the  addition  of  glucose  to  the  solutions  enables  the  beats  to  go  on  for  a 
longer  period  of  time,  and  will  in  fact  renew  the  rhythm  of  a  heart  which 
has  ceased  beating  while  being  fed  with  pure  saline  solution. 

The  following  represent  the  fluids  most  frequently  used  : 

Ringer's  Fluid 
(for  frog's  heart) 

1  per  cent,  sodium  bicarbonate     .  .  .  ,  .1  c.c. 

1         „         calcium  chloride  .  .  .  .  .1  c.c. 

1         ,,         potassium  chloride       .  .  .  .  .     0-75  c.c. 

0-6     ,,         sodium  chloride  .....  to  100  c.c. 

Locke's  Fluid 
(for  mammalian  heart) 
0-015  per  cent,  sodium  bicarbonate, 
0-024        ,,         calcium  chloride, 
0-042        ,,         potassium  chloride, 
0-92  ,,        sodium  chloride, 

0-1  ,,        glucose, 

in  distilled  water. 

The  influence  of  the  chemical  composition  of  tiio  medium  on  the  contraction  of  the 
heart  may  be  investigated  in  the  following  ways  : 

One  of  the  simplest  methods  is  that  employed  by  Ciotch.  represented  in  the  diagram 
(Fig.  442).     The  apparatus  consists  of  a  small  glass  jar  with  inlet  and  outlet  tubes. 


964 


PHYSIOLOGY 


A  disc  of  cork  is  fixed  on  to  a  brass  rod  so  that  it  can  be  let  down  into  the  fluid.  On 
the  upper  end  of  the  brass  rod  is  poised  a  light  lever  with  a  paper  point.  To  fix  the 
heart  in  the  apparatus,  the  top  of  the  ventricle  is  transfixed  by  a  fine  hook  to  which  is 
attached  a  thread  connected  with  the  lever.  The  heart  is  fastened  to  the  cork  by  a  pin 
through  the  bulbus  aortse.  The  glass  jar  is  filled  with  the  fluid  whose  action  it  is 
desired  to  investigate.  It  is  usual  to  start  with  Ringer's  fluid  in  order  to  obtain  a  normal 
beat,  and  then  to  try  in  turn  the  various  constituents  of  this  fluid. 

Another  method  of  investigating  the  action  of  the  heart  of  cold-blooded  animals  is 
by  perfusing  the  heart  cavities  with  the  fluid  under  investigation.  Two  forms  of 
perfusion  are  made  use  of.     In  the  method  first  introduced  by  Williams  a  double 


Fig.  442.      Gotch's  frog  heart  apparatus. 


Fig.  443.  Brodie's  perfusion 
apparatus  for  the  mamma- 
lian heart. 


cannula  is  tied  into  the  ventricle,  the  rest  of  the  heart  being  cut  away.  The  tubes 
leading  to  and  away  from  the  perfusion  cannula  are  armed  with  valves  so  as  to  allow 
the  fluid  only  to  pass  in  one  direction.  The  contractions  of  the  ventricle  may  be 
recorded  either  by  connecting  the  outgoing  tube  with  a  manometer,  which  may  be  a 
mercurial  or  a  membrane  manometer,  or  by  connecting  some  form  of  recording  apparatus 
with  the  vessel  in  which  the  heart  is  contained,  so  as  to  register  changes  in  the  volume 
of  the  ventricle.  A  large  number  of  different  forms  of  apparatus  have  been  devised 
for  these  purposes. 

In  another  method  the  fluid  is  allowed  to  flow  through  the  whole  heart,  passing  in 
by  the  sinus  and  out  by  the  aorta.  Here  again  the  activity  of  the  heart  may  be  registered 
either  by  recording  the  pulsations  in  the  arterial  column  of  fluid  or  by  connecting  a 
tambour  or  piston  recorder  with  the  vessel  in  which  the  heart  is  contained. 

The  heart  of  warm-blooded  animals  can  also  be  investigated  by  a  somewhat  similar 


THE  CAUSATION  OF  THE  HEART-BEAT  965 

method.  It  was  shown  by  Porter  that  the  inaininalian  heart  could  be  kept  alive  by 
transfusing  oxygenated  blood  serum  through  the  coronary  vessels,  and  Locke  found 
that  the  same  results'  could  be  obtained  by  using  oxygenated  Ringer's  solution,  modified 
so  as  to  have  the  same  tonicity  as  mammalian  blood.  A  convenient  apparatu  s  for  this 
purpose  has  been  devised  by  Brodie. 

The  apparatus  (Fig.  443)  consists  of  a  chamber  A  to  contain  the  heart,  and  of  a  tube 
B,  through  which  the  perfusion  fluid  is  carried  to  the  heart.  Both  are  enclosed  in  a 
large  outer  jacket  c,  through  which  is  kept  flowing  a  stream  of  water  at  body  tempera- 
ture. The  chamber  A  is  bell-shaped  and  is  fitted  into  the  jacketing  tube  c  by  a  ground- 
glass  joint  D.  Its  upper  orifice  is  closed  by  a  piece  of  rubber  tubing  of  such  size  that 
the  perfusion  tube  B  slips  through  it  easily.  By  means  of  the  glass  handle  F,  fused  into 
the  tube  about  half-way  down,  b  can  be  drawn  up  or  lowered  into  any  desired  position. 
To  its  lower  end  the  heart  camiula  is  attached  by  a  ground  joint.  Its  upper  end  is 
fitted,  by  a  second  ground  joint,  with  a  small  bulb  w,  with  two  tubes,  r  and  s,  fitted 
into  it.  These  latter  are  connected  by  rubber  tubing  with  aspirators  containing  the 
solutions  to  be  perfused.  The  lower  half  of  the  tube  B  is  nearly  filled  up  with  a  thermo- 
meter L,  the  bulb  of  which  projects  into  the  heart  cannula  T.  The  upper  half  is  almost 
filled  with  a  piece  of  glass  tubing  sealed  at  both  ends,  so  that  the  perfusion  fluid  passes 
in  a  thin  layer  down  the  tube  and  thus  offers  a  large  surface  for  heating  purposes.  Also 
by  filling  the  interior  of  the  tube  in  this  way  its  capacity  is  reduced  to  a  very  small 
amount. 

The  large  outer  tube  c  is  kept  supplied  with  warm  water,  entering  through  the 
tube  G  and  overflowing  through  a  side-tube  at  the  top  into  a  wide  T-piece  N.  By  raising 
or  lowering  this  T-piece  the  level  of  the  water  in  the  jacket  is  adjusted.  The  water- 
supply  comes  from  a  cold-water  tap,  but  on  its  passage  to  G  passes  through  a  metal 
spiral  heated  by  a  Bunsen  burner.  By  varying  the  rate  of  flow  and  the  position  of  the 
burner  the  temperature  of  the  water  can  be  regulated  with  considerable  accuracy. 
The  upper  end  of  the  supply-tube  G  is  provided  with  a  thermometer  so  that  the  tempera- 
ture of  the  inflowing  water  can  be  seen  and  regulated. 

In  using  the  apparatus  the  heart  cannula  is  removed,  and  the  tube  B  is  then  passed 
through  E  and  pushed  down  until  its  lower  end  issues  just  below  the  level  of  the  chamber 
A.  The  circulation  of  the  warmed  water  through  the  jacket  is  then  started  and  adjusted 
to  the  proper  temperature.  One  of  the  rubber  tubes,  s.  is  next  attached  to  the  reservoir 
containing  the  main  perfusion  fluid,  and  the  tube  B  filled  with  fluid  and  left  to  warm 
while  the  heart  is  being  prepared. 

The  heart  having  been  excised  and  washed  well  in  saline  so  as  to  remove  as  much 
blood  as  possible,  the  cannula  is  tied  into  the  aorta.  The  cannula  is  now  held  luider 
the  perfusion  tube,  filled  with  the  warm  saline,  and  at  once  attached  in  its  proper 
joosition  and  the  perfusion  started.  A  bent  pin  to  which  a  long  thread  is  tied  is  hooked 
into  the  apex  of  the  heart,  and  the  perfusion  tube  pulled  up  until  the  heart  lies  quite 
within  the  warm  chamber.  When  thus  dra^^^l  up  the  bulb  w  lies  just  below  the  surface 
of  the  water  in  the  outer  jacket.  The  tube  is  held  firmly  in  position  by  a  clamp  which 
fixes  one  arm  of  the  handle  f.  The  heart  cannula  is  pro\'ided  with  a  side  opening  v, 
on  to  which  a  long  piece  of  fine  rubber  tubing  is  passed.  This  renders  possible  the 
removal  of  any  gas  bubbles  that  may  collect  in  the  cannula,  or  the  washing  out  of  the 
cannula  with  a  stream  of  fluid  if  necessary.  The  beats  of  the  heart  are  recorded  by 
means  of  a  simple  lever  attached  by  the  thread  previously  fixed  to  the  heart. 

THE  SIGNIFICANCE  OF  THE  REACTION  OF  THE  BLOOD  FOR  THE 
HEART-BEAT.  It  was  loiio;  i\ao  shown  by  Gaskoll  that  the  reaction  of  the 
perfusing  fluid  has  a  marked  influence  on  the  frog's  heart.  AVhen  weak 
acids  are  transfused  througli  this  heart,  tliere  is  a  gradual  diniiiuitiou  of 
toiuis,  the  beats  become  smaller  and  fiiuiUy  disappear.  A  similar  relaxation 
may  be  obtained  as  the  result  of  the  action  of  carbon  dioxide.  Weak 
alkalies  on  tl\o  other  hand  produce  a  gradiud  decrease  of  tonus,  so  that  the 


966  PHYSIOLOGY 

heart  is  finally  arrested  in  a  contracted  condition.  There  will  therefore 
be  some  reaction  intermediate  between  the  weak  acid  and  the  weak  alkaline 
fluids  which  will  represent  the  optimum  reaction  for  the  beat  of  the  frog's 
heart.  Mines  has  shown  that  this  optimum  reaction  difiers  for  the  difierent 
cavities  of  the  heart,  and  also  for  the  hearts  from  different  animals,  a 
shifting  of  the  reaction  of  the  transfusing  fluid  to  the  acid  side  always 
bringing  about  a  diminished  contraction  and  tonus,  while  the  opposite 
effects  are  produced  by  an  increase    in    the  alkahne  reaction.      In  the 


iMMtiimmm*»,mmmmMMf^^^,,^^ ,,,„...,^M.*iiiiiwM*M^ 


Fig.  444.  Volume  curve  of  ventricles  (cat)  (lower  curve).  The  upper  curve  is  the 
arterial  pressure,  maintained  by  an  adjustable  resistance  at  130  mm.  Hg. 
Between  the  arrows  the  air  used  for  artificial  respiration  was  replaced  by  a 
mixture  containing  20  per  cent.  CO2  and  25  per  cent,  oxygen.  Note  the 
dilatation  with  impaired  contraction,  followed  by  increased  amplitude  of 
contractions. 

mammal  under  normal  conditions,  the  chief  factor  affecting  the  reaction  of 
the  blood  is  the  tension  of  carbonic  acid  in  this  fluid,  and  an  increase  in  the 
carbonic  acid  of  the  blood,  when  suflS.ciently  pronounced,  always  brings 
about  dilatation  of  the  heart.  The  resistance  of  the  hearts  of  different 
animals  is  however  not  of  the  same  strength.  Thus,  a  dog's  heart  is  much 
more  susceptible  to  the  presence  of  a  small  excess  of  carbonic  acid  in  the 
blood  than  is  the  cat's  heart  (cp.  Fig.  444).  There  is  probably  an  optimum 
tension  of  carbon  dioxide  in  the  blood,  varying  between  5  and  6  per  cent, 
of  an  atmosphere,  at  which  the  physiological  condition  of  the  ventricular 
muscle  is  at  an  optimum,  but  the  tension  may  be  reduced  considerably 
below  this  without  causing  any  marked  change  in  the  action  of  the 
heart. 

Yandell  Henderson  found  that  vigorous  artificial  ventilation  of  the  lungs  brought 
about  a  condition  in  which  the  heart's  contraction  was  very  forcible  and  the  heart's 
cavities  almost  empty.  He  ascribed  this  condition  to  the  hypertonicity  of  the  heart- 
muscle  produced  by  washing  the  carbonic  acid  out  of  the  blood.  These  results  were, 
however,  probably  due  to  the  mechanical  influence  of  the  respiratory  movements 
on  the  venous  filling  of  the  heart,  and  there  seems  no  reason  to  believe  that  the 
condition  of  '  acapnia  '  (deficiency  of  carbon  dioxide  in  the  blood)  had  anything  to 
do  with  the  results  observed.  The  improving  effects  of  administration  of  carbon 
dioxide  described  in  the  first  edition  of  this  work  have  not  been  confirmed  by  more 
recent  and  accurate  experiments. 


THE  CAUSATION  OF  THE  HEART-BEAT  967 

THE  NUTRITION  OF  THE  HEART 
In  the  frog's  heart  the  muscle  fibres  are  supplied  directly  by  the  blood 
within  the  cavities,  the  spongy  ventricular  wall  permitting  the  access  of 
blood  between  the  fibres.  In  the  mammalian  heart  the  muscular  tissue  is 
nourished  through  the  coronary  arteries,  which  break  up  into  a  meshwork 
of  capillaries  around  all  the  fibres. 

The  flow  of  blood  through  the  coronary  circulation  may  be  measured  either  in 
the  whole  animal  or  in  the  heart-lung  preparation  by  introducing  a  cannula  through  the 
wall  of  the  right  auricle  into  the  coronary  sinus  and  collecting  the  blood  from  the  latter 
outside  the  body.  Another  method  is  to  feed  a  heart  from  the  aorta  through  the 
coronary  arteries  -svith  blood  and  collect  the  total  outflow  from  the  cut  pulmonary  artery. 
By  a  comparison  of  these  two  methods  it  is  found  in  the  dog  that  the  blood  flow  through 
the  coronary  sinus  forms  about  three-fifths  of  the  total  blood  passing  through  the 
coronary  arteries.  It  is  therefore  possible  to  measure  the  flow  through  the  coronary 
sinus  in  the  heart-lung  preparation  under  varjang  conditions  of  pressure  and  output. 
The  figures  so  obtained  multiplied  by  f  will  represent  approximately  the  total  flow 
through  the  coronary  circulation. 

Blood  enters  the  coronary  arteries  from  the  aorta  both  during  systole 
and  diastole,  though  it  is  probable  that  the  systole  of  the  ventricles  exercises 
a  direct  effect  in  increasing  the  resistance  to  the  flow  of  blood  through  the 
heart  and  squeezes  out  the  contained  blood  into  the  coronary  veins.  This 
may  be  one  reason  why  the  flow  of  blood  through  the  coronary  system  is 
greater  in  a  beating  heart  than  in  a  heart  which  is  quiescent.  The  most 
important  factor  in  determining  the  flow  through  the  coronary  vessels  is  the 
arterial  pressure.  The  marked  effect  of  this  factor  is  sho^vn  in  the  following 
Table  : 

Heart  weight,  107  gms.,  total  output  per  minute,  1400  cc. 

Arterial  Coronary  circulation 

pressure  per  minute 

60  50 

100  90 

128  124 

166  208 

190  500 

We  see  from  this  Table  that  the  heart  muscle  is  supplied  with  blood 
in  proportion  to  its  needs,  since  its  work  and  its  respiratory  exchanges 
increase  continuously  with  the  rise  of  arterial  resistance.  Indeed,  under 
the  severe  test  of  contracting  against  an  average  pressure  of  190  mm.  Hg. 
over  one-third  of  the  whole  blood  leaving  the  heart  was  passing  through  its 
muscular  walls,  one  gramme  of  muscular  tissue  being  irrigated  with  5  cc. 
of  blood  per  minute.  Another  important  factor  in  determining  the  coronary 
flow  is  the  effect  of  the  metabolites  produced  by  the  contracting  heart-muscle 
itself.  This  is  well  shown  when  the  heart  is  asphyxiated.  Thus  in  one 
experiment  while  the  arterial  pressure  was  maintained  constant,  the  total 
coronary  flow  was  56  cc.  per  minute.  Artificial  respiration  was  then  dis- 
continued, and  during  the  succeeding  minutes  the  coronary  circulation  was 
61,  72,    150,    180.     The  circulation  then  failed.     Carbonic  acid  produces 


968  PHYSIOLOGY 

also  an  increase  in  the  flow  through  the  coronary  arteries,  but  it  is  im- 
possible with  the  highest  attainable  percentages  oi  carbonic  dioxide  in  the 
blood  to  produce  such  an  increase  in  the  coronary  flow  as  is  observed  during 
asphyxia.  The  dilatation  of  the  coronary  vessels  which  occurs  in  the  latter 
condition  must  therefore  be  ascribed  to  non-gaseous  metabohtes  produced 
by  the  contracting  muscle.  Thus  the  heart  contains  in  itself  a  mechanism 
for  increasing  the  flow  of  blood  through  its  tissues  whenever  this  becomes 
inadequate  and  the  muscle  is  suffering  for  lack  of  oxygen.  Mechanical  and 
physiological  factors  thus  co-operate  in  providing  the  most  important  muscle 
in  the  body  with  oxygen  sufficient  for  its  needs. 

If  a  coronary  artery  be  hgatured,  the  heart  very  often  beats  for  one  or 
two  minutes  with  unimpaired  force,  then  a  beat  is  dropped  occasionally, 
and  very  shortly  afterwards  the  heart  stops  altogether  and  the  blood- 
pressure  falls  to  zero.  On  inspection  of  the  heart  immediately  after  the 
blood-pressure  has  fallen,  its  muscular  wall  is  seen  to  be  in  a  state  of  fibrillar 
contractions,  or  '  delirium  cordis.'  All  the  strands  of  muscle  fibres  are 
contracting  more  or  less  rhythmically,  but  the  rhythms  of  no  two  parts 
coincide,  so  that  the  heart  dilates  and  is  incapable  of  carrying  on  the  circula- 
tion. It  is  probably  in  this  way  that  sudden  deaths  occur  in  cases  where 
the  coronary  arteries  are  diseased  or  calcified.  In  such  cases  a  man  may 
drop  down  dead,  having  previously  shown  no  symptoms  of  heart  mischief. 

Dehrium  cordis  may  be  explained  as  the  result  of  block,  produced  by 
interference  with  the  nutrition  of  a  large  part  of  the  heart-wall.  The  con- 
tractile wave  arriving  at  this  part,  in  some  directions  will  not  spread  at  all, 
in  others  will  spread  at  a  lower  rate,  so  that  different  parts  of  the  heart 
receive  the  impulse  to  contract  at  different  times  and  a  state  of  inco- 
ordination results.  The  same  condition  can  be  produced  by  freezing  the 
apex  of  the  ventricle,  so  causing  a  block,  or  by  stimulating  the  surface  of  the 
ventricle  at  a  rate  which  is  greater  than  can  be  taken  up  by  the  ventricle  as 
a  whole,  as,  e.g.,  by  tetanising  currents.  Such  a  condition  in  the  higher 
animals,  as  the  dog  and  man,  is  practically  irrecoverable,  although  in  the 
rabbit,  and  very  rarely  in  the  dog,  it  is  sometimes  possible  to  bring  the  heart 
back  to  a  state  of  rhythmic  contraction  by  kneading  it  rhythmically. 

According  to  Mines  delirium  cordis  is  susceptible  of  a  simpler  explanation.  This 
condition  is  easily  brought  on  in  the  mammalian  heart  by  stimulation  of  its  surface  by 
strong  f aradic  currents.  The  effects  of  increased  frequency  of  contraction  on  the  heart 
muscle  is  to  decrease  the  rate  of  propagation  and  to  decrease  the  length  of  the  wave 
of  excitation.  Ordinarily  in  the  naturally  beating  heart  the  wave  of  excitation  is  so  long 
and  spreads  so  rapidly,  that  it  excites  the  whole  of  the  ventricle  long  before  it  has 
ceased  in  any  one  part.  When,  however,  the  muscle  is  stimulated  more  frequently  the 
wave  becomes  slow  and  short,  so  that  more  than  one  wave  can  exist  at  one  time  in  a 
single  chamber.  The  main  factor  then  in  the  production  of  delirium  cordis  after 
obstruction  of  the  coronary  artery  would  probably  be  a  diminished  rate  of  conduction 
through  the  affected  part. 


SECTION  IX 

THE  NERVOUS  REGULATION  OF  THE   HEART 

In  order  that  the  activity  of  the  heart  may  be  adapted  to  the  needs  of  the 
body  as  a  whole,  its  automatic  mechanism  must  be  subject  to  the  central 
nervous  system,  which  must  be  able  to  affect  the  heart  in  either  of  two  ways, 
viz.  by  increasing  or  diminishing  its  activity.  This  subjection  to  the 
integrative  action  of  the  central  nervous  system  is  also  necessary  for  the 
sake  of  the  organ  itself  ;  otherwise  the  peripheral  adaptation  of  the  heart- 
muscle  to  changes  in  arterial  resistance  might  result  iu  its  exhaustion  and 
permanent  damage. 

The  regulation  is  effected  through  the  intermediation  of  afferent  and 
efferent  nerve  fibres  connecting  the  heart  mth  the  central  nervous  system. 
The  importance  of  these  nerves  is  shown  by  the  behaviour  of  animals  in  which 
they  have  been  extirpated.  Thus  a  dog  in  whom  all  the  nerves  of  the  heart 
had  been  divided  survived  the  operation  for  eight  months,  the  pulse  reading 
during  the  time  not  having  appreciably  altered  and  the  animal  being  in  a 
fair  condition  of  health.  Although  he  regained  his  normal  weight  after  the 
operation,  he  was  found  incapable  of  carrying  out  even  a  moderate  amount 
of  work,  such  as  that  represented  by  running,  since  the  mechanism  for  in- 
creasing the  action  of  the  heart  in  response  to  the  needs  of  the  muscles  had 
been  lost. 

THE  EFFERENT  CARDIAC  NERVES 
The  heart  in  vertebrates  is  supplied  with  nerve  fibres  from  two  sources, 
from  the  medulla  oblongata  along  the  vagus  nerve,  and  from  the  upper 
dorsal  region  of  the  spinal  cord  through  the  mediation  of  the  sympathetic 
system. 

The  fibres  which  run  through  the  sympathetic  system  take  a  somewhat 
different  course  in  the  animals  on  which  the  regulation  of  the  heart's  acti^^ty 
has  been  chiefly  studied,  viz.  the  frog  and  the  mammal.  In  the  frog  (Fig. 
445)  the  sympathetic  fibres  leave  the  spinal  cord  by  the  anterior  root  of  the 
third  spinal  nerve  ;  they  then  pass  through  the  ramus  communicans  to 
the  corresponding  sympathetic  ganglion,  whence  they  run  up  through 
the  second  ganglion  and  the  annulus  of  Vieussens  to  the  first  ganglion  ; 
they  then  pass  into  the  cervical  sympathetic  strand  to  the  ganglion  trunci 
vagi ;  here  they  join  the  vague  and  pass  down  with  the  true  vagus  fibres  to 
the  heart. 

969  31* 


970 


PHYSIOLOGY 


In  the  dog  (Fig.  446)  the  sympathetic  fibres  leave  the  spinal  cord 
by  the  anterior  roots  of  the  second  and  third  dorsal  nerves,  run  in  the 
white  rami  communicantes  to  the  stellate  ganghon,  and  thence  by  the 
anniilus  of  Vieussens  to  the  inferior  cervical  gangUon.  Cardiac  branches 
convey  the  sympathetic  fibres  to  the  heart  and  are  given  ofE  from  the 
stellate  ganghon,  the  inferior  cervical  ganghon,  and  from  the  trunk  of 
the  vagus. 

By  the  nicotine  method  it  is  possible  to  trace  out  the  cell  connections 
of  these  fibres.     As  they  leave  the  cord  they  are  medullated  nerve  fibres, 

^Jucj.  Ganql.  Vagus 

Vago-symparheHc 

Subclav.  a^•^ 

N.ll 


Splanchn.  n. 
Infest  arf 


N.Vii. 
N.VIII, 


Fig.  445.  Sympathetic  chain  of  frog  (right  side)  to  show  connection  with  vagus 
nerve.  The  sympathetic  ganglia  with  their  branches  are  black.  Of  the 
peripheral  branches  only  the  splanchnic  nerve  is  represented.  (Modified 
from  EcKER.) 

similar  to  the  other  fibres  making  up  the  visceral  outflow  throughout  the 
dorsal  region ;  the  white  fibres  pass  along  the  ramus  communicans  to  the 
stellate  ganghon,  where  they  end,  forming  synapses  with  the  cells  of  the 
ganglion.  Here  fresh  relays  of  fibres,  which  are  non-medullated,  start  and 
carry  the  impulses  to  the  heart  along  the  various  cardiac  nerves  just  men- 
tioned. In  the  heart  these  fibres  are  distributed  to  the  muscle  fibres 
without  the  intervention  of  any  other  ganghon-cells.  On  the  other  hand, 
the  fibres  which  leave  the  vagus  to  pass  to  the  heart  make  connection  with 
the  cells  of  Remak's  ganglion,  and  probably  all  the  other  intrinsic  cardiac 
ganglia  described  above,  whence  non-medullated  fibres  carry  their  impulses 
to  the  heart-muscle. 


THE  NERVOUS  REGULATION  OF  THE  HEART 


'J71 


ACTION  OF  THE  VAGUS 

The  action  of  the  vagus  fibres  on  the  heart  is  ahiiost  identical  in  frog  and 

mammal.     If  in  the  dog  the  peripheral  end  of  the  cut  vagus  be  stimulated 

while  the  arterial  blood  pressure  is  being  recorded  by  means  of  a  mercurial 

manometer,  the  pulse  is  seen  to  become  slower,  or  with  a  stronger  stimulus  to 

G.J. 


G.h.V- 


r.Sp.Ac. 


Fig.  446.  Diagram  of  cardiac  inhibitory  and  accelerator  fibres  in 
the  dog.  (From  Foster.) 
r.Vg,  roots  of  the  vagus  ;  r.Sp.Ac,  roots  of  the  spinal  accessory ;  GJ,  ganglion 
jugulare  ;  G.h.V,  ganglion  trunci  vagi ;  Vg,  trunk  of  vagus  nerve  ;  C.Sy,  cervical 
sympathetic  ;  GC.  inferior  cervical  ganglion  ;  AV.  annulus  of  Vieussens  ;  A.sb.  sub- 
clavian artery  ;  nc.  cardiac  nerves  ;  G.St,  ganglion  stellatum  ;  D2,  D3,  D4.  Do, 
second,  third,  fourth,  and  fifth  dorsal  spinal  roots  ;  G.Th,  ganglia  of  the  thoracic 
chain. 

cease  altogether,  and  the  blood-pressure  falls  towards  zero.  On  discon- 
tinuing the  stimulus  the  heart  begins  to  beat  again  and  the  pressure  rises 
after  a  few  beats  to  normal  (Fig.  447). 

If  the  stimulation  of  the  vagus  be  prolonged,  the  blood-pressure,  on  dis- 
continuance of  the  stimulus,  may  rise  above  normal  owing  to  the  asphyxia 
of  the  vaso-motor  centres  produced  by  the  prolonged  cessation  of  the 
circulation.  Even  during  the  application  of  the  stinmlus  the  heart  often 
begins  to  beat  again  with  a  slow  rhythm.     In  this  case  we  speak  of  an 


972  PHYSIOLOGY 

'  escape  '  of  the  heart  from  the  vagus  influence.  This  escape  is  generally 
confined  to  the  ventricles  and  the  heart-beats  are  found  on  opening  the  chest 
to  be  purely  ventricular,  the  auricles  and  great  veins  remaining  in  a  state  of 
diastole.  Vagus  escape  is  favoured  by  distension  of  the  heart  cavities,  and 
is  often  synchronous  with  the  respiratory  efforts,  which  supervene  after  a 
certain  duration  of  inhibition  as  a  result  of  the  asphyxia  of  the  respiratory 
centre. 

When  the  arterial  system  is  dilated,  so  that  the  mean  systemic  pressure, 
and  consequently  the  venous  pressure  during  cardiac  inhibition,  are  low,  or 
when  the  asphyxial  gasps  of  the  animal  are  prevented  by  anaesthesia  or  by  a 


Fig.  447.     Blood-pressure  tracing  from  carotid  of  dog  (taken  with  Hiirthle's 
manometer),  showing  effect  of  excitation  of  vagus  (between  the  arrows). 
0,  abscissa  line  of  no  pressure. 

section  of  the  spinal  cord,  the  heart  may  fail  to  recover  from  the  inhibition 
produced  even  by  a  transitory  stimulation  of  the  vagus.  In  such  cases  it  is 
necessary  to  knead  the  heart  in  order  to  restore  its  rhythmic  action. 

To  study  the  influence  of  the  vagus  on  the  auricles  and  ventricles 
respectively,  it  is  necessary  to  work  with  the  chest  opened  and  to  record 
separately  the  contractions  of  the  different  segments  of  the  heart.  It  is  then 
found  that  the  vagus  may  affect  the  heart  in  one  of  several  ways.  Its  most 
marked  action  is  on  that  part  of  the  heart  where  it  enters,  viz.  the  venous 
end.  It  may  affect  that  part  of  the  auricle  corresponding  to  the  primitive 
sinus  venosus,  where  the  rhythm  of  the  whole  heart  is  determined.  In  this 
case  the  sole  effect  of  the  vagus  on  the  auricles  and  ventricles  will  consist  in 
an  alteration  of  rhythm.  They  may  cease  to  beat  altogether  or  they  may 
give  beats  of  normal  strength  but  at  a  slower  rhythm  than  before.  Often 
indeed  under  these  conditions  the  beats  of  the  ventricles  may  be  increased 
in  size,  since  the  strength  and  extent  of  their  contractions  are  determined, 
not  by  the  strength  of  the  stimulus  arriving  from  the  auricles,  but  by 
the  length  of  their  fibres,  and  this  will  increase  with  any  prolongation 
of  the  diastolic  period,  and  consequent  increased  diastolic  filhng  of  the 
ventricle. 

If  the  vagus  acts  on  the  auricles  without  affecting  the  sinus  part  of  the 
auricles  (sino-auricular  node),  the  rhythm  will  be  unaltered,  but  the  response 
of  the  auricles  to  the  impulses  received  by  them  will  be  diminished,  and  the 
amplitude  of  the  excursions  of  the  lever  attached  to  them  will  therefore  be 


THE  NERVOUS  REGULATION  OF  THE  HEART     973 

considerably  reduced.  Indeed  the  auricular  contractions  may  be  reduced 
to  such  an  extent  that  they  cause  no  movement  of  the  lever.  It  is  only  by 
observing  their  surface  that  one  may  perceive  a  slight  contraction  of  their 
fibres.  Under  such  circumstances  the  rhythm  of  the  ventricles  will  be 
unchanged. 

Generally  the  vagus  absolutely  stops  the  action  of  all  parts  of  the  auricles  ; 
in  such  cases  the  ventricles  also  cease  beating.  Very  often  after  a  short 
pause  the  ventricles  commence  to  beat  at  a  slow  rhythm,  and  it  is  then  seen 
that  they  are  contracting  independently  of  the  auricles  and  sinus.  That 
the  ventricle  is  really  inaugurating  the  beat  is  shown  by  the  fact  that  occa- 
sionally one  may  observe  a  reversed  beat,  i.e.  a  contraction  of  the  auricle 
following  instead  of  preceding  each  ventricular  contraction.  Whether  the 
vagus  has  a  direct  action  on  the  mannnalian  ventricle  is  still  doubtful ;  its 
effect  is  at  any  rate  very  slight  as  compared  with  that  on  the  venous  end  of 
the  heart.  The  fact  that  stimulation  of  the  vagus  causes  as  a  rule  tem- 
porary cessation  of  the  ventricular  beat,  while  functional  separation  of 
the  ventricles  from  the  auricles  causes  no  such  temporary  stoppage,  would 
seem  to  indicate  that  this  nerve  has  a  direct,  though  sUght,  action  on  the 
ventricles. 

Finally  the  vagus  may  affect  the  tissue  which  conducts  the  excitatory 
process  from  one  cavity  to  another.  Under  vagus  stimulation  the  auricles 
may  beat  at  a  greater  rhythm  than  the  ventricles,  a  block  having  been  pro- 
duced in  the  tissue  passing  from  auricles  to  ventricles,  viz.  the  auriculo- 
ventricular  bundle. 

Engelmann  has  described  these  effects  of  vagus  excitation  as  negatively  chronotropic 
(diminution  of  rhythm),  negatively  inotropic  (diminished  strength  of  contraction), 
and  negatively  dromotropic  (diminished  conductivity),  and  has  distinguished  a  fourth 
action,  viz.  one  on  the  irritability  of  the  muscle  to  dii'ect  stimuli,  which  he  calls  negatively 
bathmotropic.  He  ascribes  these  four  actions  to  four  different  sets  of  nerve  fibres, 
but  it  is  evident  that  they  are  due  not  so  much  to  the  difference  in  the  nature  of  the 
impulse  as  to  a  difference  in  the  place  of  incidence  of  the  impulse. 

Thus,  if  the  vagus  fibres  which  are  distributed  to  the  remains  of  the  sinus  are  speci- 
ally active,  we  shall  get  alterations  of  rhythm  affecting  the  whole  heart.  If  those 
which  supply  the  A.V.  bundle  are  excited,  the  most  pronounced  effect  will  be  on  the 
propagation  of  the  excitatory  process  from  auricles  to  ventricles. 

Practically  the  same  description  will  apply  to  the  action  of  the  vagus 
on  the  frog's  heart.  Since  it  is  easy  in  this  animal  to  register  the  contrac- 
tions of  the  empty  heart  it  is  possible  to  show  that  the  vagus  has  a  direct 
inhibitory  action  on  the  ventricles,  diminishing  the  strength  of  its  contrac- 
tion in  response  to  the  stimuli  transmitted  to  it  from  the  venous  end.  This 
action  of  the  vagus  on  the  ventricle  is  not,  however,  universal,  and  in  the 
tortoise  it  is  impossible  to  show  any  such  action.  In  both  these  animals 
the  auricles  show  the  same  effects  as  in  the  mammal,  viz.  an  influence 
limited  to  the  rhythm  when  only  the  sinus  is  affected,  or  a  diminution  of  the 
strength  of  contraction  when  the  sinus  is  unaffected  and  the  chief  action  of 
the  vagus  is  on  the  auricular  muscle. 

Ever  since  the  discovery  in  1845  by  the  brothers  E.  H.  and  E.  F.  Weber 


974  PHYSIOLOaY 

of  the  action  of  the  vagus  on  the  heart,  much  work  has  been  expended  with 
a  ^aew  to  determining  the  intimate  nature  of  the  inhibitory  process.  In  the 
former  neurogenic  theory  it  was  supposed  that  the  vagus  altered  the  activity, 
perhaps  by  a  process  of  '  interference,'  of  the  ganghon-cells  responsible  for 
the  origination  of  the  rhythm.  Many  facts,  however,  point  to  the  in- 
hibitory impulses  as  being  continued  to  the  heart-muscle  itself.  Thus 
tetanisation  of  any  portion  of  the  frog's  ventricle,  especially  if  it  be  filled 
with  blood,  causes  an  evident  relaxation  of  the  part  between  the  electrodes. 
Application  of  nicotine  to  the  heart  prevents  stimulation  of  the  trunk  of  the 
vagus  from  having  any  influence  on  the  heart,  presumably  from  paralysis 
of  the  cells  of  Remak's  ganghon,  which  he  at  the  termination  of  the  vagus 
fibres,  or  of  the  synapses  between  the  vagus  fibres  and  the  ganglion- cells.  It 
is  still  possible  to  inhibit  the  heart  by  direct  stimulation  either  of  the  fibres 
leaving  this  ganghon  in  the  sino- auricular  junction,  or  of  the  nerve-trunks 
which  run  in  the  inter- auricular  septum.  We  must  conclude  therefore  that 
the  inhibition  of  the  heart-muscle  is  peripheral  and  depends  on  the  direct 
action  of  the  nerve  fibres  on  the  muscle-cells  themselves.  These  nerve 
fibres  are  paralysed  by  atropine,  after  administration  of  which  no  inhibitory 
effects  can  be  produced  by  stimulation  of  nerve  or  muscle  or  any  part  of  the 
heart.  On  the  other  hand,  muscarine  apparently  stimulates  the  inhibitory 
nerve-endings,  and  when  applied  to  the  isolated  auricle  or  ventricle  causes 
weakening  of  the  beat  and  finally  complete  inhibition,  an  effect  which  can 
be  removed  by  its  antagonist  atropine. 

Two  views  have  been  held  as  to  the  essential  nature  of  the  inhibitory 
process.  According  to  that  put  forward  by  Claude  Bernard,  the  natural 
tendency  of  any  tissue  during  rest  is  towards  anabolism.  Activity  in- 
volves disintegration  or  breaking  down  of  the  living  material,  and  this 
disintegration  must  be  succeeded  by  a  process  of  building  up  or  anabolism, 
which  restores  the  tissue  to  its  previous  functional  condition.  On  this  view 
the  state  of  inhibition  would  merely  prolong  the  period  of  rest  intervening 
between  two  periods  of  activity,  so  allowing  a  greater  time  for  restitution  to 
take  place,  with  a  corresponding  improvement  in  the  functional  capacity  of 
the  tissue.  According  to  Hering  and  Gaskell  a  state  of  anabohsm  can  be 
induced  in  a  tissue  comparable  to  the  state  of  sudden  disintegration  which 
is  associated  with  activity.  Excitation  of  the  vagus  nerve  does  not  merely 
allow  the  normal  process  of  building  up,  which  goes  on  during  rest,  to  take 
place,  but  actually  hastens  this  process,  just  as  the  excitation  of  a  motor 
nerve  to  a  skeletal  muscle  induces  an  active  breakdown  of  the  contractile 
tissue,  or  the  excitation  of  the  augmentor  nerve  to  the  heart  induces  an 
increased  rate  of  beat  and  therefore  increased  functional  activity. 

If  stimulation  of  an  inhibitory  nerve  induces  the  opposite  chemical 
change  to  that  occurring  during  activity,  one  would  expect  to  find  that,  just 
as  an  active  part  of  a  tissue  is  negative  to  an  inactive  part,  so  a  part  of  the 
tissue  which  is  under  the  influence  of  an  inhibitory  stimulus  should  be 
electio-'positive  to  any  part  which  is  not  being  so  stimulated.  According  to 
Gaskell  this  condition  is  realised  in  the  heart  of  the  tortoise.     The  auricles 


THE  NERVOUS  REGULATION  OF  THE  HEART  075 

are  brought  to  a  standstill  by  separating  them  from  the  sinus  venosus.  The 
apex  of  one  auricle  is  then  injured  by  heat,  and  the  injured  point  and  un- 
injured base  are  led  oft"  to  a  galvanometer.  The  usual  demarcation  current 
dependent  on  the  difference  of  potential  between  the  injured  and  uninjured 
portion  is  thus  observed.  If  the  vagus  be  now  stimulated  the  auricles 
remain  at  rest,  but  the  demarcation  current  is  increased,  i.e.  a  positive  varia- 
tion is  produced,  an  electrical  condition  opposed  in  sign  to  that  which  would 
take  place  when  the  auricles  contract.  Doubt  still  exists,  however,  as  to  the 
exact  interpretation  to  be  put  on  this  experiment. 

It  was  mentioned  above  that  potassium  salts  promote  relaxation  of  the  ventricle, 
so  acting  as  antagonists  to  calcium  salts.  If  potassium  salts  be  present  in  a  sufficient 
concentration  in  the  circulating  fluid,  the  heart  is  brought  to  a  standstill  in  a  condition 
of  diastole,  as  if  the  vagus  mechanism  were  in  action.  On  removal  of  the  excess  of  K 
ions  the  heart  at  once  starts  beating  again.  Howell  has  shown  that  dvuring  stimula- 
tion of  the  vagus  the  amount  of  potassium  in  a  diffusible  form  in  the  heart-muscle  is 
increased.  He  has  therefore  suggested  that  the  action  of  the  vagus  in  stopping  the 
heart  is  effected  by  the  liberation  of  potassium  salts.  Potassium  normally  exi^rts  in  a 
large  percentage  in  the  heart-muscle,  but  in  a  combined  form,  and  Howell  assumes 
that  stimulation  of  the  vagus  effects  a  dissociation  of  this  combined  potassium,  so  that 
the  liberated  ions  are  able  to  exert  their  inhibitor}^  influence  on  the  heart. 

THE  TONIC  ACTION  OF  THE  VAGUS 
If  both  vagi  of  a  mammal  be  divided,  the  heart  as  a  rule  beats  more 
frequently,  showing  that  under  normal  circumstances  tonic  impulses  are 
constantly  descending  the  vagi  and  holding  the  heart's  action  in  check. 
The  extent  of  the  quickening  which  is  produced  by  section  of  the  vagi  varies 
in  different  animals  and  is  apparently  associated  with  the  conditions  of  life 
of  the  animal  and  its  powers  of  carrying  out  prolonged  muscular  exertions. 
Thus  in  the  dog  or  horse  the  pulse,  which  is  normally  slow,  may  be  doubled 
in  frequency  by  section  of  the  vagi.  In  the  rabbit,  which  has  a  frequent 
pulse,  and  is  only  able  to  run  for  a  short  distance,  division  of  both  vagi 
causes  very  little  alteration  in  the  pulse-rate.  It  is  stated  that  the  tonic 
action  of  the  vagi  is  much  greater  in  the  hare  than  in  the  rabbit. 

This  tonic  action  may  be  increased  by  various  conditions  of  the  blood, 
e.g.  the  presence  of  drugs,  such  as  morphia. 

ACTION  OF  THE  SYMPATHETIC  CARDIAC  NERVES 
Stimulation  of  the  sjinpathetic  cardiac  nerves  at  any  part  of  their  course 
has  an  effect  on  the  heart  the  exact  reverse  of  that  produced  by  stimulating 
the  vagi.  In  most  cases  the  pulse  frequency  is  increased  in  consequence 
of  the  action  of  these  nerves  on  that  part  of  the  heart  from  which  the  rhythm 
starts.  The  frequency  which  is  attained  by  maximal  stimulation  of  the 
accelerator  nerves  is  independent  of  the  previous  rate  of  the  heart-beat.  The 
increase  in  rate  involves  a  shortening  of  the  time  of  the  cardiac  cycle,  which 
chiefly  affects  the  diastolic  period.  The  size  of  the  auricular  and  ventricular 
contractions  may  be  increased  at  the  same  time  as  their  rate.  In  fact,  like 
the  vagus  nerves,  the  sympathetic  fibres  of  the  heart  can  influence  either 


976 


PHYSIOLOGY 


rhythm  or  strength  of  contraction,  or  the  conduction  from  auricle  to  ventricle, 
according  to  the  part  of  the  heart-muscle  which  is  affected. 

The  augmentor  effect  on  the  strength  of  the  ventricular  beats  is  often 
very  marked.  The  sympathetic  fibres  are  much  less  easily  tired  than  the 
vagus  fibres,  and  have  a  longer  latent  period.     Whereas  the  latent  period 


Fig.  448.     Tracings  of  ventricular  (upper  curve)  and  auricular 

contractions  (lower  curve). 
From  X  to  y  the  accelerator  nerves  stimulated.     Lowest  line  =  seconds. 


4a7". 

Cjo. 

■■'^■(1 

■«llliiifi 


ii^mmm 


ji:jffi,#w*#M*lilliiliiiiiiliiiiili 


Fig.  449.  Tracing  to  show  effect  of  stimulation  of  the  vago-sympathetic  nerve  on  the 
frog's  heart.  The  rhythm  is  unaltered,  but  the  beats  of  auricle  and  ventricle 
are  much  decreased  in  size.  On  ceasing  the  stimulation  the  beats  become  augmented. 
(Gaskell.) 


Fig.  450.     A  tracing  similar  to  Fig  449.     In  this  case,  however,  the  stimulation  caused 
complete  stoppage  (inhibition)  of  both  auricular  and  ventricular  beats.     (Gaskell.) 

of  the  vagus  in  the  mammal  is  considerably  less  than  one  second,  that  of 
the  accelerator  nerves  may  amount  to  ten  or  even  twenty  seconds  (Fig.  448). 
Hence  if  the  vago-sympathetic  of  the  frog  be  stimulated,  the  first  effect  is 
inhibition  due  to  vagus  action.  The  vagus  nerve-endings  then  become 
fatigued,  and  the  influence  of  the  accelerator  fibres  makes  itself  apparent,  and 
the  heart  commences  to  beat,  and  the  beats  become  more  rapid  and  forcible 
than  before  (Figs.  449,  450). 

Like  the  vagus,  the  sympathetic  nerve  fibres  appear  to  exercise  a  tonic 


THE  NERVOUS  REGULATION  OF  THE  HEART 


977 


influence  on  the  heart,  so  that  after  extirpation  of  the  stellate  gangUon  on 
each  side,  the  pulse  frequently  becomes  permanently  slowed. 


THE  ACTION  OF  ADRENALIN  ON  THE  HEART 
The  medullary  part  of  the  suprarenal  glands  forms  and  secretes  into  the 
blood-stream  a  substance,  adrenaline,  which  has  a  marked  action  both  on  the 
heart  and  blood-vessels  and  plays  therefore  an  important  part  in  the  regula- 
tion of  the  circulation.  Whether  this  secretion  is  a  constant  one  has  not  yet 
been  fully  ascertained,  but  there  is  no  question  that  under  certain  specified 


Fig.  451. 

Intraventricular  pressure  tracings  (left  ventricle)  from  dog's  heart  (heart-lung 

preparation).     The  scale  shows  pressure  in  mm.  Hg. 

a.  Under  influence  of  adrenaline. 

b.  Under  simultaneous  influence  of  adrenaline  and  COo  (15  per  cent.)     (Patteeson\ 

conditions  there  may  be  a  marked  influx  of  this  substance  into  the  blood- 
stream. The  action  of  adrenaline  on  any  part  of  the  body  is  practically 
identical  with  that  of  excitation  of  the  sympathetic  nerve  supply  to  the  same 
part.  Its  isolated  action  on  the  heart  is  best  studied  on  the  perfused  heart  or 
in  the  heart-lung  preparation.  On  adding  jJ^  mgm.  of  this  substance  to  the 
500  c.c.  of  blood  circulating  through  the  heart-lung  preparation,  a  maxinmm 
effect  is  at  once  produced  and  this  lasts  for  15  to  20  minutes.  The  action  is, 
like  that  of  the  sympathetic  nerve,  accelerator  and  augmentor.  Through 
its  influence  on  the  sinus  or  the  sino-auricular  node  the  rhythm  of  the  heart 
is  markedly  increased,  in  the  dog  to  about  2-iO  per  minute.  At  the  same  time 
the  energy  of  each  contraction  is  increased.  This  is  especially  shown  in  a 
heart  which  is  beginning  to  fail  and  is  therefore  undergoing  a  certain  degree 
of  dilatation.  Directly  the  adrenahne  reaches  the  heart  the  contractions 
become  extremely  energetic  so  that  the  heart  rapidly  diminishes  in  volume, 
the  venous  pressure  falls,  and  the  blood  flowing  into  it  at  each  diastole  is 
thrown  out  with  violence  into  the  aorta.  The  more  powerful  beat  enables 
the  output  of  the  heart  at  each  beat  to  be  maintained  or  even  increased  in 
spite  of  the  shorter  duration  of  the  systole.     With  each  beat  the  maximum 


978  PHYSIOLOGY 

pressure  in  the  ventricle  therefore  rises  to  a  marked  extent  {see  Fig.  451). 
The  strain  on  the  ventricular  wall  of  this  sudden  contraction  which  is 
necessary  to  empty  the  heart,  during  the  period  of  systole,  is  often  so  great 
that  small  haemorrhages  are  produced  throughout  the  substance  of  the 
inuscle.  The  stimulation  efiect  of  adrenaline  is  shown,  moreover,  by  the 
considerable  rise  in  the  respiratory  exchanges  of  the  heart  under  the  influence 
of  this  substance,  the  oxygen  intake  being  increased  two  or  three  times  above 
that  which  obtained  before  the  administration  of  the  adrenahne.  The  action 
of  adrenalin  therefore  is  in  general  to  enable  the  heart  to  cope  with  a  bigger 
strain  either  in  the  shape  of  arterial  resistance  or  increased  venous  inflow 
than  it  could  do  without  the  stimulus  of  this  substance. 

The  wonderful  adaptation  of  the  heart  to  its  functions  is  illustrated, 
moreover,  by  the  fact  that  adrenahne,  which  increases  the  metabohsm  of  the 
heart  to  such  an  extent,  exercises  at  the  same  time  a  dilator  effect  on  the 
coronary  vessels,  so  that  apart  from  the  high  arterial  pressure  and  the 
metabolites  produced  by  the  contracting  heart  muscle,  the  vessels  are 
dilated  by  the  action  of  the  same  hormone  which  evokes  the  need  for  an 
increased  flow  of  blood  through  the  working  muscle. 

There  is  thus  a  marked  antagonism  in  the  influence  of  the  two  common 
hormones  on  the  heart,  both  of  them  being  produced  during  general  muscular 
activity.  Carbonic  acid  in  excess  causes  dilatation  of  the  heart,  diminished 
functional  activity,  slowing  of  rhythm.  Adrenahne  causes  increased  func- 
tional activity,  diminution  of  cardiac  volume,  and  increased  rhythm.  The 
action  of  adrenahne  is  so  pronounced  that  it  is  possible  to  administer  20  or 
30  per  cent,  carbonic  acid  to  a  heart-lung  preparation  without  altering 
its  output  if  adrenaline  be  administered  at  the  same  time.  The  heart  is 
slowed  by  the  carbonic  acid,  but  the  beat  is  maintained  and  contraction  is 
effective  in  emptying  the  heart  of  its  content. 

THE  HEART  REFLEXES 

The  part  of  the  nervous  system  chiefly  concerned  in  the  central  co- 
ordination of  the  various  afferent  impulses  which  act  on  the  heart  is  the 
medulla  oblongata.  It  is  in  this  situation  that  we  find  the  nerve-cells  giving 
origin  to  the  efferent  fibres  of  the  vagus  nerves,  and  also  the  collection  of 
grey  matter  in  which  the  afferent  fibres  of  the  vagus  terminate.  Direct 
stimulation  of  the  vagus  centre  may  cause  slowing  and  stoppage  of  the 
heart.  The  tonic  influence  of  the  vagi  can  be  abolished  by  destruction  of  this 
centre.  In  this  region  we  also  find  the  vaso-motor  centre,  so  that  the 
activity  of  one  can  affect  that  of  the  other.  This  cardiac  centre  may  be 
played  upon  by  impulses  arriving  at  it  through  various  afferent  nerves  or  from 
the  higher  parts  of  the  brain  and  giving  rise  to  the  changes  of  the  pulse-rate 
associated  with  the  emotional  conditions,  or  it  may  be  directly  affected  by 
the  composition  of  the  blood  circulating  through  its  capillaries. 

The  nerve- cells  which  give  off  the  accelerator  or  augmentor  fibres  are 
situated  in  the  intermedio-lateral  tract  of  the  spinal  cord,  near  the  point  of 
origin  of  these  fibres.     We  might  therefore  speak  of  an  augmentor  centre  in 


THE  NERVOUS  REGULATION  OF  THE  HEART     979 

this  region  ;  but  it  seems  probable  that  the  activity  of  these  cells  is  sub- 
ordinate to  impulses  arriving  at  them  from  the  common  meeting-place 
of  visceral  impulses,  viz.  the  medulla. 

The  most  important  of  the  afierent  nerves  which  affect  reflexly  the 
action  of  the  heart  are  the  nerves  coming  from  the  heart  itself  and  the  aorta. 
In  the  mammalian  ventricle  nerve  fibres  can  be  seen  running  over  the 
surface  of  the  ventricle  which  are  entirely  afferent,  stimulation  of  their 
peripheral  ends  causing  no  eft'ect  on  the  heart-beat.  Stimulation  of  their 
central  ends  may  cause  one  of  four  conditions  : 

(a)  Slowing  of  the  heart. 

(b)  Rise  of  blood-pressure  from  constriction  of  the  splanchnic  area. 

(c)  Fall  of  blood-pressure  by  dilatation  of  the  arterioles  of  the  body. 

{d)  Reflex  movements.  The  heart  does  not  seem  to  be  provided  with  the 
nerves  of  ordinarv  or  tactile  sensibility.     There  is  no  doubt,  however,  that 


Sup-.  Lar.  n.    - 


Depressor 


I 


-SCO. 


--Symp. 


,--Vaqus 


Vagus-- 


Sup-.  lar.  n.-j 


--- Sup-.  Cerv.  Gang. 
-Depressor 
Cerv.  symp.  n. 


— Vaqo.  symp. 


RABBIT 


DOG 


Fig.  452.  Diagrams  of  the  connections  of  the  depressor  nerve  in  the  rabbit  and  dog, 
according  to  C!yon.  It  will  be  noticed  that  in  the  latter  animal  the  depressor 
nerve  runs  in  the  vagus  tnink  together  with  the  sympathetic  nerve,  for  the  greater 
part  of  its  course. 

under  abnormal  circumstances  impulses  arising  in  the  heart  can  give  rise  to 
sensations  of  pain  which  are  referred  not  so  much  to  the  heart  as  to  the 
surface  of  the  body  over  the  left  side  of  the  chest  and  left  arm,  in  the  region  of 
the  distribution  of  the  cutaneous  branches  of  the  second  and  third  dorsal  roots. 
An  important  afferent  nerve  coming  from  the  heart,  or  rather  from  the 
beginning  of  the  aorta,  is  the  depressor  nerve.  In  the  rabbit  this  rises  by 
two  roots,  one  from  the  trunk  and  the  other  from  the  superior  laryngeal 
branch  of  the  vagus,  and  runs  parallel  with  the  vagus  to  the  cardiac  plexus 
(Fig.  452).  It  is  purely  afferent,  stimulation  of  its  peripheral  end  causing  no 
effect.  On  stinmlating  its  central  end  fall  of  blood-pressure  (Fig.  ir>'^)  and 
reflex  slowing  of  the  heart  are  produced,  the  latter  effect  being  abolished  by 
section  of  both  vagi.  It  has  been  shown  by  Bayliss  that  the  depressor  effect 
is  due  to  universal  dilatation  of  the  blood-vessels  of  the  body,  the  greater 


980  PHYSIOLOGY 

part,  however,  being  played  by  the  splanchnic  area.  This  nerve  is  probably 
brought  into  action  whenever  the  pressure  in  the  aorta  is  so  high  as  to  con- 
stitute a  serious  check  to  the  expulsive  action  of  the  heart.  It  is  stated  that 
under  these  conditions  a  current  of  action  may  be  detected  in  the  trunk  of  the 
depressor  nerve,  and  that  if  both  depressor  nerves  be  cut  when  the  aortic 
pressure  is  high  the  blood-pressure  rises  still  higher.  It  presents  a  means  by 
which  the  heart  can  be  reheved  of  a  load  too  great  for  its  powers,  and  therefore 
dangerous  to  its  future  welfare.  In  many  animals  the  depressor  fibres  are 
bound  up  with  the  trunk  of  the  vagus  and  cannot  be  excited  separately. 


Fig.  453.     Blood-pressure  curve  from  rabbit  showing  effect  of  excitation  of  central 
end  of  depressor  nerve  (mercurial  manometer).     (Bayliss.) 

Stimulation  of  the  central  end  of  the  vagus  generally  causes  reflex  slowing 
of  the  heart  through  the  cardiac  centre  and  the  other  vagus.  In  this  reflex 
inhibition  the  chief  fibres  stimulated  are  those  coming  from  the  lungs  (Brodie). 
Inflation  of  the  lungs  causes  acceleration  of  the  heart — whether  due  to 
diminution  of  the  tonic  action  of  the  vagi,  or  to  reflex  excitation  of  the 
accelerator  nerves,  is  not  known.  Most  sensory  nerves  of  the  body  when 
stimulated  give  either  a  slowing  or  a  quickening  of  the  heart.  Stimulation  of 
the  fifth  nerve,  as  in  the  nasal  mucous  membrane,  always  causes  reflex 
inhibition. 

The  rate  of  the  heart-beat  in  the  normal  animal  is  closely  connected 
with  the  blood-pressure.  Increase  in  blood-pressure  due  to  a  large  vaso- 
constriction is  associated  as  a  rule  (but  not  invariably)  with  a  slowing  of  the 
heart-beat.  In  fact,  '  Marey's  law  '  states  that  the  ^pulse-rate  varies  inversely 
as  the  hlood-pressure.  In  this  slowing  of  the  heart  the  vagus  nerves  are  of 
course  active.  Whether  the  blood-pressure  acts  directly  on  the  cardiac 
centre  in  the  medulla,  or  reflexly  through  afferent  nerves  distributed  to  the 


THE  NERVOUS  REGULATION  OF  THE  HEART  981 

aorta  and  heart  cavities,  is  not  yet  fully  made  out.  The  reflex  slowing  of  the 
heart  often  fails  to  accompany  rise  of  blood -pressure.  Thus  the  rise  in  blood- 
pressure  and  the  increased  filling  of  the  heart  associated  with  muscular 
exercise  are  attended  by  an  increased  pulse-rate. 


THE  PULSE-RATE  IN  MAN 
The  normal  pulse-rate  in  man  is  about  72  per  minute.     It  is  largely 
influenced  by  bodily  movements.     The  pulse-rate  varies  considerably  with 
age.     The  following  Table  represents  the  average  pulse-rate  in  man  at 
different  ages  : 

Age  in  year.s  Pulse-rate  per  minute 

0  . .  136 

5  ..  88 

10-15  .  .  78 

15-60  . .  68-72 

It  must  be  remembered  that  marked  differences  in  pulse-rate  may  be 
found  in  different  individuals  without  having  any  pathological  significance. 
Thus  pulse-rates  of  30  per  minute  and  120  per  minute  have  been  observed  in 
men  who  were  otherwise  perfectly  healthy.  The  pulse-rate  is  raised  by 
warmth  and  diminished  by  cold  applied  to  the  surface  of  the  skin.  It  is 
also  increased  somewhat  by  the  taking  of  food.  The  act  of  swallowing  causes 
a  reflex  quickening  of  the  rate  by  inhibition  of  the  tonic  vagus  action. 


SECTION   X 
THE  NERVOUS  CONTROL   OF  THE   BLOOD-VESSELS 

During  muscular  activity  the  metabolism  of  the  body  as  a  whole,  as  judged 
by  its  gaseous  interchanges,  may  be  increased  six-  or  eight-fold.  This 
increase  is  due  almost  exclusively  to  the  additional  metabolic  changes 
consequent  on  muscular  activity.  The  muscles  therefore  during  activity 
require  a  greater  supply  of  blood  in  order  to  obtain  from  it  the  oxygen  neces- 
sary for  their  contraction,  and  to  get  rid  of  the  carbon  dioxide,  which  is  the 
end-result  of  their  activity.  In  the  same  way  every  organ  of  the  body 
requires  an  increased  blood-supply  during  activity.  Blood  must  be  diverted 
from  the  inactive  to  the  active  tissues.  All  parts  of  the  body  must  co- 
operate in  subordination  to  the  activity  of  that  tissue  whose  function  for  the 
time  being  is  of  the  greatest  importance  to  the  organism.  This  subordination 
of  the  part  to  the  whole,  i.e.  of  every  part  to  the  organ  whose  activity  is 
specially  evoked  by  the  needs  of  the  whole  organism,  is  chiefly  effected 
through  the  central  nervous  system,  though  local  and  chemical  mechanisms 
also  play  some  part  in  the  process. 

Our  knowledge  of  the  nervous  control  of  the  blood-vessels  dates  from  the 
discovery  by  Claude  Bernard  that  nerve  fibres  run  in  the  cervical  sympathetic 
to  the  blood-vessels  of  the  head  and  neck,  and  maintain  them  in  a  state  of 
tonic  constriction.  Bernard  showed  that  if  in  the  rabbit  the  cervical 
sympathetic  on  one  side  be  divided,  the  vessels  in  the  corresponding  ear 
dilate.  Vessels  come  into  prominence  which  were  previously  invisible,  and 
on  account  of  the  greater  flow  of  blood  thus  produced,  the  ear  on  the  side 
of  the  section  becomes  warmer  than  the  normal  ear.  If  the  head  end  of  the 
divided  sympathetic  nerve  be  stimulated,  all  the  vessels  of  the  ear  contract, 
and  the  ear  becomes  colder  than  that  of  the  other  side.  The  fact  that  the 
dilatation  of  the  vessels  is  produced  by  section  of  the  cervical  sympathetic 
and  lasts  for  a  considerable  time  after  any  irritant  effect  of  the  section 
must  have  passed  off  shows  that  the  ear- vessels  are  continually  under  the 
influence  of  tonic  constrictor  impulses  proceeding  to  them  along  the  nerve 
fibres  of  the  cervical  sympathetic. 

It  can  be  easily  shown  that  these  impulses  take  their  origin  in  the  central 
nervous  system.  The  paralysis  of  the  ear- vessels,  though  lessening  the  resist- 
ance to  the  flow  of  blood  there,  affects  too  small  a  vascular  area  to  have 
any  marked  influence  on  the  total  resistance  of  the  circulation  and  therefore 
on  the  arterial  blood-pressure.     If  the  spinal  cord  be  divided  on  a  level 

982 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS  983 

with  the  origin  of  the  first  dorsal  nerve,  the  blood-pressure  sinks  considerably. 
In  the  dog  it  may  fall  from  120  mm.  Hg.  to  40  or  50  mm.  Hg.  The  heart 
after  the  section  beats  more  rapidly  than  before,  so  that  the  fall  of  pressure 
must  be  ascribed  to  a  change  affecting  the  blood-vessels  and  lowering  the 
resistance  to  the  flow  of  blood.  Since  a  maximal  effect  on  the  blood-pressure 
is  produced  by  section  of  the  cord  at  this  level,  one  may  conclude  that  the 
tonic  constrictor  impulses  to  all  the  vessels  of  the  body  pass  through  this 
segment  of  the  cord  before  leaving  it  to  be  distributed  to  the  arterial  walls. 
The  source  of  these  impulses  may  be  made  out  by  studying  the  effect  of 
sections  through  different  levels  of  the  nervous  system.  Division  of  the 
cord  at  about  the  first  or  second  lumbar  nerve  causes  no  effect  on  the  blood- 
pressure.  On  making  a  section  at  the  sixth  dorsal  root  a  considerable  fall 
of  pressure  is  produced,  almost,  but  not  quite,  as  great  as  that  observed  after 
section  at  the  first  dorsal  segment ;  stimulation  of  the  lower  end  of  the  cut 
cord  causes  almost  universal  vascular  constriction  and  a  large  rise  of  blood- 
pressure.  On  the  other  hand,  the  fall  of  pressure  is  maximal  when  the  section 
is  carried  through  the  first  dorsal  segment  or  through  any  part  of  the  cervical 
cord.  Section  of  the  crura  cerebri,  or  of  the  brain-stem  at  the  upper  border 
of  the  fourth  ventricle,  leaves  the  blood-pressure  unaffected.  Destruction 
of  a  small  region  of  the  medulla  situated  on  each  side  of  the  middle  line  in  the 
neighbourhood  of  the  facial  nucleus,  i.e.  in  the  forward  prolongation  of  the 
lateral  columns  after  they  have  given  off  their  fibres  to  the  decussating 
pyramids,  causes  an  immediate  and  maximal  lowering  of  the  blood- 
pressure. 

We  must  therefore  conclude  that  all  the  vessels  in  the  body  are  kept 
in  a  state  of  tonic  contraction  by  impulses  arising  in  this  poi-tion  of  the 
medulla  oblongata,  travelUng  down  the  cord  as  far  as  the  dorsal  region,  and 
then  passing  out  of  the  cord  by  the  dorsal  and  upper  lumbar  nerves.  This 
conclusion  is  confirmed  by  the  fact  that,  whereas  stimulation  of  the  anterior 
roots  of  the  cervical  and  lower  lumbar  and  sacral  nerves  has  no  influence  on 
the  blood-pressure,  a  rise  of  arterial  pressure  can  be  obtained  by  stimulating 
any  of  the  anterior  roots  from  the  first  or  second  dorsal  to  the  second  or 
third  lumbar.  The  same  effect  is  produced  by  stimulation  of  the  white 
rami  communicantes  from  these  roots  to  the  sympathetic  system,  or  by 
excitation  of  the  sympathetic  system  itself. 

The  portion  of  the  medulla  concerned  with  the  sending  out  of  the  tonic 
vaso-constrictor  impulses  is  spoken  of  as  the  vaso-motor  centre.  In  this 
region  it  is  exposed  to  and  played  upon  by  afferent  impulses  from  all  portions 
of  the  body,  from  the  higher  centres  of  the  brain  and  the  cortex  cerebri,  and 
especially  by  afferent  impulses  travelling  by  the  vagi  from  the  viscera  of  the 
chest  and  abdomen.  Whether  in  the  absence  of  all  afferent  stimuli  the 
centre  would  be  active  is  doubtful ;  all  we  know  is  that  the  sum  of 
the  stimuli  arriving  at  the  centre  produces  a  state  of  average  continued 
activity,  which  is  responsible  for  the  maintenance  of  arterial  tone  and 
for  the  regulation  of  the  arterial  blood-pressure. 

The.  centre  may  also  be  affected  directly  by  changes  in  its  blood-supply. 


V 


984  PHYSIOLOGY 

or  in  the  composition  of  the  blood  flowing  through  it.  Thus  anything  which 
interferes  with  the  gaseous  exchanges  of  the  centre,  whether  obstruction  to 
respiration,  absence  of  oxygen  in  the  air  breathed,  or  a  failure  of  the  blood- 
supply,  as  by  ligature  of  the  cerebral  arteries,  calls  forth  an  increased  state  of 
activity  of  the  centre.  This  can  be  best  studied  by  observing  the  changes 
in  the  blood  pressure  produced  in  a  curarised  animal  by  the  cessation  of 
artificial  respiration. 

These  changes  depend  partly  on  the  stimulation  of  the  vaso-motor  and 
vagus  centres  by  the  venous  blood,  and  partly  on  the  affection  of  the  heart 
itself.  We  will  first  consider  them  with  both  vagi  cut,  in  order  to  shut 
out  the  action  of  the  vagus  centre.  The  blood-pressure  is  registered  by 
means  of  a  mercurial  manometer  in  connection  with  the  carotid  artery. 
On  leaving  off  the  artificial  respiration,  the  blood-pressure  may  remain 
at  the  same  height  for  some  seconds,  the  only  change  noticed  being  the 
absence  of  the  respiratory  oscillations.  Sooner  or  later  the  blood-pressure 
suddenly  rises  rapidly  (Fig.  454,  a),  and  in  another  ten  seconds  may 
reach  a  height  twice  as  great  as  it  was  previously.  The  heart  beats 
a  little  more  forcibly  in  consequence  of  the  increased  cardiac  tension, 
but  its  frequency  is  almost  unaltered.  The  blood-pressure  remains  at  this 
height  for  about  a  minute,  and  then  gradually  falls,  the  heart-beats  becoming 
smaller  and  smaller,  until  the  pressure  has  sunk  to  a  point  very  little  above 
the  abscissa  line  (level  of  no  pressure).  This  fall  in  pressure  is  due  to  the 
failure  of  the  heart.  The  heart,  badly  suppHed  with  oxygen,  cannot  overcome 
the  high  resistance  presented  by  the  contracted  arterioles  ;  it  gets  overfilled, 
and  gradually  loses  the  power  of  expelling  any  of  its  contents.  If,  when  the 
blood- pressure  has  sunk  to  its  lowest  point,  the  heart  be  rapidly  cut  out  of  the 
body,  it  will  begin  to  beat  fairly  forcibly,  being  relieved  of  the  excessive 
internal  tension.  The  vessels,  however,  remain  constricted  until  the  death 
of  the  animal.  This  is  shown  by  two  facts.  If,  while  the  pressure  is  sinking, 
artificial  respiration  be  recommenced,  the  heart  supplied  with  oxygen  at  once 
begins  to  beat  more  forcibly,  and  the  blood- pressure  may  rise  to  an  even 
greater  height  than  immediately  after  the  commencement  of  the  asphyxia. 
Again,  if  the  volume  of  the  kidney  be  recorded  by  means  of  the  oncometer, 
the  rise  of  general  blood-pressure  produced  by  asphyxia  is  seen  to  be  accom- 
panied by  a  marked  shrinking  of  the  kidney,  and  this  shrinking  endures  until 
the  animal  dies,  showing  that  the  fall  of  blood-pressure  following  the  rise 
is  due,  not  to  a  giving  way  of  the  arterial  resistance,  but  to  failure  of  the 
heart. 

Similar  results  are  obtained  when  the  vessels  to  the  brain  are  ligatured, 
or  when  the  animal  has  to  respire  an  indifferent  gas  free  from  oxygen,  such  as 
nitrogen  (Fig.  454,  b)  or  hydrogen.  In  the  uncurarised  animal  the  rise 
of  blood- pressure  is  associated  with  increased  respiratory  movements  and 
finally  with  convulsive  spasms  which  may  involve  practically  every  muscle 
of  the  body. 

We  have  spoken  above  of  the  phenomena  of  asphyxia  as  being  due  to  the 
circulation  of  venous  blood.     There  are,  however,  two  factors  which  may 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS 


985 


be  concerned  and  which  may  influence  the  medullary  centres  and  the  heart. 
When  the  renewal  of  the  lung  ventilation  is  stopped  by  ligature  of  the 
trachea  or  by  cessation  of  the  respiratory  movements,  the  increasing  venosity 
of  the  blood  involves  a  diminished  percentage  of  oxygen  and  an  increased 
percentage  of  carbon  dioxide,  and  when  asphyxia  is  excited  by  cessation 
of  the  circulation  through  the  medullary  centres,  these  centres  may  suffer 
at  the  same  time  from  lack  of  oxygen  and  from  the  accumulation  of  carbon 
dioxide.  The  question  arises  whether  one  or  both  of  these  factors  are  con- 
cerned. It  is  easy  to  investigate  the  action  of  each  separately.  A  pure 
oxygen  lack  may  be  brought  about  by  allowing  an  animal  to  breathe  some 


t    Resp.off   -100 

M  I  f  I  f  M  I 


A 

-220 

/A 

J 

l^off^ 

-/SO 

lA^ 

on 

'100 

\  \ 

Nitrogen 

\    \    ]    \    \ 

\  \  \ 

1 

Fig.  454.     Blood-pressure  changes  in  a  cat.     A.  after  cessation  of  respiratory  move- 
ments.    B,  as  a  result  of  artificial  respiration  with  nitrogen.     (Mathison.) 


inert  gas,  such  as  nitrogen  or  hydrogen,  or  in  the  curarised  animal  one  of  these 
gases  may  be  administered  by  the  pump  used  for  artificial  respiration.  The 
effects  of  accumulation  of  carbon  dioxide  in  the  blood  and  tissues  may  be 
produced  by  the  administration  of  gaseous  mixtures  containing  excess  of 
oxygen,  i.e.  39  to  40  per  cent.,  with  varying  percentages  of  carbon  dioxide. 
In  the  first  case,  the  tension  of  the  carbon  dioxide  in  the  blood  will  be  kept 
below  normal  ;  in  the  second  case,  the  tension  of  oxygen  in  the  blood  will 
be  kept  above  normal.  In  order  to  obtain  results  uncomplicated  by  the 
influence  of  anaesthetics,  the  experiments  may  be  carried  out  in  animals 
which  have  been  deprived  of  consciousness  by  destruction  of  the  brain  above 
the  superior  corpora  quadrigemina.  At  different  times  physiologists  have 
been  inchned  to  ascribe  the  excitatory  phenomenon  of  asphyxia  either  to 
absence  of  oxygen  or  to  excess  of  carbon  dioxide.  Mathison  has  shown  that 
both'conditions  may  concur  in  the  production  of  the  rise  of  blood-pressure 
in  asphyxia.     In  Figs.  -lo-I  and  15.")  the  rise  of  arterial  pressure  produced  by 


986 


PHYSIOLOGY 


a  short  period  of  asphyxia  is  compared  with  that  produced  by  oxygen  lack, 
by  a  surplus  of  carbon  dioxide,  and  by  the  injection  of  lactic  acid  into  the 
circulation.  There  are  certain  minor  details  in  these  curves  which  are  of 
interest.  When  the  oxygen  of  the  lungs  is  rapidly  washed  out  with  a  neutral 
gas  the  asphyxial  rise  comes  on  about  half  a  minute  later  than  it  would 
with  pure  asphyxia.  In  the  latter  case  it  seems  that  the  first  rise  is  due 
to  the  accumulation  of  carbon  dioxide.  The  rise,  however,  under  nitrogen 
when  it  occurs  is  extremely  abrupt,  and  the  subsequent  fall  of  blood-pressure, 
i.e.  the  heart  failure,  is  earlier  in  onset  and  more  rapid  than  with  ordinary 
asphyxia.     When  excess  of  carbon  dioxide  is  administered,  i.e.  5  to  10 


220- 


t  /oo- 

on 


CO 2  12"^  per  cent 
O2  30  per  cent 


Fig.  455.     Asphyxial  blood-pressure  changes  in  curarised  cat.     A,  inhalation  of 
CO2.     B,  injection  of  lactic  acid.     (Mathison.) 

per  cent.,  a  marked  rise  of  pressure  occurs  which,  hke  that  produced  by 
oxygen  lack,  is  almost  entirely  conditioned  by  stimulation  of  the  vaso-motor 
centres  and  resulting  constriction  of  the  peripheral  arterioles.  If  a  loop  of 
intestine  be  placed  in  a  plethysmograph,  it  will  be  seen  that  the  rise  of 
pressure  coincides  with  a  shrinkage  in  volume  of  the  intestine,  pointing  to 
a  vascular  constriction  (Fig.  456).  The  rise  of  blood-pressure  due  to  the 
vascular  constriction  may  be  maintained  for  a  considerable  period,  e.g.  ten  to 
fifteen  minutes,  and  we  do  not  get  the  rapid  fall  of  pressure  due  to  failure 
of  the  heart  that  is  observed  in  an  ordinary  asphyxia  tracing.  If  partial 
oxygen  lack  or  abnormally  increased  tension  of  carbon  dioxide  be  continued 
for  some  time,  a  state  of  narcosis  or  paralysis  finally  ensues  which  affects  not 
only  the  higher  centres  but  also  those  of  the  medulla,  so  that  death  may  ensue 
without  convulsions  or  excessive  rise  of  blood-pressure. 

Is  there  any  common  factor  in  the  two  conditions  of  oxygen  lack  and 
carbon  dioxide  excess  which  may  account  for  the  similarity  in  their  effects  ? 
It  has  been  shown  that  whenever  there  is  a  deficiency  of  oxygen  the  metabo- 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS 


987 


/  off 

♦MJ»%ft«V^"''%y    ^^     -100 


lism  of  the  tissues  undergoes  alteration,  so  that  as  a  result  of  activity,  e.cj.  in 
muscles,  lactic  acid  is  formed  instead  of  carbon  dioxide.  Lactic  acid  can 
therefore  be  detected  in  the  blood  whenever  violent  exercise  is  taken  sufificient 
to  produce  dyspnoea,  or  when  the  access  of  oxygen  is  diminished  by  poisoning 
with  carbon  monoxide,  or  by  reducing  the  tension  of  this  gas  in  the  air 
breathed.  Oxygen  lack  can  be  regarded  therefore  as  synonymous  with  the 
production  of  lactic  acid.  Lactic  acid  in- 
troduced into  the  blood-stream,  as  is  shown 
in  the  curve  in  Fig.  455,  b,  is  equally  effica- 
cious with  oxygen  lack  or  with  carbon  dioxide 
excess  in  the  production  of  a  rise  of  blood- 
pressure  indistinguishable  from  the  asphyxial 
rise.  It  seems  therefore  that  the  common 
factor  in  asphyxia  is  the  increased  acidity 
or  H'  ion  concentration  of  the  blood.  We 
shall  have  occasion  to  return  to  this  ques- 
tion in  dealing  with  the  regulation  of  the 
respiratory  movements. 

If  in  the  dog,  and  to  a  less  extent  in 
other  animals,  the  vagi  be  left  intact,  the 
blood- pressure  tracing  during  asphyxia  has 
quite  another  appearance.  At  the  point  of 
the  tracing  corresponding  to  the  rapid  rise 
in  the  previous  experiment  there  is  in  this 
case  only  a  slight  rise  of  pressure,  but  the 
heart  begins  to  beat  very  slowly.  At  each 
beat  it  necessarily  sends  out  a  greater 
volume  of  blood  than  when  it  is  beating 
more  frequently,  and  hence  the  oscillations 
on  the  blood-pressure  curve  caused  by 
the  heart-beats  become  very  large.  This 
slow  beat  is  due  to  the  action  of  the  vagus 
centre,  and  is  at  once  abolished  by  section  of  the  two  vagi.  The  sparing 
of  the  heart  by  means  of  this  vagus  action  enables  it  to  last  longer,  and 
th3  final  fatal  fall  of  blood-pressure  due  to  heart  failure  comes  on  rather 
later  than  when  the  vagi  are  divided.  In  the  increased  vagus  action  which 
occurs  during  asphyxia  two  factors  are  probably  involved.  The  cardial 
inhibitory  centre  in  the  medulla  probably  partakes  of  the  general  excita- 
tion of  the  medullary  centres  due  in  the  first  place  to  carbon  dioxide 
excess,  in  the  second  to  oxygen  lack.  More  important  is  the  direct 
action  of  the  rise  of  blood-pressure  on  the  medullary  centre.  The  rise 
of  arterial  pressure  causes  increased  intracranial  tension,  and  any  increase 
of  the  latter  excites  the  vagus  centre  and  produces  slowing  of  the  pulse^ 
The  vagus  slowing  is  therefore  absent  in  asphyxia  if  the  arterial  blood  be 
allowed  to  escape  through  a  mercury  '^valve  so  as  to  prevent  any  rise  of 
pressure  in  the  brain  cavity. 


CO2   7% 


on 


Int.  Vol. 


B.P. 


Fig.  456.  Tracing  of  arterial  blood- 
pressure  and  of  intestinal  volume, 
to  show  the  influence  of  a  moder- 
ate increase  in  the  CO2 tension  of 
the  blood.     (Mathison.) 


988 


PHYSIOLOGY 


During  the  period  of  increased  pressure  waves  are  often  observed  on  the  blood- 
pressure  curve.  These  are  of  two  kinds.  In  the  first  place,  in  completely  curarised 
animals  we  may  observe  oscillations  of  blood-pressure  corresponding  with  the  respira- 
tory rhythm  before  the  administration  of  curare,  or  if  the  vagi  are  cut,  presenting  a 
rhythm  similar  to  that  usual  in  animals  with  divided  vagi.  These  waves  are  known  as 
the  Traube-Hering  curves  from  the  physiologists  by  whom  they  were  first  observed. 
They  are  certainly  due  to  irradiation  of  impulses  from  the  excited  respiratory  centre 
to  the  vaso-motor  centre  in  the  medulla.  In  fact,  if  the  curarisation  is  not  complete 
a  slight  twitch  of  the  diaphragm,  insufficient  by  itself  to  have  any  mechanical  influence 
on  the  circulation,  may  be  observed  to  accompany  each  rise  on  the  blood-pressure 
curve.  Besides  the  Traube-Hering  curves  others  are  occasionally  seen  which  must 
arise  in  a  slow  rhythmic  variation  of  the  constrictor  impulses  sent  out  from  the  vaso- 
motor centre.  These  waves  are  known  as  the  Mayer  curves,  and  are  not  to  be  confused 
with  the  waves  on  an  ordinary  pressure  curve  due  to  respiration,  being  much  slower  in 


Fig.  4.57.     Blood-pressure  tracings  showing  S.  Mayer  curves.     (C.  J.  Martin.) 


their  rhythm  than  the  latter.  They  are  observed  not  only  during  asphyxia,  but  may 
occur  in  blood-pressure  tracings  from  normal  dogs,  and  are  frequent  in  dogs  poisoned 
with  morphia.  Fig.  457  represents  tracings  obtained  from  a  dog  under  the  influence 
of  morphia  and  curare.  The  upper  curve,  taken  while  artificial  respiration  was  being 
carried  on,  shows  the  three  forms  of  curves — the  oscillations  due  to  the  heart-beat 
next  in  size  those  due  to  the  respiratory  movements,  which  in  their  turn  are  superposed 
on  the  slow  prolonged  curves,  i.e.  the  Mayer  curves.  The  lower  curve  is  taken  imme- 
diately after  cessation  of  the  artificial  respiration,  and  shows  only  the  heart-beats  and 
the  Mayer  curves.  The  presence  of  Mayer  curves  may  generally  be  ascribed  to  a  state 
of  abnormal  excitation  of  the  vaso-motor  centre.  This  excitation  may  arise  in  various 
ways.  A  very  frequent  cause  is  the  one  just  described,  viz.  increased  venosity  of  the 
blood  supplied  to  the  centre.  Well-marked  Mayer  curves  are  often  observed  in  cases 
of  haemorrhage.  In  spite  of  the  loss  of  blood,  the  vaso-motor  centres  maintain  a  normal 
arterial  blood-pressure  by  means  of  vascular  constriction.  As  the  bleeding  continues, 
this  means  becomes  inadequate,  and  at  this  point  the  '  efforts  '  of  the  centres  take  on  a 
rhythmic  character,  giving  well-marked  Mayer  curves,  just  as  the  arm  of  a  man  holding 
up  a  weight  begins  to  shake  before  he  is  obliged  to  give  way  through  fatigue.  If  the 
bleeding  still  continues,  the  pressure  sinks  steadily  and  the  curves  disappear.  The 
curves  may  also  be  often  observed  during  operations  involving  exposure  of  the  cord. 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS  989 

and  may  possibly  be  ascribed  in  this  case  to  abnormal  irritations  ascending  the  posterior 
columns. 

The  vaso-motor  centre  may  also  be  directly  atfected  by  drugs  such  as  digitalis  or 
strophanthus,  both  of  which  cause  a  rise  in  general  blcod-preshure  from  stimulation  of 
the  centre. 

SPINAL  CENTRES 

The  great  fall  of  blood-pressure  observed  after  section  of  the  cord  in  the 
lower  cervical  region  is  not  permanent.  After  one  or  two  hours  the  pressure 
begins  to  rise,  and  if  the  animal  be  kept  alive,  may  attain  a  height  only  a 
little  inferior  to  that  found  in  normal  animals. 

If  the  spinal  cord  of  such  an  animal  be  destroyed,  the  blood-pressure 
sinks  practically  to  zero  and  the  circulation  comes  to  an  end,  because  the 
animal  has  been,  so  to  speak,  bled  to  death  into  its  own  dilated  blood-vessels. 
In  addition  to  the  chief  vaso-motor  centre  in  the  medulla  there  is  a  series 
of  subsidiary  centres  in  the  spinal  cord,  centres  which  we  may  probably 
locate  in  the  portions  of  grey  matter  situated  in  the  lateral  horns  of  the 
cord  and  giving  origin  to  the  fibres  which  go  to  make  up  the  white  rami 
communicantes.  By  means  of  these  spinal  centres  a  certain  degree  of 
adaptation  is  possible  between  the  blood-supply  of  the  various  parts  of  the 
trunk.  The  important  co-ordination  between  the  state  of  the  blood-vessels 
and  the  condition  of  the  central  pump,  the  heart,  is,  however,  wanting,  since 
the  blood-vessels  are  now  cut  of?  from  the  cardiac  centres  and  from  the 
part  of  the  central  nervous  system  which  receives  the  afferent  impulses 
carried  by  the  vagi. 

The  spinal  centres,  like  the  chief  vaso-motor  centre,  are  susceptible  to 
changes  in  the  composition  of  the  blood  suppUed  to  them.  If  an  animal  be 
kept  alive  by  means  of  artificial  respiration  for  a  Uttle  time  after  division 
of  the  cord  just  below  the  medulla,  the  blood-pressure  slowly  rises  as  the 
spinal  centres  begin  to  take  on  their  automatic  functions.  If  artificial 
respiration  be  now  discontinued  the  asphyxia  excites  the  centres  of  the  cord. 
The  motor  discharge  to  the  skeletal  muscles  reveals  itself  in  a  single  prolonged 
spasm,  since  the  respiratory  centre  is  unable  to  take  any  part  in  directing  the 
motor  discharges.  Simultaneously  with  the  spasm  of  the  skeletal  muscles 
general  constriction  of  the  blood-vessels  occurs  which  outlasts  the  muscular 
spasms  and  causes  a  considerable  rise  of  blood-pressure  (Fig.  4:dS). 

In  this  rise  of  pressure  the  main  factor  is  lack  of  oxygen,  and  precisely 
similar  curves  are  obtained  whether  the  asphyxia  be  produced  by  cessation 
of  artificial  respiration  oi-  by  administration  of  nitrogen.  The  same  eliect 
may  be  produced  by  a  very  large  excess  of  carbon  dioxide,  or  by  the  injection 
of  acids  into  the  circulation.  There  is  a  striking  difference  between  the 
sensibility  of  the  spinal  centres  to  these  substances  as  compared  with  the 
medullary  centres.  Thus  the  medullary  vaso-motor  centre  is  readily 
excited  by  ventilation  with  .5  per  cent,  carbon  dioxide,  whereas  a  rise  of 
blood-pressure  is  only  obtained  from  the  spinal  animal  when  mixtures  con- 
taining 25  per  cent,  and  upwards  of  carbon  dioxide  are  employed.  The 
excitation  of  the  medullary  centre  conies  on  about  thirty  seconds  after  the 


990  PHYSIOLOGY 

administration  of  nitrogen  has  commenced  in  contrast  to  that  of  the  spinal 
centres  which  does  not  occur  until  two  minutes  or  more  have  elapsed.  In 
the  intact  animal  a  maximal  stimulation  of  the  vaso-motor  centre  is  pro- 
duced in  the  cat  by  the  injection  of  2  c.c.  N/20  lactic  acid,  whereas  5  c.c. 
of  N/2  acid  are  required  to  excite  spinal  cord  centres.     Here  therefore,  as  in 


Fig.  458.  Blood-pressure  tracing  taken  by  a  mercurial  manometer  from  carotid 
artery  of  a  dog,  three  hours  after  section  of  the  cord,  just  below  the  medulla 
oblongata.  At  o  the  artificial  respiration  was  discontinued.  A  general  spasm 
of  the  skeletal  muscles  occurred  between  x  and  x.  The  muscles  then  relaxed, 
and  were  flaccid  during  the  rest  of  the  rise  of  blood-pressure. 

the  medulla,  the  common  factor  is  probably  increased  H  ion  concentration, 
the  excitation  threshold  for  the  medullary  centres  being  only  about  one- 
fifth  that  of  the  spinal  centres. 

The  local  spinal  centres  are  connected  with  the  medullary  vaso-motor 
centre  on  each  side  by  tracts  of  nerve  fibres  which  descend  in  the  lateral 
columns  of  the  cord. 

THE  PERIPHERAL  TONE  OF  THE  BLOOD-VESSELS 
Division  of  the  sciatic  nerve  causes  an  immediate  dilatation  of  the 
vessels  of  the  lower  limbs  in  consequence  of  their  severance  from  the  tonic 
activity  of  the  vaso-motor  centres.  This  dilatation  passes  off  in  a  day  or 
two  and  the  vessels  acquire  a  tone,  i.e.  remain  in  a  state  of  average  constric- 
tion which  can  be  increased  or  diminished  by  local  conditions.  This  recovery 
of  tone  has  been  ascribed  by  many  physiologists  to  the  existence  of  a  third 
set  of  nerve-centres  in  the  walls  of  the  arteries.  In  the  absence  of  any 
direct  histological  evidence  of  the  existence  of  such  centres  it  seems  more 
rational  to  ascribe  the  tonus  to  the  automatic  activity  of  the  muscular  fibres 
themselves. 


THE  COURSE  AND   DISTRIBUTION  OF  THE  VASO-MOTOR  NERVES 

Since  the  blood-vessels,  like  the  heart,  are  the  seat  of  an  automatic 
activity,  complete  nervous  control  of  these  tubes  can  only  be  secured  by  the 
provision  of  two  sets  of  nerves  :   one  set — augmentor  or  motor — which  will 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS 


991 


increase  the  state  of  constriction  of  the  vessels  ;  another  set — inhibitor  or 
dilator — which  will  diminish  the  tone  of  the  arteriole  muscle  and  cause 
vascular  dilatation.  Our  knowledge  of  the  existence  of  this  second  class 
of  nerve  fibres  to  the  vessels  we  owe  also  to  Claude  Bernard,  who  observed 
that  stimulation  of  the  chorda  tympani  nerve  not  only  evoked  secretion 
from  the  submaxillary  gland  but  also  increased  the  blood-flow  through  its 
vessels  five-  or  sixfold.  Subsequent  researches  have  revealed  the  fact  that 
nearly  all  the  vessels  of  the  body  receive  vaso-constrictor  fibres,  and  that 
many  receive  also  vaso-dilator  fibres.  In  order  to  determine  the  course 
and  distribution  of  the  vascular  nerves  it  is  necessary  to  have  means  at  our 
disposal  for  investigating  the  condition  of  the  blood-flow  through  different 
parts   and   organs   of    the    body. 

Let  us  see  what  effects  will  ensue  

on  the  local  circulation  by  con- 
striction or  dilatation  of  the  arte- 
rioles with  which  it  is  suppHed. 
If  the  arterioles  a  in  the  organ  b 
dilate  (Fig.  459),  the  first  effect  is 
a  diminution  of  the  resistance  to 
the  flow  of  blood  into  the  capil- 
laries beyond.  Supposing  that 
the  arterial  pressure  in  the  trunk 
C  remain  constant,  a  local  diminu- 
tion of  resistance  in  a  will  at  once 
determine  an  increased  flow  of 
blood  through  the  arterioles,  and 
the  fall  of  pressure  from  A  to  the 

capillaries  will  be  less  than  when  the  arteriole  was  constricted.  If  the 
organ  is  distensible  and  elastic,  the  increased  pressure  in  the  arterioles  and 
capillaries  will  cause  dilatation  of  these  vessels,  and  a  consequent  dilatation 
of  the  whole  organ.  The  same  effect  on  intracapillary  pressure,  and  there- 
fore on  the  volume  of  the  part,  may  be  caused  by  obstruction  to  the  flow 
of  blood  from  the  veins.  Provided  that  there  is  no  obstruction  to  the  flow  of 
blood  through  the  vein,  and  that  the  general  blood-pressure  in  c  remains 
constant,  dilatation  of  an  organ  may  be  taken  as  an  expression  of  vaso- 
dilatation in  the  arteries  with  which  it  is  supplied.  The  diminution  of  the 
resistance  in  A  may  also  increase  the  velocity  of  the  flow  through  the  part, 
since  the  amount  of  blood  flowing  in  a  given  period  of  time  through  any 
vessel  varies  directly  as  the  difference  of  pressure,  and  inversely  as  the 
resistance  in  the  vessel. 

We  can  therefore  use  the  following  criteria  for  the  occurrence  of  a  vaso- 
dilatation in  the  arterial  supply  to  any  part  or  organ  : 

(1)  If  the  surface  of  the  part  is  translucent,  the  increased  filling  of  the 
blood-vessels  will  cause  redness  or  blushing. 

(2)  The  increased  size  of  the  vessels  will  cause  an  increase  in  the  volume 
of  the  organ  concerned. 


Fig.  459. 


992 


PHYSIOLOGY 


(3)  An  increased  velocity  of  blood-flow  will,  if  the  part  be  normally 
below  the  temperature  obtaining  in  the  central  organs  of  the  body,  raise  its 
temperature,  and  vaso- dilatation  can  thus  be  detected  by  the  application  of 
the  hand  or  of  a  thermometer. 

(4)  Any  of  the  methods  mentioned  in  a  previous  chapter  may  be  used 
to  determine  the  velocity  in  the  arteries  going  to  the  part,  and  an  increased 
velocity  may  be  interpreted  as  due  to  vaso-dilatation. 

(5)  The  increased  flow  through  the  part  may  be  detected  by  cutting 
the  main  efferent  vein  and  measuring  the  total  volume  of  blood  which  flows 
from  it  in  a  given  time. 

Of  these  methods  the  two  most  used  are  those  based  on  determination 
either  of  the  volume  of  the  part,  or  of  the  venous  outflow  from  the  part. 


■  to  oncometer 


Fig.  460.     Diagram  of  oncometer. 


Fig.  461.     Diagram  of  oncograph. 


A  fallacy  may,  however,  arise,  unless  means  be  taken  to  ensure  that  the 
general  arterial  pressure  remain  constant  during  the  experiment.  A  rise 
of  general  blood-pressure  will  cause  an  expansion  of  the  vessels  and  of  the 
part  supplied,  and  also  increased  velocity  of  blood-flow  through  the  part. 
In  all  cases  therefore  where  it  is  desired  to  investigate  the  conditions  of  the 
local  circulation,  it  is  necessary  to  combine  a  determination  of  the  general 
blood-pressure  with  some  means  of  estimating  changes  in  the  local  conditions. 
We  may  take  as  an  instance  an  experiment  on  the  blood-supply  to  the 
kidney. 

For  this  purpose  we  may  use  a  kidney  plethysmograph  or  oncometer.  The  structure 
of  Roy's  oncometer  is  shown  in  Fig.  460.  The  oncometer  is  a  metal  capsule,  the  two 
halves  of  which  are  hinged  together  and  come  in  contact  at  the  whole  of  their  circum- 
ference except  at  h,  where  a  small  depression  is  left  in  each  half  for  the  passage  of  the 
kidney  vessels  and  ureter.  A  piece  of  peritoneal  membrane  is  attached  to  the  rim  of 
each  half  of  the  oncometer,  the  space  between  this  and  the  brass  capsule  being  filled 
with  warm  oil.  The  kidney  rests  in  the  oncometer  on  this  bed  of  warm  oil,  from  which 
it  is  separated  by  a  membrane.  A  tube  leads  from  the  cavity  between  the  brass  capsule 
and  membrane  to  a  registering  apparatus,  or  oncograph  (Fig.  461),  which  is  a  piston 
recorder  containing  oil.  Any  swelling  of  the  kidney  will  drive  oil  out  of  the  oncometer 
into  the  cylinder  of  the  oncograph  and  so  raise  the  piston,  the  excursions  of  which  are 
recorded  by  a  lever  writing  on  a  blackened  surface. 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS 


993 


Schafer's  plethysmograph  (Fig.  462),  which  can  be  adapted  to  ahnost  any  organ  of 
the  body,  is  made  of  vulcanite  *  previously  moulded  to  the  size  of  the  organ  whose 
volume  is  the  object  of  investigation.  In  one  side  of  the  box  a  depression  is  left  sufficient 
to  accommodate  easily  the  vessels,  nerves,  or  ureter  going  to  the  organ.  The  oncometer 
is  covered  with  a  glass  lid  which  is  made  air-tight  by  means  of  vaseline,  the  space 


Fig.  462.     Diagram  of  Schafer's  air  plethysmograph. 

between  the  lid  and  the  vessels  being  also  packed  with  cotton-wool  and  vaseline.  A 
glass  tube  is  fixed  into  one  corner  of  the  plethysmograph  and  leads  to  a  piston  recorder  or 
tambour.  Every  variation  in  the  volume  of  the  organ  causes  a  movement  of  air  into  or  out 
of  the  oncometer  and  thus  gives  rise  to  a  corresponding  movement  of  the  recording  lever 


^„«,f"w^t,^.S(<X^, 


^'^^^<-.<^, 


Blood-pressure 


Kidney  volume 


Fig.  463.  Simultaneous  tracings  of  carotid  blood-pressure  and  volume  of  kidney. 
Between  x  and  x  the  peripheral  end  of  the  divided  tenth  dorsal  nerve  was 
stimulated.     Time-marking  =  seconds,     (Bradford.) 

The  kidney  being  placed  in  some  such  apparatus,  a  cannula  is  also  placed 
in  the  carotid  artery  and  connected  AA^th  a  mercurial  manometer,  so  that 
two  tracings  are  obtained  at  the  same  time  on  the  mo\ang  blackened  surface. 
In  the  figure  given  (Fig.  463),  the  upper  curve  represents  the  carotid  blood- 

*  A  very  good  material  for  this  purpose  is  '  Stent's  composition,'  used  by  dentists 
for  taking  a  mould  of  the  jaw  in  fittmg  artificial  teeth. 

32 


994  PHYSIOLOGY 

pressure,  while  the  lower  is  the  tracing  of  the  oncograph  lever.  At  the 
beginning  of  the  experiment  the  lower  dorsal  nerve-roots  had  been  dissected 
out  and  prepared  for  stimulation.  The  peripheral  end  of  the  anterior  root 
of  the  tenth  dorsal  nerve  was  excited  by  means  of  an  interrupted  current 
at  the  point  marked  vnth  a  cross  on  the  tracing.  This  stimulation  was 
followed  by  a  rise  of  blood-pressure  together  with  a  diminution  in  the  kidney 
volume.  The  increased  blood-pressure  would  by  itself  tend  to  force  more 
blood  into  the  kidney  and  so  increase  its  volume.  The  fact  that  the  kidney 
volume  diminished  shows  that  there  must  have  been  active  contraction  of 
the  arterioles  of  the  kidney,  emptying  this  organ  of  blood  and  so  causing  it 
to  decrease  in  size.  This  contraction  of  the  vessels  would  tend  to  cause  a 
rise  in  general  blood-pressure  and  must  have  taken  some  part  at  any  rate 
in  the  rise  actually  observed.  If  the  oncometer  in  this  experiment  had  been 
used  alone,  it  would  have  been  impossible  to  have  determined  whether  the 
shrinkage  of  the  kidney  might  not  have  been  due  to  a  lowering  of  general 
blood-pressure,  in  consequence  of  vaso-dilatation  occurring  elsewhere,  or  in 
consequence  of  the  failure  of  the  heart's  activity.  On  the  other  hand, 
without  the  oncometer  it  would  only  have  been  possible  to  determine 
that  there  was  increased  peripheral  resistance  somewhere  or  other  in  the 
body. 

Instead  of  taking  the  volume  of  the  kidney  we  might  have  determined  the  blood- 
fiow  through  its  vessels  either  directly  by  means  of  a  cannula  in  the  renal  vein,  or  by 
the  indirect  method  of  Brodie.  This  method  depends  on  the  fact  that  under  normal 
conditions  the  amount  of  blood  leaving  an  organ  is  equal  to  that  entering  it  during  any 
short  space  of  time.  If  the  efferent  vein  be  clamped  for  five  or  ten  seconds,  the  blood 
entering  the  organ  during  this  time  cannot  escape,  and  therefore  accumulates  in  the 
organ  and  increases  its  volume.  If  the  organ  be  in  a  plethysmograph  the  increase  of 
volume  during  this  period  may  be  measured  and  is  exactly  equal  to  the  volume  of  blood 
passing  through  the  artery  into  the  organ  during  the  five  or  ten  seconds  of  the  closure. 
The  vein  must  not  be  obstructed  too  long,  otherwise  the  increasing  distension  of  the 
organ  will  appreciably  increase  the  resistance  to  the  entry  of  blood,  and  so  diminish  the 
velocity  of  the  blood  in  the  artery. 

The  direct  determination  of  the  venous  outflow  is  not  well  adapted  to  large  organs 
on  account  of  the  very  rapid  loss  of  blood  which  occurs  through  the  open  vein.  The 
method  is,  however,  of  great  value  in  dealing  with  the  circulation  through  small  organs 
such  as  the  submaxillary  glands.  In  such  a  case  it  is  usual  to  hinder  or  prevent  the 
clotting  of  the  blood  by  the  preliminary  injection  of  leech  extract,  and  then,  after 
placing  a  cannula  in  the  efferent  veins  of  the  organ,  to  allow  blood  from  the  cannula 
to  drop  on  to  a  mica  disc  attached  to  a  Marey  tambour.  This  tambour  is  connected 
by  a  tube  with  a  registering  tambour,  every  drop  on  the  disc  giving  rise  to  a  small 
elevation  of  the  lever  of  the  second  tambour. 

COURSE  OF  THE  VASO-CONSTRICTOR  FIBRES 

In  investigating  the  course  of  the  vaso-constrictor  fibres  we  have  to 
determine  : 

( 1 )  The  origin  of  the  fibres  from  the  central  nervous  system  ; 

(2)  The  course  of  the  fibres  on  their  way  to  their  peripheral  distribution 
in  the  blood-vessels  ; 

(3)  Their  connections  with  nerve-cells. 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS  09o 

The  two  first  details  can  be  found  by  stimulating  various  nerves  alid 
nerve-roots  in  different  parts  of  their  course  and  observing  the  effects  pro- 
duced on  the  local  and  general  circulation.  The  importance  of  the  third 
heading  is  due  to  the  fact  that  the  vascular  nerves,  like  the  visceral  nerves 
generally,  do  not  have  their  last  cell-station  in  the  spinal  cord.  The  fibres 
carrying  vaso-constrictor  impulses,  on  leaving  the  cord,  do  not  pass  direct 
to  the  blood-vessels,  but  come  to  an  end  in  a  collection  of  ganglion-cells, 
which  may  belong  to  the  main  chain  of  the  sympathetic,  or  be  situated  more 
peripherally  and  belong  to  the  group  of  collateral  or  peripheral  gangUa. 
These  fibres,  as  they  leave  the  central  nervous  system,  are  small  medullated 
nerves.  They  end  in  the  ganglion  by  arborising  round  ganglion-cells, 
whence  a  fresh  relay  of  fibres  starts  and  carries  the  impulses  on  to  the  muscle 
fibres  of  the  blood-vessels.  The  post- ganglionic  fibres  differ  from  the  pre- 
ganglionic fibres  in  being  non-medullated. 

The  discovery  of  the  ganglia,  with  which  any  given  set  of  nerve  fibres 
is  connected,  is  rendered  easy  by  the  fact  that  in  many  animals  the  sympa- 
thetic ganglion- cells  are  paralysed  by  nicotine  (Langley).  The  nicotine 
may  be  painted  on  the  ganghon  or  may  be  injected  into  the  blood-stream. 
The  first  eft'ect  of  the  drug  is  a  powerful  stimulation  of  the  ganglion-cells, 
so  that,  if  the  drug  be  injected,  there  is  an  enormous  rise  of  blood-pressure 
owing  to  the  universal  vaso-constriction  that  is  produced.  The  stimulation 
gives  place  to  a  condition  of  paralysis ;  the  blood-pressure  falls  below  normal, 
owing  to  the  cutting  off  of  the  peripheral  vascular  nerves  from  the  vaso- 
motor centre.  Stimulation  of  the  pre-ganglionic  fibre  is  now  without  effect, 
although  the  normal  results  follow  stimulation  of  the  post-gangHonic  non- 
medullated  fibre. 

By  these  methods  it  has  been  determined  that  all  the  vaso-constrictor 
nerves  of  the  body  leave  the  spinal  cord  by  the  anterior  roots  of  the  spinal 
nerves  from  the  first  dorsal  to  the  third  or  fourth  lumbar  inclusive.  From 
the  roots  they  pass  by  the  white  rami  communicantes  to  the  ganglia  of  the 
sympathetic  chain  lying  along  the  front  of  the  vertebral  column.  Here 
they  take  different  courses  according  to  their  destination. 

The  fibres  to  the  head  and  neck  leave  by  the  first  four  thoracic  nerves, 
pass  into  the  sympathetic  chain  through  the  ganglion  stellatum  and  ansa 
Vieussenii  to  the  inferior  cervical  ganglion,  and  up  the  cervical  sympathetic 
trunk  to  the  superior  cervical  ganglion.  Here  they  end,  and  the  impulses 
are  carried  by  a  fresh  relay  of  fibres,  which  start  from  cells  in  this  ganglion 
and  travel  as  non-medullated  fibres  on  the  walls  of  the  carotid  artery 
and  its  branches. 

The  constrictors  to  the  fore  limb  in  the  dog  leave  the  cord  by  the  white 
rami  of  the  fourth  to  the  tenth  thoracic  nerves.  The  fibres  run  up  the 
sympathetic  chain  to  the  stellate  ganglion,  where  they  all  end  in  synapses 
round  the  cells  of  this  ganglion.  The  impulses  are  carried  on  by  non- 
medullated  fibres  along  the  grey  rami  of  the  sympathetic  to  the  cer\'ical 
nerves  which  make  uji  the  brachial  plexus,  and  run  down  in  the  branches  of 
this  plexus  to  be  distributed  to  the  vessels  of  the  fore  limli. 


996  PHYSIOLOGY 

The  constrictor  impulses  to  the  hind  limb  in  the  dog  arise  from  the 
nerve-roots  between  the  eleventh  dorsal  and  third  lumbar  roots.  All 
the  fibres  end  in  connection  with  cells  in  the  sixth  and  seventh  lumbar 
and  first  and  second  sacral  gangha  of  the  sympathetic  chain,  whence 
the  impulses  are  carried  by  grey  rami  to  the  nerves  making  up  the  sacral 
plexus. 

The  most  important  vaso -motor  nerve  of  the  body  is  the  splanchnic 
nerve.  This  nerve  receives  most  of  the  fibres  forming  the  white  rami  from 
the  lower  seven  dorsal  and  upper  two  or  three  lumbar  roots,  the  latter  fibres 
often  taking  a  separate  course  as  the  lesser  splanchnics.  The  fibres  can  be 
seen  to  pass  through  the  sympathetic  chain  of  the  thorax  without  interrup- 
tion, and  for  the  most  part  have  their  cell-station  in  the  large  ganglia, 
especially  the  semilunar  ganglia,  of  the  solar  plexus,  whence  a  thick  mesh- 
work  of  non-meduUated  fibres  is  distributed  along  all  the  vessels  of  the 
abdominal  viscera.  The  area  of  the  vessels  innervated  by  this  nerve  is  so 
large  that  section  of  this  nerve  on  each  side  causes  a  large  fall  in  the  general 
blood-pressure.  This  fall  is  more  marked  in  animals  such  as  the  rabbit  and 
other  herbivora,  in  which  the  ahmentary  canal  is  proportionately  very 
much  developed,  and  has  consequently  a  very  large  blood-supply. 

VASO- DILATOR  NERVES 

Since  the  arteries  are  in  a  constant  condition  of  moderate  contraction, 
a  dilatation  might  be  brought  about  by  a  relaxation  of  this  tone  by  an 
inhibition  of  the  normal  constrictor  impulses  proceeding  to  the  vessels  from 
the  vaso-motor  centre.  We  find,  however,  in  many  parts  of  the  body 
evidence  of  the  existence  of  a  nerve-supply  to  blood-vessels  antagonistic 
in  its  function  to  the  vaso- constrictors.  Thus,  if  the  chorda  tympani  nerve 
going  to  the  submaxillary  gland  be  cut,  no  change  is  evident  in  the  blood- 
vessels of  the  gland.  But  if  its  peripheral  end  be  stimulated  there  is  instantly 
free  secretion  of  sahva  from  the  gland,  and  all  the  blood-vessels  are  largely 
dilated.  In  consequence  of  this  dilatation  the  blood  rushes  through  the 
capillaries  so  quickly  that  it  has  no  time  to  lose  much  of  its  oxygen ;  the 
blood  flowing  from  the  vein  is  therefore  bright  arterial  in  colour,  and  is  in- 
creased to  six  or  eight  times  the  previous  amount.  If  atropine  be  injected 
into  the  animal,  the  action  of  the  chorda  tympani  on  the  blood-vessels  is 
unafiected,  although  the  secretion  on  stimulation  is  abolished.  The  chorda 
tympani  is  therefore  said  to  contain  vaso- dilator  fibres  for  the  vessels  of  the 
submaxillary  gland.  Other  examples  of  vaso-dilator  (or  dilatator)  nerves 
are  the  small  petrosal  nerve  to  the  parotid  gland,  the  lingual  nerve  to  the 
blood-vessels  of  the  tongue,  and  the  nervi  erigentes  or  pelvic  visceral  nerves 
to  those  of  the  penis. 

The  course  of  these  typical  dilator  nerves  differs  widely  from  that  of  the 
constrictors.  Whereas  the  latter  leave  the  central  nervous  system  over  a 
limited  area  of  the  cord,  the  vaso-dilators  take  their  origin  together  with 
any  of  the  cerebro- spinal  nerves.  Thus  the  chorda  tympani  fibres,  and 
probably  those  contained  in  the  petrosal  nerve,  arise  from  the  nervus  inter- 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS 


997 


medius  between  the  seventh  and  eighth  cranial  nerves.  The  nervi  erigentes 
leave  the  lower  end  of  the  cord  by  the  anterior  roots  of  the  second  and  third 
sacral  nerves.  All  of  them,  like  the  vaso- constrictors  and  probably  all 
visceral  nerve  fibres,  are  interrupted  by  ganglion-cells  before  reaching  to 
their  destination.  These  cells,  however,  lie,  not  in  the  lateral  chain  of  the 
sympathetic,  with  which  the  nerves  have  no  connection  at  all,  but  peripherally, 
and  are  generally  embedded  in  the  organs  to  which  the  nerves  are  distributed. 
Thus  the  chorda  tympani  fibres  to  the  submaxillary  glands  are  interrupted 
by  cells  embedded  in  the  gland  itself.  The  nervi  erigentes  pass  to  ganglion- 
cells  in  the  hypogastric  plexus  lying  on  the  neck  of  the  bladder. 

Whether  any  large  numbers  of  the  fibres  making  up  the  sympathetic 
system  of  nerves  are  vaso-dilator  in  function  is  still  uncertain.  In  the  dog 
dilatation  of  the  vessels  of  the  soft  palate  and  gums  can  be  produced  by 

A  B 


/ 

Nerve  freshly  divided.  Nerve  four  days  degenerated. 

Constriction.  Dilatation. 

Fig.  464.     Plethysmographic  tracing  of  hind  limbs,  showing  effect  of  stimulating 

the  sciatic  nerve  on  the  volume  of  the  limb,  A,  immediately  after  section  of  the 

nerve  ;  B,  four  days  after  section.     The  nerve  was  stimulated  between  the  two 

vertical  lines.     Curves  to  be  read  fro77i  right  to  left.     (Bowditch  and  Wakeex.) 

stimulation  of  the  cervical  sympathetic  of  the  same  side,  or  of  the  stellate 
ganglion  or  its  rami  communicantes.  The  effect  has  not  yet  been  observed 
in  any  other  animals.  It  is  probable  that  the  splanchnic  nerves  convey  vaso- 
dilator fibres  to  the  vessels  of  the  abdomen,  since  stimulation  of  these  nerves 
may  cause  a  fall  of  blood-pressure,  provided  that  the  constrictor  fibres,  which 
predominate,  have  been  paralysed  by  the  previous  administration  of  large 
doses  of  ergotoxin,  derived  from  ergot. 

The  presence  of  vaso-dilator  fibres  in  the  nerves  going  to  the  limbs  has 
been  the  subject  of  much  debate.  Since  these  nerves  contain  also  con- 
strictor fibres,  the  effect  of  the  constriction  overpowers  any  eft'ects  due  to 
simultaneous  stimulation  of  possible  dilator  fibres.  Moreover  the  dilators 
apparently  do  not  conduct  any  tonic  influences  to  the  blood-vessels,  so  that 
the  only  eft'ect  of  section  of  a  mixed  nerve  is  that  due  to  the  removal  of  the 
tonic  constrictor  influences,  and  the  vessels  in  the  area  of  distribution  of  the 
nerves  are  dilated. 

Various  methods  have  been  employed  to  show  the  presence  of  dilator 
fibres  in  such  a  mixed  nerve-trunk.  Of  these  the  chief  two  are  those  depend- 
ing on  the  unequal  time  taken  for  the  two  sets  of  fibres  to  degenerate  and 
on  the  varying  excitability  of  the  two  sets  of  fibres  to  difi'erent  kinds  of 
stimulation.  Thus,  if  the  sciatic  nerve  be  cut,  a  primary  dilatation  of  the 
vessels  of  the  leg  and  foot  is  produced,  which,  however,  passes  off  after  two 


998 


PHYSIOLOGY 


or  three  days.  If  now  the  peripheral  end  of  the  divided  nerve  is  stimulated, 
dilatation  of  the  vessels  is  produced  (Fig.  464).  Apparently  the  constrictor 
fibres  degenerate  before  the  dilator  fibres,  so  that  at  a  certain  period  after  the 
nerve  section  only  the  latter  respond  to  stimulation.  On  the  other  hand, 
it  is  often  possible  in  the  freshly  cut  nerve  to  obtain  dilatation  by  stimulat- 
ing its  peripheral  end  with  induction  shocks  repeated  at  slow  intervals — • 


I   per  sec. 

4  per  sec. 

16  per  sec. 
64  per  sec. 


Fig.  465.  Effect  on  the  volume  of  the  hind  limbs  of  the  cat  stimulating  of  the  sciatic 
nerve  with  induction  shocks  at  different  rates.  It  will  be  noticed  that  with  one 
shock  per  second  there  is  hardly  any  constriction,  but  considerable  dilatation, 
whereas  with  64  shocks  per  second  the  only  effect  produced  is  vaso-constriction. 
Curves  to  be  read  from  right  to  left.     (Bowditch  and  Waeren.) 

one  to  four  per  second.     The  effects  of  different  rates  of  stimulation  on  the 
limb-nerves  of  the  cat  are  shown  in  Fig.  465. 

When  we  endeavour  to  trace  these  hmb  dilator  fibres  back  to  the  cord 
we  find  no  trace  of  their  passage  through  the  sympathetic  system.  It  was 
shown  by  Strieker  and  Morat  that  dilatation  of  the  vessels  of  the  hind  limb 
can  be  produced  by  stimulating  the  posterior  roots  of  the  nerves  goipg  to  the 
limb.  i.e.  far  below  the  point  of  origin  from  the  cord  of  the  constrictof  fibres  to 
the  same  part  of  the  body.  Since  it  has  been  definitely  shown  by  embryologists 
and  histologists  that  in  higher  mammals  all  the  fibres  making  up  the  posterior 
roots  have  their  origin  in  the  cells  of  the  posterior  root-ganglion,  this  observa- 
tion was  widely  discredited,  until  it  was  confirmed  by  Bayliss  for  all  manner 
of  stimuli.  Stimulation  of  the  posterior  roots,  either  before  or  after  they 
have  passed  through  the  ganglia,  causes  dilatation  of  the  vessels  in  the  area 
of  the  supply  of  the  roots,  whatever  be  the  nature  of  the  stimulus  employed, 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS 


999 


whether  electrical,  chemical,  or  mechanical  (Fig.  466).  This  effect  is  not 
destroyed  by  previous  section  of  the  posterior  roots  on  the  proximal  side 
of  the  ganglia,  sho^\^ng  that  the  fibres  by  means  of  which  the  dilatation  is 
produced  have  the  same  origin  and  course  as  the  ordinary  sensory  nerves 
to  the  limbs.  Since  the  vaso-dilator  impulses  pass  along  these  nerves  in  a 
direction  opposite  to  that  taken  by  the  normal  sensory  impulses,  Bayliss 
has  designated  them  as  antidromic  impulses.  So  far  this  phenomenon  of 
a  nerve-fibre  functioning  (not  merely  conducting)  in  both  directions  is 
almost  without  analogy  in  our  knowledge  of  the  other  nerve-functions  of  the 
body.     There  is  no  doubt,  however,  that  similar  antidromic  impulses  are 


Fig.  466.     Effect  of  excitation  of  peripheral  end  of  the  seventh  lumbar  posterior 
root  in  the  dog.     (Bayliss.) 

Uppermost  curve,  volume  of  left  hind  limb ;  next  below,  arterial  blood 
pressure  ;  the  third  line  marks  the  period  of  stimulation ;  bottom  line,  time- 
marking  in  seconds. 

involved  in  the  production  of  the  so-called  trophic  changes,  such  as  locahsed 
erythema  or  the  formation  of  vesicles  (as  in  herpes  zoster),  which  may  occur 
in  the  course  of  distribution  of  a  sensory  nerve,  and  is  always  found  to  be 
associated  with  changes,  inflammatory  or  otherwise,  in  the  corresponding 
posterior  root  gangha.  Moreover  evidence  has  been  brought  forward  that 
these  fibres  may  take  part  in  ordinary  vascular  reflexes  of  the  body,  that  in 
fact  they  are  normally  traversed  by  impulses  in  either  direction. 

Some  observations  by  Hans  Meyer  and  Bruce  tend  to  indicate  that  in 
the  antidromic  vaso-dilatation.  as  well  as  in  the  reddening  and  inflammatory 
changes  ensuing  on  local  excitation,  we  are  deahng  with  axon  reflexes,  perhaps 
the  only  remains  of  the  local  reflexes  of  a  primitive  peripheral  subcutaneous 
nervous  system.  If  croton  oil  or  mustard  oil  be  applied  to  the  skin  or  to  the 
conjunctiva,  redness,  swelling,  and  all  the  signs  of  a  local  inflammation  are 
produced.  The  course  of  events  is  not  altered  by  destruction  of  the  central 
nervous  system  or  by  section  of  the  sensory  nerve-roots  (posterior  spinal 
root  or  trigeminus)  on  the  central  side  of  the  ganglion.  If,  however,  they 
be  divided  peripherally  of  the  ganglion,  and  time  be  allowed  for  complete 


1000 


PHYSIOLOGY 


degeneration  of  the  nerve  fibres  to  their  peripheral  terminations,  the  applica- 
tion of  croton  or  mustard  oil,  even  to  the  deUcate  conjunctiva,  is  without 
efEect.  The  same  results  may  be  produced  if  the  peripheral  terminations  of 
the  nerves  be  paralysed  by  the  subcutaneous  injection  of  local  anaesthetics. 
"We  must  assume  that  the  axons  of  the  peripheral  sensory  nerves  branch, 
some  branches  going  to  the  surface,  others  to  the  muscle- cells  of  the  cutaneous 
arterioles,  as  indicated  in  the  diagram  (Fig.  467). 

Gaskell  has  drawn  an  analogy  between  the  nerves  distributed  to  the 
blood-vessels  and  those  going  to  the  heart,  which  is  indeed  only  a  speciahsed 
part  of  the  general  blood-tubes  of  the  body.     These  nerves,  according  to 

sup.  nerve  plex. 


Fig.  467.    Diagram  to  illustrate  the  production  of  vaso-dilatation  in  the  area 
of  distribution  of  a  sensory  nerve. 
frg,  posterior  root  ganglion  ;  sens.nf,  sensory  nerve  fibre,  branching  to  supply 
dilator  fibres  to  the  skin  arteries,  and  sensory  fibres  to  the  skin. 

their  action  on  the  metabolic  activity  of  the  tissues  supplied,  are  divided  by 
Gaskell  into  anabolic  and  catabolic  nerves.  The  anabohc  nerves,  as  indicated 
by  their  name,  cause  a  building  up  or  regeneration  of  the  contractile  tissue. 
They  therefore  act  as  inhibitory  nerves.  This  class  would  include  the  vagus 
and  the  vaso-dilator  fibres.  The  catabolic  nerves  cause  an  increased 
activity  of  the  contractile  tissue,  and  active  contraction  is  associated  with 
and  derives  its  energy  from  disintegration  or  catabolism  of  the  muscular 
substance.  An  ordinary  motor  nerve  to  a  muscle  is  therefore  a  catabolic 
nerve.  This  class  would  include  the  accelerator  nerves  to  the  heart,  and 
the  vaso-constrictors.  The  course  of  these  two  sets  of  nerves  bears  out  this 
comparison,  the  path  taken  by  the  accelerator  nerves  being  identical  at 
first  with  that  of  the  vaso-constrictor  fibres  to  the  head  and  neck. 


VASO-MOTOR  REFLEXES 
The  vaso-motor  centre  with  its  efferent  tracts  is  constantly  played  upon 
by  impulses  arriving  at  it  from  the  vascular  system,  including  both  heart 
and  blood-vessels,  from  the  viscera,  from  the  muscles,  and  from  the  surface 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS  1001 

of  the  body.  The  reflex  effects  produced  by  stimulation  of  the  various 
afferent  nerves  may  be  classified,  according  as  they  affect  the  general  blood- 
pressure  or  the  circulation  through  restricted  areas  of  the  body,  as  general 
and  local. 

The    afferent  impulses  affecting  the  general  blood-pressure  are  distin- 
guished as  pressor  and  depressor,  and  these  names  are  sometimes  applied 


Fig.  468.     Blood-pressure  curve  from  carotid  of  dog.     Between  the  arrows  the 
central  end  of  a  sensory  nerve  was  stimulated.     (Huethle's  manometer.) 

to  the  nerves  which  carry  the  impulses.  A  pressor  reflex  is  one  which 
induces  a  rise  of  general  blood-pressure  by  constriction  of  the  blood-vessels, 
especially  in  the  splanchnic  area  (Fig.  468).  Effects  of  this  kind  are  pro- 
duced by  stimulation  of  nearly  all  the 
sensory  nerves  of  the  skin.  Practi- 
cally all  impulses  which,  if  conscious- 
ness were  present,  would  be  attended 
with  pain  cause  also  a  rise  of  general 
blood-pressure.  A  rise  of  pressure 
may  be  produced  by  the  stimulation 
of  such  nerves  as  the  fifth,  the  central 
end  of  the  splanchnic  nerves,  or  of 
the  nerves  distributed  to  the  surface 
of  the  body.  This  rise  occurs  in  all 
animals  under  morphia  and  curare. 
In  the  rabbit,  when  anaesthesia  is 
induced  by  means  of  chloral  or 
chloroform,  stimulation  of  sensory 
nerves  may  cause  a  fall  of  blood- 
pressure. 

The  chief  example  of  a  depressor 
nerve  we  have  already  studied  in 
deahng  with  the  reflexes  from  the  heart.  The  fall  of  pressure  produced  by 
stimulation  of  this  nerve  is  effected  chiefly  by  dilatation  of  the  splanchnic 
area  (Fig.  469),  though,  as  Bayliss  has  shown,  practically  all  the  vessels  of 
the  body  partake  in  the  relaxation.  The  lowering  of  blood-pressure  produced 
by  stimulation  of  this  nerve  differs  from  that  obtained  on  stinmlating  the 
sensory  nerves  of  the  rabbit  under  cliloral.  in  that  its  effect  lasts  as  long  as 

32* 


Fig.  469.  Sinniltancous  tracing  of  arterial 
blood-pressure  and  splenic  volume  from 
a  rabbit,  showing  the  marked  swelling  of 
the  spleen  associated  with  fall  of  general 
blood-pressure  on  stimulation  of  the  cen- 
tral end  of  the  depressor  nerve.  The  nerve 
was  excited  between  a  and  b.    (Bayliss.) 


B.P. 


plecn 


1002  PHYSIOLOGY 

the  stimulation  is  continued,  whereas  in  the  latter  case  the  effect  shows  signs 
of  fatigue  and  disappears  before  the  excitation  is  shut  off. 

So  far  as  the  general  blood-pressure  is  concerned  the  most  important 
impulses  arriving  at  the  centre  are  those  from  the  vascular  system,  especially 
from  the  heart  itself,  and  those  from  the  higher  parts  of  the  brain.  Whatever 
the  condition  of  the  heart  the  brain  always  demands  a  normal  arterial 
pressure,  since  on  this  depends  the  supply  of  a  proper  quantum  of  blood  to  the 
master  tissues  of  the  body.  A  failing  heart  therefore  evokes  indirectly  con- 
striction of  the  blood-vessels,  a  fact  which  may  lead  to  a  vicious  circle  in 
cases  where  the  heart  is  unable  to  perform  its  normal  functions  and  to 
empty  itself  against  the  resistance  of  the  blood-vessels.  In  this  case  the 
heart  dilates  more  and  more,  until  the  slightest  increase  in  the  demands  upon 
it,  as  by  a  slight  muscular  exertion,  may  suffice  to  stop  its  action  altogether. 

Under  normal  circumstances  every  part  of  the  body  receives  just  so 
much  blood  as  it  needs  for  its  metabolic  requirements.  Hence  activity  must 
be  associated  with  an  increased  flow  of  blood  through  the  part.  Two 
mechanisms  are  involved  in  the  production  of  this  adaptation.  In  the  first 
place,  stimuli  arising  in  any  part  of  the  body  many  affect  the  vascular  system 
in  two  directions,  causing  reflexly  dilatation  of  blood-vessels  in  the  part 
which  is  the  origin  of  the  impulses  and  constriction  of  the  blood-vessels  in 
the  rest  of  the  body,  so  that  a  normal  or  raised  blood-pressure  is  available 
for  driving  an  increased  supply  of  blood  through  the  dilated  vessels  of  the 
part.  Thus,  if  both  hind  hmbs  of  an  animal  be  placed  in  a  plethysmograph, 
it  will  be  seen  that  stimulation  of  the  anterior  crural  or  peroneal  nerve  in 
the  left  leg  causes  dilatation  of  this  leg  and  constriction  of  the  leg  of  the  other 
side.  At  rest  the  organs  of  the  chest  and  abdomen  contain  more  than  half 
of  the  total  quantity  of  blood  in  the  body,  so  that  very  little  change  in  the 
capacity  of  these  organs  suffices  to  furnish  the  extra  supply  of  blood  needed 
by  any  part  during  a  state  of  increased  activity. 

THE  CHEMICAL  REGULATION  OF  THE  BLOOD-VESSELS 

Another  factor  which  is  possibly  involved  in  the  production  of  the 
increased  blood-flow  through  active  organs  is  a  chemical  stimulation  of  the 
vessels  themselves,  by  means  of  substances  (metabolites)  produced  as  a 
result  of  the  chemical  changes  accompanying  activity.  The  great  increase 
in  the  flow  through  the  muscles  which  accompanies  muscular  exercise  is 
probably  brought  about  largely  by  this  means.  It  has  been  shown  that  the 
passage  of  blood  containing  lactic  acid  or  carbon  dioxide  (both  results  of 
muscular  metabolism)  causes  a  marked  dilatation  of  the  blood-vessels  of  a 
limb.  The  Table  on  the  next  page  shows  the  influence  of  activity  on  the 
blood- flow  through  various  organs. 

We  thus  see  that  carbon  dioxide,  which  is  the  universal  hormone  set  free 
in  the  circulation  when  the  activity  of  the  body  as  a  whole  is  increased,  has 
a  double  effect  on  the  blood-vessels — a  central  effect  through  the  vaso- 
motor centres,  medulla  and  spinal  cord,  causing  contraction  of  the  blood- 
vessels, and  a  local  peripheral  effect  causing  dilatation  of  the  blood-vessels. 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS 


1003 


The  general  result  therefore  will  be  to  cause  dilatation  of  the  blood-vessels 
of  the  part  where  the  carbon  dioxide  is  produced  and  where  it  is  present 
m  greatest  concentration,  and  vascular  constriction  elsewhere  under  the 
influence  of  the  sensitive  nervous  centres. 


Flow  in  Cubic  Centimetres  per  Minute  per  100  Grm.  Tissue 

At  rest 

Active 

Levator  labii  superioris  (of  the  horse) 

17-5 

85 

Kidney     ....... 

— 

140 

Hind  limb          ...... 

3-4 

— 

Hind  limb  (after  section  of  nerves) 

9-9 

— 

Thyroid  gland    ...... 

590-0 

— 

Rabbit's  brain  ...... 

1360 

— 

Heart         ....... 

— 

500 

ACTION  OF  ADRENALINE.  This  substance,  produced  by  the  supra- 
renal glands,  has  also  a  marked  influence  on  the  calibre  of  the  blood-vessels. 
If  1  c.c.  of  a  1  in  10,000  solution  of  this  substance  is  injected  into  the  jugular 
vein,  there  is  at  once  a  universal  constriction  of  the  arterioles  with  the 
exception  of  those  of  the  brain.  If  the  vagi  are  cut  we  obtain  a  simultaneous 
augmentor  action  of  this  drug  on  the  heart  and  constrictor  effect  on  the 
blood-vessels,  so  that  the  arterial  pressure  rises  to  an  enormous  extent,  up 
to  300  mm.  Hg.  or  more.  The  same  result  occurs  after  section  of  the  vaso- 
motor nerves  or  after  destruction  of  the  brain  and  spinal  cord,  so  that  there 
is  no  doubt  that  adrenaline  acts  directly  on  the  blood-vessel  wall.  The 
action  of  this  drug  as  a  whole  is  therefore  largely  to  augment  the  energy  of 
the  circulation.  The  arterial  pressure  rises,  and  the  blood  will  be  therefore 
travelling  at  a  much  greater  pace  through  any  part  of  the  body  where  the 
vessels  are  maintained  in  a  dilated  condition,  e.g.  in  an  active  muscle,  or 
where  there  are  no  vaso-motor  nerves,  as  in  the  vessels  of  the  brain.  It  is 
therefore  not  surprising  that  we  have  evidence  of  the  secretion  of  adrenaline 
in  increased  quantities  into  the  blood  during  any  condition  of  stress.  When- 
ever the  splanchnic  nerve  is  stimulated,  there  is  an  increased  production  of 
adrenaline.  On  this  account  the  rise  of  pressure  produced  under  these 
circumstances  shows  a  stepped  curve,  the  first  rise  being  due  to  the  direct 
action  of  the  vaso-motor  nerves  of  the  blood-vessels,  the  second  being 
brought  about  by  the  stimulation  of  the  suprarenals  and  the  discharge  of 
adrenaline  into  the  general  circulation.  Simultaneously  with  this  second 
rise  of  blood-pressure  we  notice  in  the  curve  given  in  Fig.  -473  a  diminished 
volume  of  the  heart  due  to  more  efiective  contraction  of  this  organ. 

This  diminished  volume  of  the  heart  is  often  associated  with  a  marked 
quickening  of  the  heart-rate,  both  effects  being  due  to  the  action  of  adrenaline 
on  the  heart.  During  asphyxia  the  rise  of  arterial  pressure  is  largely  brought 
about  through  the  intermediation  of  the  splanchnic  nerves  and  is  therefore 
also  associated  with  the  discharge  of  adrenaline.     It  is  on  this  account  that 


1004 


PHYSIOLOGY 


Spl.  exc. 

Time 
10  sec. 


Tig.  470.     Effect  of  excitation  of  splanchnic  nerves  on  the  blood-pressure  and 
on  the  volume  of  the  denervated  hind  limb  of  the  cat.     (Bayliss.) 


Hind  limb 


B.P. 


Signal 
Time  10  sec. 


Fig.  471.  Effect  of  temporary  compression  of  the  abdominal  aorta  on  the  volume  of 
the  denervated  hind  limb.  Two  compressions,  the  second  not  marked  by  the 
signal.  Blood-pressure  taken  in  the  femoral  artery  of  one  hind  limb,  the  other 
hind  limb  being  in  the  plethysmograph.     (Bayliss.) 


NERVOUS  CONTROL  OF  THE  BLOOD-VESSELS  1005 

in  the  whole  animal,  provided  that  sufficient  oxygen  is  supplied,  very  large 
percentages  of  carbon  dioxide  may  be  inhaled  without  causing  fatal  dilata- 
tion of  the  heart,  the  effect  of  the  adrenaline  discharged  into  the  blood-stream 
serving  to  counteract  the  injurious  influence  of  carbon  dioxide  on  the  heart 
muscle.  These  two  chemical  influences,  the  local  production  of  carbon 
dioxide  and  the  discharge  of  adrenaline  into  the  general  circulation,  must 
always  be  kept  in  mind  in  trying  to  account  for  the  behaviour  of  the  blood- 
vessels under  the  most  various  conditions.  Thus  in  Fig.  470  is  shown  the 
effect  of  temporary  stimulation  of  the  splanchnic  nerve  on  the  blood-pressure 
and  on  the  volume  of  the  hind  hmb  of  the  cat.  It  will  be  noticed  that  the 
volume  of  the  hind  limb  increases  passively  with,  the  rise  of  pressure  and  then 
diminishes  much  below  its  previous  amount.  This  diminution  is  due  to  the 
discharge  of  adrenaline  into  the  blood-stream  as  the  result  of  stimulation  of 
the  splanchnic  nerve  and  is  absent  if  the  suprarenals  have  been  previously 
destroyed.  The  curve  shown  in  Fig.  471,  which  with  the  foregoing  one  was 
taken  by  Bayliss,  to  indicate  a  local  adaptation  of  the  blood-vessels  to  their 
internal  pressure,  is  probably  brought  about  by  the  local  production  of  carbon 
dioxide  {v.  Anrep).  Temporary  occlusion  of  the  abdominal  aorta  is  here 
shown  to  cause  first  a  diminution  of  the  volume  of  the  hind  limb,  followed  by 
a  marked  increase.  During  the  period  of  obstruction  the  circulation  of  the 
hind  Hmb  was  interrupted  and  there  was  therefore  accumulation  of  carbon 
dioxide  in  the  tissues  and  around  the  blood-vessels.  This  caused  a  relaxa- 
tion of  the  blood-vessel  walls  and  a  corresponding  increased  volume  of  the 
limb  when  the  blood  was  allowed  once  more  to  flow  by  release  of  the 
aortic  obstruction. 


SECTION  XI 

THE  EFFECT   OF  MUSCULAR  EXERCISE  ON 
THE  CIRCULATION 

Any  muscular  exercise,  even  moderate,  produces  rise  of  blood-pressure 
and  acceleration  of  the  pulse,  associated  with  an  increase  of  pulmonary 
ventilation — hyperpnoea.  These  effects  can  be  readily  shown  by  running  up 
and  down  stairs  for  half  a  minute.  The  following  Table  by  Pembrey  and 
Todd  shows  the  effect  of  such  a  form  of  exercise  on  the  pulse-rate  and  systolic 
blood-pressure  in  two  individuals,  one  trained  and  the  other  untrained  : 


A.B.  (trained) 

A.H.T.  (untrained) 

Rest 

Just  after 
exercise 

5  min. 

later 

Rest 

Just  after 
exercise 

6  min. 
later 

1.  B.P.  mm.  Hg.      . 
Pulse  J  min. 

2.  B.P.  mm.  Hg.      . 
Pulse  J  min. 

110 
13 

122 
16 

134 
28 

134 
29 

118 
14 

126 
17 

104 
18 

110 
23 

134 

27 

140 

30 

108 
24 

106 
26 

Several  factors  may  concur  in  the  production  of  these  effects.  Increased 
contractions  of  voluntary  muscles  will  in  the  first  place  quicken  the  return 
of  venous  blood  to  the  heart,  and  so  will  cause  a  greater  diastolic  distension 
of  this  organ  and  therefore  a  greater  output  of  blood  by  the  left  ventricle. 
The  increased  respiratory  movements  will  also  aid  the  venous  circulation 
and  have  a  similar  effect  in  increasing  the  systolic  output.  It  must  be 
remembered  that  the  heart  cannot  put  out  more  blood  than  it  receives. 
Since  during  active  exercise  the  output  may  be  increased  four  to  six  times 
above  the  normal,  it  is  evident  that  the  venous  circulation  must  be  corre- 
spondingly increased,  and  this  increase  can  only  be  ascribed  to  the  pumping 
action  of  the  contracting  muscles  and  to  the  movements  of  respiration.  All 
these  factors  will  thus  concur  in  producing  a  rise  of  pressure  even  when  the 
heart  and  blood-vessels  are  cut  off  from  the  central  nervous  system.  The 
latter  also  is  concerned  in  the  rise  of  pressure.  The  mere  act  of  attention 
preparatory  to  muscular  effort  is  in  itself  sufficient  to  raise  the  blood-pressure, 
and  it  seems  probable  that  the  increased  activity  of  the  motor  centres  actually 
spreads  to  the  medullary  centres  which  preside  over  the  heart  and  blood- 

1006 


Pulse  rate 


EFFECT  OF  EXERCISE  ON  CIRCULATION  1007 

vessels,  and  that  there  is  an  active  constriction  of  the  vessels,  especially  of 
the  splanchnic  area,  so  that  the  greater  part  of  the  blood  in  circulation  is 
available  for  the  use  of  the  actively  contracting  muscles.  On  this  account 
hard  exercise  is  not  easily  carried  out  after  a  meal,  and,  if  forced,  seriously 
interferes  with  digestion,  by  the  diversion  of  the  current  of  blood  needed  for 
the  carrying  out  of  this  function. 

It  has  been  shown  by  Cannon  that  every  state  of  excitement,  and  probably 
also  the  effort  of  concentration  which  precedes  muscular  effort,  is  attended 
with  increased  secretion  of  adrenaline  into 
the  blood.  At  the  same  time  the  contracting 
muscles  are  producing  carbon  dioxide  in 
large  quantities,  and  also  if  the  supply  of 
oxygen  is  not  sufficient  for  their  needs,  lactic 
acid.  Both  these  substances  co-operate  in 
increasing  the  hydrogen  ion  concentration 
(the  acidity)  of  the  blood.  Where  they  are 
present  in  greatest  concentration  they  will 
produce  local  dilatation  of  the  blood-vessels, 
i.e.  in  the  contracting  muscles.  But  as  they 
are  carried  by  the  blood-stream  to  the  medul- 
lary centres,  they  will  cause  a  general 
vaso-constriction  especially  marked  in  the 
splanchnic  area.  On  the  heart,  as  already 
mentioned,  the  detrimental  effect  of  increased 
acidity  will  be  more  than  counterbalanced  by 
the  adrenaline  which  enters  the  circulation 
at  the  same  time.  But  the  nervous  irritation 
of  effort  probably  sets  all  these  mechanisms 
in  action  at  the  same  time.  The  quickening 
of  the  pulse,  which  is  a  normal  concomitant 
of  muscular  effort,  as  well  as  the  quickening 
of  the  respiration,  and  the  rise  of  pressure, 


may  be  observed  to  begin  before  the  actual 


Fig.  472.  Curves  showing  the  in- 
fluence of  exercise  on  the  circula- 
tion. The  exercise  was  a  six-mile 
run.  Ordinates  =  mm.  Hg.  pres- 
sure and  rate  per  minute.     (0.  S. 

LOWSLEY.) 


muscular  contractions,  so  that  the  brain, 

while  sending  impulses  along  the  pyramidal 

tracts  to  the  skeletal  muscles,  sends  also 

impulses  to  the  medullary  centres   which 

quicken  the  respiration  and  the  pulse  and  sends  up  the  blood-pressure  by 

constriction  of  the  splanchnic  area.     Under  these  circumstances,  therefore, 

there  is  an  abrogation  of  the  normal  rule  that  a  rise  of  blood-pressure  is 

attended  with  a  slowing  of  the  pulse.     Chemical  mechanisms  come  in  as  a 

sort  of  second  line  in  maintaining  the  conditions  favourable   for  exercise, 

which  are  initiated  by  the  direct  action  of  the  central  nervous  system. 

Slight  acceleration  of  the  heart  is  observed,  after  division  of  all  its  nervous  connec- 
tions, on  tetanising  the  lower  limbs.  Mansfekl  has  shown  that  probably  the  chief,  if  not 
the  only,  factor  in  this  case  is  the  rise  of  temperature  in  the  blood  flowing  to  the  heart. 


1008  PHYSIOLOGY 

When  exercise  is  discontinued  the  pulse-rate  and  blood  pressure  rapidly 
fall  to  normal,  the  return  being  quicker  in  the  case  of  a  trained  individual, 
as  is  seen  in  the  Table  quoted  above. 

SECOND  WIND,  It  is  a  familiar  experience  that  in  a  running  race  of 
any  duration  the  competitors  after  some  time  become  less  distressed  than  at 
the  commencement  of  the  race.     The  runner  is  now  said  to  have  got  his 


Fig.  473.      Curve   showing  the  effect  of  a  sudden  rise  in  the  arterial  resistance  on 
the  output  and  volume  of  the  ventricles.    Systole  causes  a  downward  movement 
of  the  lever. 
H,  heart  volume  ;  bp,  arterial  blood -pressure  ;  s,  signal  showing  duration  of 
stimulation  of  splanchnic  nerve  ;  t,  time-marker,  10  sees. 

'  second  wind,'  and  can  continue  running  with  comparative  comfort.  There 
are  several  factors  which  may  account  for  this  accommodation.  In  the  first 
place,  as  a  result  of  the  production  of  metabolites  in  the  contracting  muscles, 
their  vessels  may  be  more  dilated,  so  that  the  flow  of  blood  through  them  is 
easier.  More  important  is  the  change  in  the  heart  accompanying  the  onset 
of  second  wind.  As  Pembrey  and  Cook  have  shown,  the  onset  of  second 
wind  is  always  attended  with  a  diminution  in  the  pulse-rate.  At  the  same 
time  there  is  an  alteration  in  the  respiratory  quotient.  During  distress 
the  respiratory  quotient  is  high,  i.e.  more  carbon  dioxide  is  being  given  out 
than  oxygen  taken  in.  As  the  distress  diminishes,  the  respiratory  quotient 
also  falls.  The  improved  action  of  the  heart  may  be  partly  due  to  the 
increased  coronary  circulation,  partly  to  the  entry  of  adrenaline  into  the 
circulation. 


SECTION  XII 

THE  INFLUENCE  ON  THE  CIRCULATION  OF  VARIATIONS 
IN  THE  TOTAL  QUANTITY  OF  BLOOD 

PLETHORA  AND   HYDR^EMIC  PLETHORA 
The  effects  of  increasing  the  total  volume  of  circulating  fluid  may  be  studied 
by  injecting  several  hundred  cubic  centimetres  of  defibrinated  blood  or 
normal  saline  fluid  into  a  vein.     In  the  latter  case,  since  the  blood  is  rendered 


12     13     W     15     16     17      18        2\     22 

Fig.  474.  Effects  of  hydrsemic  plethora  on  the  pressures  in  the  carotid  artery  (thick 
line),  portal  vein  (thin  line),  and  inferior  vena  cava  (dotted  line).  (Bayliss  and 
Stakling.) 

The  arterial  pressure  is  in  mm.  Hg.  ;  the  venous  pressures  in  mm.  HoO. 

more  dilute,  the  condition  is  called  hydraemic  plethora  (Fig.  474).  On  the 
arterial  pressure  the  result  of  such  an  injection  is  not  very  marked.  There  is 
a  slight  initial  increase  in  the  pressure,  but  the  increase  is  by  no  means 
proportional  to  the  amount  of  fluid  injected,  showing  that  the  fluid  is  not 
to  any  large  extent  contained  in  the  arterial  system.  On  examining  the 
pressure  in  the  veins,  however,  we  find  a  very  great  relative  rise  of  pressure, 

1009 


1010 


PHYSIOLOGY 


and  on  opening  the  abdomen  it  is  seen  that  all  the  veins  are  distended  and 
that  the  liver  is  swollen.  The  effect  of  increasing  the  volume  of  circulating 
fluid  would  be  to  increase  the  mean  systemic  pressure,  and  therefore  one 
would  expect  to  find  a  large  increase  both  in  arterial  and  venous  systems. 
But  the  organism  prevents  the  rise  on  the  arterial  side  by  relaxing  the 
whole  system  of  arterioles,  so  that  the  distribution  of  pressures  is  altered, 


Systole 


Fig.  475.  Cardiometer  tracing  from  dog's  heart  to  show  effect  of  increasing  the 
volume  of  circulating  blood  (hydrsemc  plethora)  on  the  total  output  and  the 
volume  of  the  heart.  Between  the  parts  a  and  b  30  c.c.  of  warm  normal  salt 
solution  were  injected  intravenously,  and  between  b  and  c  20  c.c.  more.  It  will 
be  noticed  that  both  the  systolic  and  the  diastolic  volume  are  increased,  i.e. 
the  heart  is  more  distended  during  diastole,  and  does  not  contract  to  its 
normal  size  in  systole.  The  contraction  volume,  and  therefore  the  output, 
is  very  largely  increased.     (Roy.) 

and  the  venous  approximates  more  closely  to  the  arterial  pressure.  This 
arterial  dilatation  augments  the  velocity  of  the  blood  :  it  has  been  found  that 
the  velocity  may  be  accelerated  to  six  or  eight  times  the  normal  rate  by 
injecting  an  amount  of  salt  solution  equivalent  to  50  per  cent,  of  the  total 
blood. 

The  high  venous  pressure  causes  increased  diastohc  filHng  of  the  heart,  and 
therefore  augments  the  strength  of  the  beat.  The  frequency  is  also 
generally  increased  if  the  vagi  are  intact.  Thus  the  work  of  the  heart  is 
increased  in  three  ways,  viz.  by 

(1)  Rise  of  arterial  pressure. 

(2)  Greater  frequency  of  beat. 

(3)  Increased  output  at  each  beat  (Fig.  475). 


VARIATIONS  IN  TOTAL  QUANTITY  OF  BLOOD  1011 

These  series  of  changes  result  in  the  reUef  of  the  vascular  system.  The 
heightened  pressure  in  the  abdominal  veins  and  capillaries  causes  a  great 
leakage  of  fluid  in  the  form  of  lymph  from  the  capillaries  of  the  intestines  and 
liver,  while  the  increased  pressure  and  velocity  of  the  blood  in  the  glomeruU  of 
the  kidney  induce  a  copious  secretion  of  urine,  so  that  within  a  couple  of  hours 
after  the  injection  of  salt  solution  the  volume  of  the  circulating  fluid  may 
have  returned  to  normal. 

This  recovery  is  effected  with  geater  difl&culty  if  the  plethora  has  been 
brought  about  by  the  injection  of  defibrinated  blood,  since  this  fluid  cannot 
escape  rapidly  from  the  capillaries,  nor  can  it  be  excreted  unchanged  by  the 
kidneys.  Hence  it  is  easy  to  kill  an  animal  by  wearing  out  its  heart,  if  too 
large  quantities  of  defibrinated  blood  be  injected.  The  ultimate  fate  of  the 
injected  blood  is  to  be  used  as  food  by  the  tissues,  and  to  be  ehminated  by 
the  ordinary  channels. 

It  must  be  remembered  that  the  blood-serum  of  one  animal  is  often  poisonous  for 
the  corpuscles  of  another.  Thus  a  few  cubic  centimetres  of  dog's  serum  injected  into 
the  peritoneal  cavity  of  a  rabbit  will  cause  death.  This  poisonous  action  is  also  shown 
by  mixing  dog's  serum  with  defibrinated  rabbit's  blood,  in  which  case  the  red  corpuscles 
of  the  latter  are  broken  up,  settiug  free  haemoglobin  {hcemolysis). 

THE  EFFECTS  OF  HEMORRHAGE.  ANEMIA 
Any  diminution  of  the  total  volume  of  the  blood,  as  by  bleeding,  would 
tend  to  lower  the  pressure  on  both  sides  of  the  system.  The  vaso-motor 
centre,  however,  strives  to  maintain  the  normal  arterial  pressure,  and  so  the 
circulation  through  the  brain,  unaltered.  This  object  is  attamed  by  a 
general  vascular  constriction,  which  diminishes  the  total  capacity  of  the 
system  and  alters  the  distribution  of  pressures  throughout  the  system,  so 
as  to  keep  the  blood  as  much  as  possible  on  the  arterial  side.  Thus  a  shght 
loss  of  blood  has  no  influence  on  the  arterial  blood-pressure,  but  causes  a  fall 
of  pressure  in  the  veins,  blanching  of  the  abdominal  organs,  and  diminished 
flow  of  urine.  The  heart  beats  more  frequently,  and  so  aids  in  emptying  the 
venous  into  the  arterial  system. 

The  deficiency  of  circulating  fluid  caused  by  bleeding  is  soon  remedied  by 
a  transfer  of  fluid  from  the  tissues  to  the  blood.  This  transfer  is  independent 
of  the  flow  of  lymph  from  the  thoracic  duct  into  the  blood,  and  is  the  direct 
consequence  of  the  universal  fall  of  capillary  pressure  which  results  from 
the  bleeding.  The  abstraction  of  fluid  from  the  tissues  is  responsible  for 
the  extreme  thirst  which  is  the  result  of  haemorrhage,  and  which  directs  the 
animal  to  take  up  by  the  alimentary  canal  the  fluid  which  is  wanting  to  the 
body.  The  transfer  of  fluid  from  tissues  to  blood  is  extremely  rapid  ;  even 
during  the  course  of  a  bleeding  it  is  found  that  the  later  samples  of  blood  are 
more  dilute  than  those  obtained  at  the  beginning.  This  mechanism  suffices 
only  to  make  up  the  supply  of  circulating  fluid.  After  a  bleeding,  however, 
an  animal  has  lost  proteins  and  blood-corpuscles,  and  these  constituents  of 
the  blood  are  but  slowly  restored,  the  former  directly  from  the  food,  the  latter 
by  an  increased  activity  of  the  blood-forming  cells  in  the  red  marrow. 


CHAPTER  XIV 

LYMPH   AND  TISSUE  FLUIDS 

In  no  part  of  the  body  does  the  blood  come  in  actual  contact  with  the  living 
cells  of  the  tissue.  In  all  parts  the  blood  flows  in  capillaries  "^ith  definite 
walls  consisting  of  a  single  layer  of  cells,  and  is  thus  separated  from  the 
tissue-elements  by  these  walls  and  by  a  varying  thickness  of  tissue.  In  some 
organs,  such  as  the  liver  and  lung,  every  cell  is  in  contact  with  the  outer 
surface  of  some  capillary  ;  while  in  others,  such  as  cartilage  (which  is  quite 
avascular),  a  considerable  thickness  of  tissue  may  separate  any  given  cell 
from  the  nearest  capillary.  A  middleman  is  thus  needed  between  the  blood 
and  the  tissues,  and  this  middleman  is  the  tissue-fluid  or  lymph  which  fills 
spaces  between  all  the  tissue- elements,  so  that  any  tissue  can  be  regarded  as 
a  sponge  soaked  with  lymph. 

Throughout  these  spaces  we  find  a  close  network  of  vessels  lined,  and 
separated  from  the  tissue  spaces,  by  a  layer  of  extremely  thin  endothehal 
cells,  and  this  plexus  communicates  with  definite  channels— lymphatics, 
by  which  any  excess  of  fluid  in  the  part  is  drained  off.  The  lymphatics 
all  run  towards  the  chest,  where  those  of  the  hmbs  join  a  large  vessel  (the 
receptaculum  chyh),  which  receives  the  lymph  from  the  ahmentary  canal,  to 
form  the  thoracic  duct.  This  runs  up  on  the  left  side  of  the  oesophagus,  to 
open  into  the  venous  system  at  the  junction  of  the  left  internal  jugular  with 
the  subclavian  vein.  A  small  vessel  on  the  right  side  drains  the  lymph  from 
the  right  upper  extremity  and  right  side  of  the  chest  and  neck. 

The  lymph  may  be  looked  upon  as  a  part  of  the  plasma  which  exudes 
through  the  capillary  wall,  bathes  all  the  tissue-elements,  passes  between 
the  endothelial  cells  into  the  peripheral  lymphatic  network,  whence  it  is 
carried  by  lymphatic  trunks  into  the  thoracic  duct,  by  which  it  is  returned 
again  to  the  blood. 

It  is  easy  to  obtain  lymph  for  examination  by  putting  a  cannula  (a  small 
tube  of  glass  or  metal)  into  the  thoracic  duct,  and  collecting  the  fluid  that 
drops  from  it  in  a  glass  vessel. 

We  may  also  tap  in  a  similar  way  one  of  the  large  lymphatic  trunks  of  the 
limbs  ;  but  in  the  latter  case  we  have  to  use  artificial  means  to  induce  a  flow 
of  lymph,  since  little  or  none  can  be  obtained  from  a  limb  at  rest,  the  only 
part  of  the  body  where  there  is  normally  a  constant  flow  of  lymph  being  the 
alimentary  canal.  And  thus  we  cannot  regard  the  flow  of  lymph  from  a  part 
as  any  index  of  the  chemical  changes  going  on  at  that  part.     In  a  limb  at  rest 

1012 


LYMPH  AND  TISSUE  FLUIDS  1013 

food-stuffs  are  being  taken  up  from  the  blood  and  being  burnt  up  by  the 
muscles  with  the  production  of  CO2,  although  we  may  not  be  able  to  obtain 
a  drop  of  lymph  from  a  cannula  in  one  of  the  lymphatics.  The  lymph 
is  thus  truly  a  middleman  ;  as  any  substance,  oxygen  or  food-stuff,  is  taken 
up  by  a  tissue-cell  from  the  lymph  surrounding  it,  this  latter  recoups  itself 
at  once  at  the  expense  of  the  blood.  Thus  there  would  seem  to  be  no  need 
for  lymphatics  to  drain  the  hmb,  were  it  not  that  under  many  conditions 
which  we  shall  study  directly,  the  exudation  of  lymph  from  the  blood-vessels 
is  so  excessive  that,  if  it  were  not  carried  off  at  once  and  restored  to  the  blood, 
it  would  accumulate  in  the  tissue  spaces,  give  rise  to  dropsy,  and  by  pressure 
on  the  cells  and  blood-vessels  affect  them  injuriously. 

PROPERTIES  OF  LYMPH 

Lymph  obtained  from  the  thoracic  duct  of  an  animal  varies  in  compo- 
sition and  appearance  according  to  the  condition  of  the  animal,  whether 
recently  fed  or  fasting.  From  a  fasting  animal  the  lymph  is  a  transparent 
liquid,  generally  sUghtly  yellowish,  and  sometimes  reddish  from  admixture 
of  blood-corpuscles.  When  obtained  from  an  animal  shortlv  after  a  meal, 
it  is  milky  from  the  presence  of  minute  particles  of  fat  that  have  been 
absorbed  from  the  ahmentary  canal.  In  the  latter  case,  if  the  intestines  be 
exposed,  the  small  lymphatics  are  to  be  seen  as  white  lines  running  from  the 
intestine  to  the  attached  part  of  the  mesentery.  It  is  owing  to  this  fact 
that  these  lymphatics  have  received  the  special  name  lacteals,  the  lymph 
in  them  being  called  the  chyle.  The  fatty  particles  form  the  molecular 
basis  of  the  chyle. 

On  microscopic  examination  the  transparent  lymph  of  fasting  animals 
presents  colourless  corpuscles  similar  to  those  of  blood,  or  perhaps  we  ought 
to  say  identical,  since  the  leucocytes  of  the  blood  are  partly  derived  from  the 
corpuscles  that  have  entered  with  the  lymph  through  the  thoracic  duct. 

All  the  lymphatics  pass  at  some  point  of  their  course  through  Ivmphatic 
glands,  which  we  may  look  upon  as  factories  of  leucocytes,  since  these  are 
much  more  numerous  in  the  lymph  after  it  has  traversed  the  gland  than 
before.  Leucocytes  are  also  formed  in  all  the  numerous  localities  where 
we  find  adenoid  tissues,  such  as  the  tonsils,  air  passages,  alimentary  canal 
(Peyer's  patches  and  soUtary  follicles),  Malpighian -bodies  of  the  spleen,  and 
thymus. 

The  lymph  from  the  thoracic  duct  is  alkaline,  has  a  specific  gra^dty  of 
about  1015,  and  clots  at  a  variable  time  after  it  has  left  the  vessels,  forming 
a  colourless  clot  of  fibrin,  just  like  blood-plasma.  It  contains  about  6  per 
cent,  of  solid  matters,  the  proteins  consisting  of  fibrinogen,  paraglobulin,  and 
serum  albumen.  The  salts  are  similar  to  those  of  the  hquor  sanguinis,  and 
are  present  in  the  same  proportions. 

THE  PRODUCTION  OF  LYMPH 
Many  physiologists  liave  thought  that,  in  the  transudation  of  the  fluid 
which  forms  the  lymph,  there  is  an  active  intervention  on  the  part  of  the 


1014  PHYSIOLOGY 

endothelial  cells  forming  the  capillary  wall,  and  that  lymph  is  therefore 
to  be  regarded  as  a  true  secretion.  A  careful  investigation  of  the  known 
experimental  facts  has  failed  to  show  that  the  endothelial  cells  act  otherwise 
than  passively,  as  filtering  membranes  of  variable  permeabihty.  The  factors 
which  are  responsible  for  the  transudation  of  lymph  may  be  divided  into 
two  classes — mechanical  and  chemical,  the  former  depending  largely  on  the 
pressure  of  the  blood  in  the  vessels,  and  the  latter  chiefly  on  the  metabohsm 
of  the  cells  outside  the  vessels. 

According  to  the  views  here  laid  down,  the  formation  of  lymph  may  be 
compared  to  a  process  of  filtration.  If  this  be  correct  the  amount  of  lymph 
formed  in  any  given  capillary  area  must  be  dependent  on  the  difference 
of  pressure  between  the  blood  in  the  vessels  and  the  fluid  in  the  extra  vascular 
tissue  spaces. '  This  latter  pressure  is  normally  extremely  low,  so  that  in 
attempting  to  test  the  truth  of  this  view  we  must  try  the  effects  of  altering 
the  pressure  inside  the  vessels,  in  the  expectation  of  finding  that  the  lymph 
production  will  rise  and  fall  as  the  capillary  pressure  is  increased  or  dimin- 
ished. On  attempting  to  carry  out  such  experiments  in  different  parts  of 
the  body,  we  have  to  recognise  another  factor  besides  the  capillary  pressure, 
viz.  the  permeabihty  of  the  vessel- wall.  Whereas  the  capillary  waUs  in  the 
limbs  and  connective  tissues  generally  present  a  very  considerable  resistance 
to  the  filtration  of  lymph  through  them,  and  keep  back  the  larger  portion  of 
the  proteins  of  the  blood-plasma,  the  intestinal  capillaries  are  much  more 
permeable,  giving  at  moderate  capillary  pressures  a  continual  flow  of  lymph 
and  separating  off  only  a  small  proportion  of  the  proteins.  It  is  in  the 
Hver,  however,  that  we  find  the  greatest  permeability.  Here  a  very  small 
pressure  suffices  to  produce  a  great  transudation  of  lymph,  containing 
practically  the  same  amount  of  protein  as  the  blood-plasma  from  which  it  is 
formed. 

The  ease  with  which  fluid  passes  out  from  the  capillaries  of  the  liver  is  probably  due 
to  the  fact  that  these  vessels,  unlike  most  other  capillaries  of  the  body,  have  not  a  com- 
plete endothelial  lining.  Thus  it  is  impossible  to  display  a  continuous  endothelial  lining 
by  means  of  silver  nitrate.  The  cells  surrounding  the  capillaries  are  large  and  branched, 
and  possess  marked  phagocytic  powers,  so  that  after  an  injection  of  carmine  granules 
or  bacteria  into  the  blood-stream  these  bodies  are  found  in  quantity  within  the  cells. 
Owinof  to  the  incompleteness  of  this  investment  the  liver-cells  in  many  places  abut 
on  the  lumen  of  the  capillary.  On  injecting  the  blood-system  of  the  liver  the  injection 
is  found  to  run  with  ease  into  channels  situated  within  the  cells  themselves,  and  it  is 
reasonable  to  conclude  that  the  blood-plasma  takes  the  same  course  through  these 
intracellular  channels,  by  which  it  passes  into  the  lymphatics  which  lie  at  the  periphery 
of  the  lobules. 

In  experiments  on  the  lymph  production  in  the  limbs  alterations  of 
capillary  pressure  have  but  shght  effect.  The  lymph-flow  from  a  limb 
lyruphatic  is  practically  unaltered  by  changes  in  its  arterial  supply,  although 
a  definite  increase  may  be  obtained  by  ligaturing  all  the  veins  of  the  hmb 
so  as  to  cause  a  very  great  rise  of  capillary  pressure.  The  lymph-flow  from 
the  intestines  can  be  measured  by  collecting  the  lymph  from  the  thoracic 
duct.     If  the  lymphatics  which  leave  the  liver  in  the  portal  fissure  be 


LYMPH  AND  TISSUE  FLUIDS  10L5 

previously  ligatured,  the  whole  of  the  thoracic  duct  lymph  in  an  animal  at 
rest  is  derived  from  the  intestines.  It  will  be  found  that  lowering  of  the 
capillary  pressure  in  these  organs  by  obstructing  the  thoracic  aorta  stops 
the  flow  of  lymph  absolutely,  whereas  a  rise  of  capillary  pressure,  such  as  that 
produced  by  ligature  of  the  portal  vein,  causes  a  four-  or  fivefold  increase 
of  the  lymph. 

The  effect  of  rise  of  capillary  pressure  on  the  lymph-flow  is  still  more 
striking  in  the  case  of  the  liver.  If  the  inferior  vena  cava  be  obstructed 
just  above  the  opening  of  the  hepatic  veins,  there  is  a  great  fall  of  arterial 
pressure,  but,  owing  to  the  damming  back  of  the  blood,  a  rise  of  pressure 
in  the  hver  capillaries  to  three  or  four  times  the  normal  height.  This  rise 
causes  a  large  increase  in  the  lymph-flow  from  the  thoracic  duct.  The 
lymph  may  be  increased  eight  to  ten  times  in  amount,  and  it  contains  more 
protein  than  before.  If  the  portal  lymphatics  be  previously  hgatured, 
obstruction  of  the  inferior  vena  cava  has  no  efEect  on  the  lymph-flow, 
showing  that  the  whole  of  this  increase  is  derived  from  the  one  region  of  the 
body  where  the  capillary  pressure  is  increased,  viz.  the  liver. 

We  must  conclude  that  in  those  regions  of  the  body  where  the  capillaries 
are  fairly  permeable  the  most  important  factor  in  lymph  production  is  the 
intracapillary  pressure. 

In  the  case  of  the  hmbs  and  connective  tissues  generally,  the  pressure 
factor  is  probably,  under  normal  conditions,  of  less  importance,  so  that  the 
second  condition,  the  chemical,  comes  here  more  into  prominence.  The 
capillary  wall  not  only  permits  of  filtration  under  certain  pressures  but  also 
allows  the  passage  of  water  and  dissolved  substances  by  diffusion  and 
osmosis.  These  osmotic  interchanges  between  blood  and  cell  through  the 
intermediation  of  the  lymph  are  constantly  going  on  in  the  normal  hfe  of  the 
tissue,  and  are  quite  independent  of  the  amount  of  lymph  produced.  Thus  a 
gland-cell  may  use  up  oxygen,  calcium,  or  sugar,  and  create  a  vacuum  of 
these  substances  in  the  layer  of  lymph  immediately  surrounding  the  cell. 
There  is  at  once  a  disturbance  of  the  equilibrium,  and  a  flow  of  these  sub- 
stances from  blood  to  lymph  is  set  up.  In  consequence  of  the  wonderful 
arrangements  in  the  tissues  for  ensuring  the  intimate  contact  of  blood  and 
lymph  without  interminghng,  these  changes  can  occur  with  great  rapidity. 
We  find,  for  instance,  that  if  a  very  large  amount  (40  grm.)  of  dextrose  be 
injected  into  the  circulation,  osmotic  equilibrium  between  blood  and  l}'Tnph 
is  established  within  half  a  miiuite  of  the  termination  of  the  injection.  In 
this  case  the  rise  of  osmotic  pressure  caused  by  the  injection  of  the  sugar 
attracts  water  from  the  tissue-fluid,  and  this  in  its  turn  from  the  tissue-cells, 
until  the  osmotic  pressure  inside  and  outside  the  vessels  is  the  same.  By 
this  means  the  volume  of  the  circulating  blood  is  increased  at  the  expense  of 
the  tissues.  A  process  of  this  character  may,  however,  work  under  normal 
circumstances  in  the  reverse  direction,  and  lead  to  a  passage  of  fluid  from 
blood  to  tissues  and  tissue  spaces.  Every  active  contraction  of  a  muscle,  for 
instance,  is  attended  by  the  breaking  down  of  a  few  large  molecules  into  a 
number  of  smaller  ones,  and  this  increase  in  the  number  of  molecules  causes 


1016  PHYSIOLOGY 

a  rise  of  osmotic  pressure  in  the  muscle  fibre  and  surrounding  lymph,  and 
therefore  a  passage  of  fluid  from  blood  to  lymph.  In  the  same  way  a  cell 
of  the  submaxillary  gland,  when  stimulated  by  means  of  its  nerve,  pours  out 
a  quantity  of  fluid  into  the  gland-duct,  and  so  into  the  mouth.  This  fluid 
comes  in  the  flrst  instance  from  the  cell  itself,  but  the  cell  recoups  itself  from 
the  surrounding  lymph,  raising  the  concentration  of  this  fluid,  and  the 
difference  in  concentration  thus  caused  at  once  induces  a  passage  of  water 
from  blood  to  lymph.  Hence  sahvary  secretion  is  associated  with  a  large 
flow  of  fluid  through  the  capillary  walls  of  the  gland.  In  this  passage  the 
endothehal  cells  of  the  capillaries  play  no  part,  the  whole  process  being  con- 
ditioned by  changes  in  the  extra  vascular  gland- cell.  We  have  only  to 
paralyse  the  gland-cell  by  means  of  atropin  in  order  to  see  that  the  active 
flushing  of  the  gland  which  accompanies  activity  produces  merely  a  minimal 
increase  in  the  lymph-flow  from  the  gland. 

The  influence  of  tissue  activity  in  the  production  of  lymph  is  still  better 
shown  in  the  case  of  a  large  gland,  such  as  the  liver.  Stimulation  of  this 
organ  by  the  injection  of  bile  salts  into  the  blood- stream  causes  a  large 
increase  in  the  lymph-flow  from  the  organ,  and  therefore  in  the  lymph-flow 
from  the  thoracic  duct. 

It  is  important  to  remember  that  the  relative  insusceptibihty  of  the 
limb  capillaries  to  pressure  holds  only  for  the  absolutely  normal  capillary. 
Any  factor  which  leads  to  impaired  nutrition  of  the  vascular  wall,  such 
as  deficiency  of  supply  of  blood  or  oxygen,  the  presence  of  poisons  in 
the  blood  or  in  the  surrounding  tissues,  scalding  or  freezing,  increases 
at  the  same  time  its  permeabihty.  Under  such  conditions  the  limb 
capillary  reacts  to  changes  of  pressure  like  a  liver  capillary,  the  sHghtest 
increase  of  pressure  causing  an  appreciable  increase  in  the  lymph  produc- 
tion. This  increased  lymph  production  may  be  too  great  to  be  carried 
off  by  the  lymphatic  channels,  so  that  the  exuded  fluid  stays  in  the 
tissue  spaces,  distending  them  and  causing  the  condition  known  as  oedema 
or  dropsy. 

LYMPHAGOGUES.  Among  the  substances  which  have  a  direct  action 
on  the  vessel- wall  are  a  number  of  bodies  which  were  described  by  Heidenhain 
as  lymphagogues  of  the  first  class.  As  their  name  implies,  these  bodies 
on  injection  into  the  blood-stream  cause  an  increased  flow  of  lymph  from 
the  thoracic  duct.  They  may  be  extracted  from  the  dried  tissues  of  crayfish, 
mussels,  or  leeches  by  simple  boihng  with  water.  Commercial  peptone  has 
a  similar  effect.  Heidenhain  regarded  these  bodies  as  direct  excitants  of 
the  secretory  activities  of  the  endothehal  cells.  They  are,  however,  general 
poisons,  having  a  special  action  on  the  vascular  system,  and  their  effect  on 
lymph  production  is  probably  due  simply  to  their  deleterious  action  on  the 
capillary  wall.  Although  .these  bodies  act  chiefly  on  the  liver  capillaries,  so 
that  the  main  increase  in  the  thoracic  duct  lymph  is  derived  from  the  liver, 
they  can  be  shown  also  to  have  some  effect  in  the  same  direction  on  the 
intestinal  and  skin  capillaries.  In  fact  the  injection  or  ingestion  of  these 
bodies  often  gives  rise  to  a  copious  eruption  of  nettle-rash,  i.e.  swelhngs  of 


LYMPH  AND  TISSUE  FLUIDS 


1017 


the  skin  due  to  an  increased  exudation  of  lymph  into  the  meshes  of  the 
cutis. 

An  increased  lymph-flow  from  the  thoracic  duct  may  be  produced  ako 
by  the  injection  of  large  amounts  (10  to  40  grm.)  of  innocuous  crystalloids, 
such  as  dextrose,  urea,  or  sodium  chloride,  into  the  circulation.  In  this 
case  the  lymph  becomes  much  more  dilute.  The  explanation  of  the  action 
of  these  bodies  is  very  simple.  We  have  already  seen  that  injection  of 
large  amounts  of  dextrose  into  the  circulating  blood  raises  the  osmotic  pres- 
sure of  this  fluid.  The  blood  therefore  imbibes  water  from  the  tissues  and 
swells  up,  i.e.  a  condition  of  hydrsemic  plethora  is  brought  about  as  surely  as 
if  several  hundred  cubic  centimetres  of  normal  salt  solution  were  injected 
into  the  circulation.     This  increase  in  the  total  volume  of  the  blood  causes 


epminutes 
inj.  of  mussel  extract 

Fig.  476.  Changes  in  lymph  flow  in  portal,  inferior  cava,  and  arterial  pressures, 
resulting  from  injection  of  a  member  of  the  first  class  of  lymphagogues  (extract 
of  mussels).     (Starling.) 

a  rise  of  pressure  throughout  the  vascular  system — arteries,  capillaries, 
and  veins — and  the  increased  capillary  pressure,  combined  ^^ith  the  watery 
condition  of  the  blood,  induces  a  great  transudation  of  lymph,  especially 
in  the  abdominal  organs  (Fig.  477).  The  lymph  is  more  watery  because  the 
blood  also  is  diluted.  That  the  action  of  these  bodies  is  purely  mechanical 
is  shown  by  the  fact  that,  if  the  rise  of  capillary  pressure  be  prevented  by 
bleeding  the  animal  immediately  before  the  injection,  the  increase  in  the 
lymph-flow  is  also  prevented  (Fig.  477,  b),  although  the  concentration  of  the 
sugar  or  salt  in  the  blood  is  still  greater  than  in  the  experiments  in  which 
bleeding  was  not  performed. 

MOVEMENT  OF  LYMPH 

In  the  frog  the  circulation  of  lymph  is  maintained  by  rhythmically  con- 
tracting muscular  sacs,  which  are  placed  in  the  course  of  the  main  lymph- 
channels,  and  pump  the  lymph  into  the  veins.  In  the  higher  animals  and  in 
man  the  onward  flow  of  lymph  is  eftected  partly  by  the  pressure  at  which  it 
is  secreted  from  the  capillaries  into  the  interstices  of  the  tissues,  but  also  to 


1018 


PHYSIOLOGY 


a  large  extent  by  the  contractions  of  the  skeletal  muscles.  In  the  smaller 
lymph-radicles  the  pressure  of  lymph  may  attain  8  to  10  mm.  soda  solution. 
In  the  thoracic  duct,  at  the  point  where  it  opens  into  the  great  veins  of  the 
neck,  the  pressure  is  obviously  the  same  as  in  these  veins,  that  is  to  say, 


0  12345678910 


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60  minutes 


inJ.oF 40qrams  dextrose 


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Bled  to  240  ccm       Inj.  18 grams  dextrose 


Fig.  477.     Effect  on  lymph  flow  and  on  arterial  and  venous  pressures  of  injection 
of  concentrated  solution  of  glucose. 
In  B  the  animal  was  bled  to  240  c.c.  before  the  injection.     The  double  line 
=  lymph  flow  in  c.c.  per  ten  minutes  ;  thin  line  =  portal  vein;  thick  line  — 
carotid  artery  ;  dotted  line  =  inferior  vena  cava. 


from  —  4  to  0  mm.  Hg,  the  negative  pressure  being  occasioned  by  the  aspira- 
tion of  the  thorax.  This  difference  of  pressure  is  sufl&cient  to  cause  a  certain 
amount  of  flow.  It  must  be  remembered,  however,  that  under  normal 
circumstances  no  lymph  at  all  flows  from  a  resting  limb.  The  only  part  of 
the  body  which  gives  a  continuous  stream  of  lymph  during  rest  is  the  ahmen- 
tary  canal,  the  lymph  in  which  is  poured  out  into  the  lacteals,  and  thence 
makes  its  way  through  the  thoracic  duct.  Movement,  active  or  passive, 
of  the  limbs  at  once  causes  a  flow  of  lymph  from  them.     Since  the  lymphatics 


LYMPH  AND  TISSUE  FLUIDS  1019 

are  all  provided  with  valves  (Fig.  478),  the  effect  of  external  pressure  on  them 
is  to  cause  the  lymph  to  flow  in  one  direction  only,  i.e.  towards  the  thoracic 
duct  and  great  veins.  Hence  we  may  look  upon  muscular  exercise  as  the 
greatest  factor  in  the  circulation  of  lymph.  The  flow  of  lymph  from  the 
commencement  of  the  thoracic  duct  in  the  abdominal  cavity  to  the  main 
part  of  it  in  the  thoracic  cavity  is  materially  aided  by  the  respiratory  move- 


Fig.  478.     A  lymphatic  vessel  laid  ojjen  to  show  arrangement  of 
the  valves.     (Testut.) 

ments  ;  since,  with  every  inspiration,  the  lacteals  and  abdominal  part  of  the 
duct  are  subjected  to  a  positive  pressure,  and  the  intrathoracic  part  of  the 
duct  to  a  negative  pressure,  so  that  lymph  is  continually  being  sucked  into 
the  thorax. 

THE  ABSORPTION  OF  LYMPH   AND  TISSUE  FLUIDS 

On  injecting  a  coloured  solution  or  suspension  into  the  connective  tissues 
of  any  part  of  the  body,  and  gently  kneading  the  part,  it  is  found  that 
the  fluid  fills  all  the  lymphatic  channels  running  from  the  part ;  and  we  can 
in  this  way  inject  the  lymphatics  of  the  limb  and  trace  their  course  on  to 
the  thoracic  duct.  The  same  path  is  taken  by  micro-organisms  as  they 
spread  in  the  tissues,  or  by  particles  of  carmine  or  Indian  ink  which  have  been 
introduced  in  tattooing.  It  is  on  account  of  these  facts  that  the  lymphatics 
are  often  spoken  of  as  the  '  absorbent  system.' 

This  process  of  lymphatic  absorption,  except  in  the  case  of  the  pleural 
and  peritoneal  cavities  is,  however,  a  slow  one,  unless  aided  to  a  large  extent 
by  passive  or  active  movements  of  the  surrounding  parts,  and  cannot  therefore 
account  for  the  rapid  symptoms  of  poisoning  which  supervene  within  two  or 
three  minutes  after  the  hypodermic  injection  of  a  solution  of  strychnine  or 
other  poison.  That  this  absorption  is  not  dependent  on  the  lymphatics  is 
shown  by  the  fact  that  the  symptoms  occur  almost  as  quickly  when  all  the 
tissues  of  the  limb  have  been  severed  with  the  exception  of  the  main  artery 
and  vein.  In  the  same  way,  after  injecting  methylene  blue  or  indigo  carmine 
into  the  pleural  cavity  or  subcutaneous  tissues,  the  dyestuff  appears  in  the 
urine  long  before  any  trace  of  colour  can  be  perceived  in  the  lymph  flowing 
from  the  thoracic  duct.  The  absorption  in  these  cases  is  by  the  blood-vessels, 
and  consists  in  an  interchange  between  blood  and  extravascular  fluids, 
apparently  dependent  entirely  upon  processes  of  diffusion  between  these 
two  fluids.  So  long  as  any  difference  in  composition  exists  between  the 
intra-  and  extravascular  fluids,  so  long  will  diffusion-currents  be  set  up, 
tending  to  equahse  this  difference. 


1020  PHYSIOLOGY 

More  difficulty  is  presented  by  the  question  of  the  mechanism  of  absorp- 
tion by  the  blood-vessels  of  the  normal  tissue  fluids — such  an  absorption  as 
we  have  seen  to  occur  after  loss  of  blood  by  haemorrhage.  It  seems  probable 
that  this  absorption  depends  on  the  small  proportion  of  protein  contained  in 
the  tissue  fluid  as  compared  with  the  blood-plasma,  and  is  due  to  the  osmotic 
pressure  of  the  protein.  If  blood-serum  be  placed  in  a  bell-shaped  vessel 
(the  mouth  of  which  is  closed  by  a  gelatinous  membrane  which  does  not 
permit  the  passage  of  protein),  and  suspended  in  normal  salt  solution,  it  is 
found  that  the  serum  absorbs  the  salt  solution  until  the  manometer  attached 
to  the  bell-jar  indicates  a  pressure  of  25-30  mm.  Hg.  Thus  we  may  con- 
ceive that  there  is  normally  a  balance  in  the  capillaries  between  the  processes 
of  exudation  and  of  absorption,  the  former  being  conditioned  by  the  capillary 
blood-pressure  and  the  latter  by  the  difference  in  protein  content,  and  there- 
fore of  osmotic  pressure  between  the  blood-plasma  and  tissue-lymph.  A  rise 
of  capillary  pressure  will  upset  this  balance  in  favour  of  transudation  and 
the  blood  will  become  more  concentrated,  whereas  a  fall  of  pressure  will  turn 
the  scale  in  favour  of  absorption  and  the  volume  of  blood  will  be  increased 
at  the  expense  of  the  tissue  fluids. 

THE  PART  PLAYED  BY  THE  LYMPH  IN  THE  NUTRITION 
OF  THE  TISSUES 

The  fact  that  the  tissue-cells  are  separated  by  the  lymph  and  the  capillary 
wall  from  the  blood  shows  that  in  all  interchanges  between  the  blood  and 
tissues  the  lymph  must  act  as  the  medium  of  communication.  The  lymph- 
flow  plays  very  little  part  in  this  process.  The  muscles  of  a  resting  limb 
are  taking  up  nourishment  as  well  as  oxygen  from  the  blood  and  giving  off 
their  waste  products — carbonic  acid  and  ammonia,  though  not  a  drop  of 
lymph  may  flow  from  a  cannula  placed  in  a  lymphatic  trunk  of  the  limb.  In 
fact  the  interchange  of  material  between  tissue-cell  and  blood  through  the 
mediation  of  the  lymph  is  carried  out  in  the  same  way  as  are  the  gaseous 
interchanges,  viz.  by  a  process  of  diffusion.  This  explanation,  however,  holds 
good  only  for  the  diffusible  constituents  of  the  blood  and  will  not  account 
for  the  supply  of  the  indifiusible  protein  molecules  to  the  cell.  Apparently 
the  only  way  in  which  the  tissues  can  obtain  their  supply  of  protein  is  from 
the  small  proportion  of  this  substance  which  has  filtered  through  the  vessel- 
wall  into  the  lymph.  The  increased  exudation  of  concentrated  lymph  to 
the  tissues  which  occurs  in  inflammatory  conditions  or  as  the  result  of  injury 
is  therefore  of  advantage,  since  it  furnishes  an  abundant  supply  of  protein 
food  to  be  used  up  in  the  regeneration  of  the  damaged  cells. 


CHAPTER  XV 
THE  DEFENCE  OF  THE  ORGANISM  AGAINST  INFECTION 

SECTION  I 

THE  CELLULAR  MECHANISMS  OF  DEFENCE 

One  of  the  main  distinctions,  perhaps  the  most  important,  between  the 
animal  and  vegetable  kingdoms  lies  in  the  inabihty  of  animals  to  build 
up  their  tissues  at  the  expense  of  inorganic  salts,  and  especially  to  synthetise 
the  various  groups  necessary  for  the  formation  of  the  protein  molecule. 
They  are  thus  rendered  dependent  on  the  assimilative  powers  of  the  vegetable 
kingdom,  and  have  to  supply  their  needs  by  using  the  members  of  this  king- 
dom as  food.  The  protozoa,  for  example,  subsist  largely  on  bacteria.  To 
obtain  a  pure  culture  of  any  form  of  amoeba  it  is  necessary  to  cultivate  this 
along  with  some  form  of  bacteria.  The  power  of  the  unicellular  animals 
to  digest  bacteria  meets  with  a  response  on  the  part  of  the  latter,  many  of 
them  developing,  by  way  of  self-defence,  the  habit  of  forming  and  excreting 
poisons  which  will  deter  the  amoeba  from  taking  them  up  or  injure  it  after 
it  has  ingested  them.  There  is  thus  a  continuous  struggle  among  the  various 
grades  of  unicellular  organisms  in  which  sometimes  one,  sometimes  another 
type  survives.  An  amoeba  placed  in  contact  with  most  kinds  of  bacteria, 
living  or  dead,  will  rapidly  englobe  and  digest  them.  There  is,  however,  a 
small  organism  known  as  microsphera  which  is  taken  up  by  the  amoeba,  but 
is  not  thereby  destroyed.  Retaining  its  vitality,  it  reproduces  itself  rapidly 
in  the  body  of  its  host  and  finally  leads  to  disintegration  of  the  latter.  In  the 
same  way  the  flagellate  protozoa  are  often  infected  by  a  species  of  fungus 
known  as  chytridium,  and  die  in  consequence. 

The  liability  of  organisms  to  infection  by  others  endeavouring  to  hve  a 
parasitic  existence  at  their  expense  extends  throughout  the  whole  of  the 
animal  and  vegetable  kingdoms.  In  some  cases  the  host  and  the 
parasite  arrive  at  a  compromise  in  which  each  benefits  the  other.  This 
condition  is  known  as  symbiosis.  We  have  examples  of  it  in  the  union  of 
fungi  and  algse  which  occurs  in  lichens  ;  in  the  association  of  nitrogen- 
fixing  bacteria  with  many  plants,  especially  those  belonging  to  the  natural 
order  Leguminosa?.  Ii\  herbivorous  animals  the  presence  of  specific  bacteria 
in  the  paunch  or  caecum  causes  the  breakdown  of  the  cellulose  walls  of  the 
food  and  may  indeed  lead  to  a  building  up  of  protein  from  amino-acids  or 

1021 


1022 


PHYSIOLOGY 


even  from  salts  of  ammonia.  It  is  probable  that  in  these  cases  the  animal  is 
decidedly  benefited  from  the  presence  of  these  bacteria  in  its  ahmentary 
canal,  so  that  here  also  we  may  speak  of  a  symbiosis.  In  most  cases  invasion  of 
a  higher  animal  or  plant  by  some  lower  organism  is  fraught  with  danger  to 
the  host,  so  that  special  mechanisms  have  to  be  provided  for  the  protection 
of  the  tissues  from  infection.  The  most  primitive  means  of  defence,  and 
one  which  is  found  throughout  the  whole  animal  kingdom,  is  exactly  ana- 
logous to  the  process  by  which  the  amoeba  destroys  and  utihses  any  bacteria 
present  in  its  environment.  The  prevention  of  infection  is  of  course  the 
function  of  the  external  layers  of  the  organism,  i.e.  the  epithehal  covering, 
either  of  the  skin  or  of  the  surface  of  the  gut.     Protection  here  may  be 

A  T? 


a^ — 


Fig.  479. 


A,  amoeba,  infected  by  Microsphcera  :    a,  early    stage,     b,  a  dying 
amoeba,  full  of  parasitic  Microsphceroe.     (Metchnikoff.) 


of  a  physical  or  chemical  character.  The  cells  may  secrete  a  horny  or 
chitinous  layer  which  presents  a  mechanical  obstruction  to  the  entry  of 
bacteria.  They  may  secrete  mucin,  which  entangles  and  hinders  the  move- 
ments of  invading  micro-organisms,  or  they  may  secrete  substances  which 
actually  destroy  the  life  of  such  organisms.  When,  however,  a  micro- 
organism has  obtained  entrance  to  the  interior  of  the  body,  e.g.  through  a 
wound  of  the  surface  epithelium,  the  task  of  deahng  with  the  invader 
becomes  the  office  of  a  special  type  of  cells  belonging  to  the  mesoblast. 
These  cells  are  similar  in  character  to  the  amoeba.  They  have  the  power 
of  extruding  pseudopodia,  of  wandering  from  place  to  place,  and  of  englobing 
and  digesting  particles  of  food  or  bacteria  with  which  they  come  in  contact. 
On  account  of  these  latter  properties  they  have  been  called  by  Metchnikoff 
'phagocytes,  and  the  whole  process  by  which  foreign  material  or  the  animal's 
own  dead  tissues  are  got  rid  of  is  spoken  of  as  phagocytosis.  The  process  can 
be  well  studied,  as  has  been  shown  by  Metchnikofi,  in  the  sponge  or  in  the 
larva  of  the  echinoderm.     At  one  stage  in  the  development  of  the  latter  the 


THE  CELLULAR  MECHANLSMS  OF  DEFENCE 


1023 


larva  consists  of  a  sack  which  is  involuted  at  one  extremity  to  form  the 
alimentary  cavity,  while  the  mesoblast  is  represented  by  amoeboid  cells 
suspended  in  a  semi-liquid  substance  filUng  the  body  cavity.  If  a  particle 
of  foreign  substance  be  introduced  into  the  body  cavity  the  wandering 
mesoderm  cells  collect  round  the  particle  and  fuse  into  plasmodial  masses, 
thus  forming  a  wall,  as  it  were,  around  it.  If  bacteria  be  introduced,  the 
phagocytes  may  be  seen  to  adhere  to  and  ingest  the  still  living  bacteria, 
which  are  then  rapidly  digested  and  destroyed.  A  similar  process  may  be 
observed  in  the  transparent  crustacean  known  as  the  water-fiea  (Daphnia), 
and  here  it  may  be  noted  that  the  process  of  phagocytosis  is  not  always 
successful  in  maintaining  the  health  or  life  of  the  host.     Thus  if  the  spores 


Fig.  480.  1,  gastrula  stage  of  starfish  embryo,  with  a  foreign  substance,  pi,  in  its 
body  cavity ;  end,  endoderm  ;  ect,  ectoderm  ;  mcs,  wandering  mesoblastic 
cells.  2,  the  foreign  body  of  1,  surrounded  by  a  plasmodium  of  phagocytes 
(highly  magnified).     (After  Metchnikoff.) 

of  a  yeast-like  organism,  the  Monospora,  be  introduced  into  the  body  caxaty 
of  Daphnia,  the  leucocytes  may,  if  the  spores  be  few  in  number,  lay  hold  of 
the  latter  and  digest  them.  If  the  spores  be  in  excess  the  phagocytes  may 
fail  to  ingest  them  or  may  indeed  be  destroyed  as  soon  as  they  approach 
them.  In  this  case  the  spores  germinate,  fill  up  the  body  cavity,  and 
finally  lead  to  the  death  of  the  host.  The  same  process  of  phagocytosis  may 
be  studied  in  its  simple  form  by  injuring  or  infecting  some  tissue  which 
is  free  from  blood-vessels.  Thus  the  tail  fin  of  an  embryonic  axolotl  may 
be  cauterised  with  silver  nitrate,  or  a  small  quantity  of  fluid  containing 
carmine  granules  may  be  introduced  by  means  of  a  hypodermic  syringe.  In 
either  way  a  certain  number  of  cells  are  destroyed  and  the  dead  tissue  there- 
upon acts  as  a  foreign  body.  As  a  result  the  wandering  mesoderm  cells  or 
leucocytes  move  from  the  surrounding  tissues  towards  the  seat  of  the  injury, 
amd  the  day  after  the  injury  has  been  inflicted  a  collection  of  leucocytes 
can  be  seen,  many  of  which  contain  particles  of  carmine  or  debris  of  the 
destroyed  tissue  which  they  have  taken  up.  The  cells  finally  wander  away 
from  the  part,  and  the  destruction  is  made  good  by  the  proliferation  of  the 


1024  PHYSIOLOGY 

connective  tissue-cells  and  of  the  epithelium  immediately  adjoining  the 
injury.  In  the  lowest  types  of  metazoa  it  is  impossible  to  speak  of  more 
than  one  type  of  wandering  mesoderm  cell.  It  is  probable  indeed  that  the 
same  type  of  cell  may  at  one  time  act  as  a  scavenger  and  at  another  as  the 
chief  agent  in  the  formation  of  connective  tissues.  Even  in  Daphnia, 
according  to  Hardy,  only  one  form  of  leucocyte  is  present,  whereas  in  the 
much  more  highly  organised  crayfish,  belonging,  however,  to  the  same 
family,  three  difierent  types  of  leucocyte  may  be  distinguished.  These 
leucocytes  may  be  present  free  in  the  body  cavity  or  they  may  form  an 
element  of  the  connective  tissues.  With  the  formation  of  a  closed  vascular 
system  many  of  the  wandering  mesoderm  cells  became  attached  to  this 
system,  so  that  we  may  distinguish  a  group  of  blood  leucocytes  or  phagocytes 
and  a  group  of  connective  tissue  or  body-cavity  leucocytes.  Moreover  by 
the  formation  of  a  blood  vascular  system  all  the  tissues  of  the  body  are 
brought  into  material  relationship  with  one  another,  so  that  distant  parts 
may  be  drawn  upon  to  supply  the  needs  of  any  one  part.  It  is  evident  that 
injury  of  a  tissue  in  a  higher  animal  containing  blood-vessels  will  involve 
more  complex  consequences  than  a  similar  injury  or  infection  of  the  avascular 
tissue  of  an  invertebrate,  and  that  the  accumulation  of  cells  for  the  defence  of 
the  organism  against  invading  microbes  will  be  much  more  effective  if  the 
blood-vessels  participate  in  the  process  so  that,  by  their  means,  the  phago- 
cytic resources  of  all  parts  of  the  body  can  be  drawn  upon  to  ward  off  a 
locahsed  attack.  The  process  of  phagocytosis  thus,  in  the  higher  animals, 
becomes  merged  into  the  more  complex  series  of  phenomena  to  which  the 
term  '  inflammation '  has  been  apphed.  This  process  can  be  studied  by 
observing  the  effects  of  sHght  injury  to  some  transparent  part  of  the  body, 
e.g.  the  frog's  tongue  or  mesentery,  or  the  web  of  the  frog's  foot.  For  this 
purpose  a  small  piece  of  the  skin  of  the  frog's  web  is  snipped  off  with  fine 
curved  scissors,  the  section  being  sufficiently  deep  to  remove  the  skin  with- 
out causing  haemorrhage.  The  first  effect  noticed  in  the  immediate  neigh- 
bourhood of  the  injury  is  a  dilatation  of  the  vessels,  especially  of  the  venules, 
with  acceleration  of  the  blood-flow.  In  the  course  of  an  hour  the  capillaries 
also  become  dilated,  and  many  capillary  channels,  previously  invisible,  are 
now  occupied  with  blood.  Through  the  dilated  capillaries  there  is  a  rapid 
blood-stream,  the  corpuscles  occupying  the  axis  of  the  vessel,  so  that  there 
is  a  periaxial  layer  of  plasma.  A  Httle  later  this  acceleration  gives  place 
to  a  slowing  of  the  blood-stream,  and  simultaneously  the  leucocytes  of  the 
blood  are  seen  to  be  adherent  to  the  capillary  wall.  Apparently  the  latter 
becomes  what  we  may  call  '  sticky,'  the  effect  of  the  stickiness  being  to 
increase  the  resistance  to  the  passage  of  the  blood  through  the  vessel  and 
also  to  cause  the  adhesion  of  the  leucocytes  to  the  wall.  As  the  current 
becomes  still  slower  the  distinction  between  axial  and  peripheral  streams 
disappears.  The  corpuscles  are  closely  packed  together,  the  white  cor- 
puscles being  predominant  at  the  margins  of  the  capillary,  where  they  form 
a  fining  to  the  vessel  (Fig.  481).  The  next  stage  is  the  emigration  of  the 
leucocytes.     These  may  be  observed  to  thrust  a  process  through  the  vessel- 


THE  CELLULAR  MECHANISMS  OF  DEFENCE 


1025 


wall  (according  to  Arnold  this  process  of  emigration  always  occurs  through 
the  stigmata,  i.e.  the  points  where  the  endothehal  cells  come  in  contact — 
Fig.  482).  The  prolongation  enlarges  on  the  outer  side  of  the  vessel,  while 
the  portion  of  the  leucocyte  within  the  vessel  becomes  smaller,  so  that  finally 


Fig.  481.  Inflamed  mesentery  of  frog,  to  show  margination  of  leucocytes  in  the 
inflamed  capillaries,  a  ;  migration  of  leucocytes,  h  ;  escape  of  red  corpuscles,  c  ; 
accumulation  of  leucocytes  outside  the  capillaries,  d.      (From   Adajii  after 

RiBBERT.) 

the  whole  leucocyte  passes  through  and  lies  in  the  lymph  spaces  outside 
the  capillary.  In  the  course  of  five  or  six  hours  all  the  capillaries  and  small 
veins  in  the  neighbourhood  of  the  injury  may  show  a  crowd  of  leucocytes 
along  their  outer  surfaces.  The  use  of  this  emigration  seems  to  be  to  re- 
move the  tissue  injured  by  the  primary  lesion.     As  soon  as  this  is  effected, 


Fio.  482.     Emigration  of  leucocytes  through  capillary  wall.     (Arxold.) 


regeneration  of  the  injured  tissue  occurs  by  a  proliferation  of  the  connective- 
tissue  corpuscles  and  the  epithelium,  while  the  leucocytes  move  away  and 
disappear.  The  essential  phagocytic  character  of  the  i)iflammatory  process 
may  be  shown  if  the  primary  lesion  be  attended  with  infection.  Thus  if  a 
small  quantity  of  the  staphylococcus  be  injected  into  the  subcutaneous  tissue 
of  the  rabbit,  the  vessels  surrounding  the  point  of  injection  within  four  hours 
may  be  found  densely  filled  with  corpuscles.  In  ten  hours'  time  the  leuco- 
cytes are  present  in  large  numbers  outside  the  vessels,  while  the  injected 
cocci  have  spread  for  some  distance  along  the  lymphatic  spaces  and,  while 
partly  free,  have  been  to  a  large  extent  ingested  by  the  leucocytes.     In 


1026  PHYSIOLOGY 

twenty  hours'  time  the  connective-tissue  fibrils  at  the  point  of  injection  are 
found  to  be  mdely  separated  by  the  aggregation  of  leucocytes.  In  forty- 
eight  hours'  time  a  well-defined  abscess  is  produced.  At  the  centre  all 
traces  of  previous  connective  tissue  have  disappeared  and  its  place  has 
been  taken  by  a  dense  mass  of  leucocytes,  many  i-n  a  state  of  degeneration, 
mingled  with  staphylococci,  partly  within,  partly  outside  the  cells.  The 
margin  of  the  abscess  is  formed  by  connective  tissue  infiltrated  with  living 
leucocytes.  A  certain  number  of  cocci  are  to  be  seen  free  in  the  tissue  out- 
side this  layer,  but  in  the  course  of  a  day  or  two  these  free  cocci  disappear, 
and  there  is  thus  a  continuous  layer  of  phagocytes  surrounding  the  abscess 
cavity  and  preventing  any  further  invasion  of  the  body  as  a  whole  from  the 
seat  of  infection.  The  abscess  subsequently  discharges  on  to  the  exterior 
by  a  process  of  necrosis  of  the  superjacent  skin,  and  regeneration  of  tissue 
takes  place  in  the  same  manner  as  in  the  more  trivial  injury.  Inflamma- 
tion in  warm-blooded  animals  thus  gives  rise  to  dilatation  of  vessels  and 
increased  vascularity  of  a  part,  to  alteration  of  a  vessel- wall,  and  therefore  to 
increased  effusion  of  fluid.  There  are  increased  warmth  and  redness  of 
the  part  from  the  vascular  dilatation,  swelling  from  the  increased  diffusion 
of  lymph,  and  very  often,  as  a  result  of  the  injury  or  the  swelling  and  the 
consequent  involvement  of  sensory  nerves,  pain.  The  four  cardinal  symp- 
toms of  inflammation,  namely,  rubor,  color,  turgor,  and  dolor,  which  have 
been  described  for  generations  as  typical  of  this  condition,  leave  out  of 
account  altogether  the  phenomenon  which  Waller's  and  Cohnheim's  obser- 
vations, in  the  light  of  the  comparative  studies  of  Metchnikoff,  have  shown 
us  to  be  the  essential  feature  of  the  process,  namely,  phagocytosis,  the 
accumulation  of  wandering  mesoderm  cells  round  the  seat  of  injury  with 
the  objects  of  removing  injured  tissue,  of  destroying  micro-organisms,  of 
protecting  the  body  from  general  infection,  and  of  preparing  the  way  for 
reintegration  of  tissue. 

Prior  to  the  work  of  Metchnikoff ,  the  changes  in  the  blood-vessels  fettered 
the  attention  of  physiologists,  and  the  accumulation  of  leucocytes  was 
regarded  as  secondary  to  these  changes.  Though  the  alteration  of  the 
capillary  wall,  by  permitting  the  adhesion  of  the  leucocytes,  must  no  doubt 
favour  their  emigration  and  their  passage  from  all  parts  of  the  body  into  the 
inflamed  part,  we  know  that  the  same  accumulation  of  leucocytes  occurs 
in  the  entire  absence  of  a  vascular  system.  The  movement  of  the  corpuscles 
towards  dead  or  injured  tissue  must  therefore  have  some  other  explanation. 
We  have  abundant  evidence  to  show  that  the  essential  factor  in  this  aggrega- 
tion of  leucocytes  is  their  chemical  sensibility,  and  that  the  phenomenon 
is  simply  one  of  chemiotaxis.  A  capillary  glass  tube  containing  a  suspension 
of  dead  micrococci,  or  peptone,  or  broth  extracted  from  dead  tissue,  if 
introduced  into  the  anterior  chamber  of  the  eye  or  into  the  subcutaneous 
tissue,  is  found  after  a  short  time  to  be  full  of  leucocytes.  We  must  assume 
that  the  chemical  products  diffusing  out  of  the  ends  of  the  capillary  tube  have 
acted  like  the  malic  acid  discharged  by  the  cells  forming  the  female  organ,  the 
archegonium,  of  ferns.     Just  as  the  latter  causes  a  movement  of  the  anthero- 


THE  CELLULAR  MECHANLSMS  OF  DEFENCE  1027 

zoids,  the  male  cells,  towards  the  ovule,  so  the  chemical  substances  dilffusing 
from  the  capillary  tube  have  occasioned  a  positive  cheniiotaxis  on  the  part 
of  the  leucocytes.  It  is  worthy  of  note  that  the  positive  chemiotactic 
influence  exerted  by  any  given  species  of  pathogenic  bacterium  is  roughly 
inversely  proportional  to  its  virulence.  A  culture  lacking  in  virulence  may 
cause  a  very  pronounced  aggregation  of  leucocytes  which  speedily  ingest  and 
destroy  the  micro-organism,  whereas  if  a  culture  of  a  more  virulent  variety 
of  the  same  microbe  be  injected,  there  may  be  all  the  signs  of  inflammation, 
swelling,  and  large  effusion  of  fluid,  but  the  tissues  may  contain  very  few 
leucocytes.  Under  these  circumstances  the  micro-organism  rapidly  pro- 
liferates and  spreads  from  the  seat  of  the  lesion,  giving  rise  finally  to  general 
infection. 

So  far  we  have  spoken  merely  of  leucocytes  or  phagocytes,  and  have 
not  attempted  to  distinguish  between  the  parts  played  by  the  various  types 
of  leucocyte  which  are  found  in  the  blood  and  connective  tissues.  In  the 
higher  animals  there  are,  however,  very  many  varieties  of  leucocytes  belong- 
ing partly  to  the  blood,  partly  to  the  connective  tissues.  The  follo\^nng 
Table,  modified  from  Adami,  enumerates  the  leucocytes  which  may  be 
concerned  with  inflammation  in  a  mammal  or  man  : 

Polymorijhonuclear     (polynuclear,     finely     Originating  in  adult  mammals  from   the 
granular      oxyphile,      neutrophile,      or  bone  marrow,  and  migrating  from  the 

amphophile  cell).  blood  into  the  inflammatory  area. 

Eosinophile   (coarsely  granular  oxyphile, 
macroxycyte). 

Lymphocyte  (?  of  two  types).  Originating  from  lymphoid  tissue  and  froir. 

Plasma-cell  (?  histogenous).  vascular   and   other  endothelia  respec- 

Endotheloid  leucocyte  (mononuclear  leuco-  tively  ;    present  in  inHamed  area  cither 

cyte,  hyaline  cell  (in  part),  '  epithelioid  by  migration  from  blood  or  as  result  of 

cell '  (in  part).  local  proliferation. 

Connective  tissue  wandering  cell  (includ-     Originating    locally    as    result    of    tissue 
ing  clasmatocyte).  proliferation. 

The  part  played  by  each  of  these  forms  is  still  to  a  large  extent  the 
subject  of  discussion.  There  is  no  doubt  that  in  all  active  inflammations 
the  polymorphonuclear  leucocyte  is  the  form  which  is  attracted  first  and 
in  largest  numbers  to  the  seat  of  injury.  It  is  the  characteristic  cell  from 
which  pus  is  formed,  and  is  actively  phagocytic.  It  has  nothing  to  do  with 
the  regeneration  of  the  destroyed  tissue.  The  eosinophile  corpuscle  is  also 
present  at  an  early  stage  around  the  inflammatory  focus,  but  is  never  present 
in  numbers  at  all  comparable  with  those  of  the  polymorphonuclear  leucocyte. 
It  is  especially  abundant  in  chronic  inflammations  of  certain  tissues,  such  as 
the  skin.  According  to  Kanthack  and  Hardy,  these  cells  discharge  their 
granules  into  the  surrounding  fluid,  rendering  this  fluid  toxic  for  bacteria. 
Although  later  observations  have  failed  to  confirm  these  views,  no  other 
satisfactory  explanation  has  been  given  as  to  the  part  played  by  these  cells. 
They  are  rarely  seen  to  ingest  bacteria  and  therefore  cannot  be  spoken  of  as 
phagocytic.    The  lymphocyte  predominates  in  certain  chronic  inflammations, 


1028  PHYSIOLOGY 

especially  in  those  caused  by  the  tubercle  bacillus.  They  do  not  ingest 
bacteria.  The  histogenous  wandering  cells  appear  in  the  inflammatory 
area  at  a  later  period  than  the  polymorphonuclear  and  eosinophile  cells. 
They  are  actively  phagocytic  and  are  motile.  As  a  rule  their  phagocytic 
properties  are  exerted,  not  on  bacteria,  but  on  other  cells  and  cell- 
debris.  After  an  acute  inflammation  their  chief  office  is  to  clear  away  the 
remains  of  the  polymorphonuclear  leucocytes  and  dead  tissues  so  as  to 
prepare  the  way  for  subsequent  regeneration.  It  is  possible  that  these 
cells  may  take  a  part  in  the  formation  of  new  connective  tissue.  They  are 
indistinguishable  from  the  immature  form  of  connective  tissue-cells.  It  is 
therefore  difficult  to  be  certain  whether  the  wandering  and  the  fixed  con- 
nective-tissue corpuscles  are  of  identical  or  of  difierent  origin.  Metchnikoif 
speaks  of  these  cells  as  macrophages,  to  distinguish  them  from  the  poly- 
morphonuclear type,  which  he  terms  microphages. 

We  thus  see  that  several  types  of  the  wandering  cells  of  mesoblastic 
origin  which  take  part  in  inflammation  do  not  exert  active  phagocytic 
properties  and  cannot  therefore  destroy  bacteria  or  other  invading  organisms 
by  the  process  of  ingestion  and  digestion.  Yet  we  have  evidence  that  the 
part  played  by  such  cells  in  the  defence  of  the  organism  is  no  less  important 
than  that  of  the  actively  phagocytic  cells.  In  the  alimentation  of  the  more 
primitive  invertebrata  the  cells  Hning  the  digestive  cavity  take  up  the 
particles  of  food  directly,  and  the  processes  of  digestion  are  carried  out  in 
vacuoles  within  the  cells  themselves.  In  the  higher  animals  this  process  of 
intra- cellular  digestion  has  almost  disappeared,  and  the  cells  Uning  the 
ahmentary  tract  have  become  differentiated  into  those  which  secrete 
digestive  ferments  and  those  which  absorb  the  products  of  the  action  of  the 
ferments  on  the  food-stuffs.  Digestion  has  thus  become  extra-cellular.  It 
seems  that  a  similar  modification  has  taken  place  to  some  extent  in  the 
means  adopted  by  the  organism  for  its  defence  from  infection,  and  that  the 
leucocytes  destroy  bacteria  not  only  by  the  process  of  intracellular  digestion 
but  also  by  the  excretion  of  substances  into  the  surrounding  body  fluids 
which  have  a  deleterious  influence  on  bacteria.  Thus  normal  blood-serum 
is  found  to  have  a  strong  destructive  influence  on  most  species  of  bacteria, 
whether  pathogenic  or  not.  Since  this  property  is  not  shared  to  anything 
like  the  same  extent  by  the  blood-plasma,  it  may  be  ascribed  to  the  breaking 
down  of  leucocytes  in  the  process  of  clotting  and  the  consequent  liberation 
of  bactericidal  substances.  Extracts  made  from  any  collection  of  leuco- 
cytes have  a  similar  bactericidal  effect,  and  it  has  been  shown  by  Wright 
that  the  ingestion  of  bacteria  by  normal  leucocytes  goes  on  much  more 
rapidly  in  the  presence  of  blood-serum  or  if  the  bacteria  have  been  previously 
subjected  to  the  action  of  blood-serum.  This  adjuvant  action  of  blood- 
serum  on  phagocytes  is  destroyed  if  the  serum  be  heated  to  55°  C,  so  that  it 
must  be  due  to  the  presence  of  some  chemical  substance  in  the  serum  which 
is  unstable  and  destroyed  by  heat  at  a  temperature  far  below  the  coagula- 
tion point  of  the  serum  proteins.  Moreover,  there  are  many  species  of 
pathogenic  bacteria  which  cannot  infect  the  animal  as  a  whole.     These 


THE  CELLULAR  MECHANISMS  OF  DEFENCE  1029 

nevertheless  may  multiply  on  the  surface  of  the  body  or  in  an  abscess  cavity 
and  lead  to  the  death  of  the  host,  in  consequence  of  the  production  by  the 
bacteria  of  soluble  toxins  which  are  absorbed  into  the  blood-stream. 
Examples  of  such  micro-organisms  are  those  which  are  associated  with 
tetanus  and  diphtheria.  The  process  of  intracellular  digestion  is  obviously 
inadequate  to  deal  with  such  cases,  and  since  we  have  the  power  of  resisting 
and  recovering  from  these  diseases  there  must  be  other  mechanisms  at  the 
disposal  of  the  body  for  the  neutrahsation  of  these  toxins.  The  protec- 
tion of  the  body  against  destruction  by  bacterial  toxins  involves  in  fact 
a  whole  series  of  chemical  mechanisms  which  we  must  regard  as  of  equal 
importance  and  as  co-operating  with  the  phagocytic  mechanism. 


SECTION  II 

THE   CHEMICAL   MECHANISMS   OF  DEFENCE 

IMMUNITY.  All  infectious  diseases  are  caused  by  the  agency  of  micro- 
organisms. The  greater  number  of  these,  the  bacteria,  belong  to  the  class 
of  fungi  or  schizomycetes  ;  a  certain  number  must  be  classed  with  the 
yeasts,  while  others  are  protozoal  in  character.  It  is  especially  in  the  first 
class  of  diseases,  namely,  those  due  to  bacteria,  that  the  organism  has 
developed  chemical  mechanisms  of  defence.  In  the  protozoal  diseases  the 
micro-organisms  occur  for  the  greater  part  as  intra-cellular  parasites.  One 
attack  of  the  disease  does  not  as  a  rule  confer  immunity,  and  the  treatment 
has  to  be  sought  along  the  lines  of  medication  by  drugs  rather  than  by  the 
development  of  methods  of  protection  normally  displayed  or  developed  by 
the  animal  which  is  the  subject  of  the  infection.  The  diseases  due  to  bacteria 
include  diphtheria,  tetanus,  tubercle,  anthrax,  pyaemia,  and  many  others. 
In  these  diseases  we  have  to  deal  with  a  number  of  phenomena  more  or  less 
common  to  all.  The  infection  in  each  case  is  due  to  the  actual  transference 
of  the  specific  organism  from  one  animal  to  another.  After  the  micro- 
organism has  attained  entrance  into  the  system  there  is  a  period  of  incuba- 
tion before  the  disease  actually  breaks  out.  When  this  occurs  the  specific 
microbe  is  to  be  found  in  large  quantities  either  in  the  blood  OT  in  the  tissues 
of  the  body.  The  disease  is  generally  characterised  by  fever  and  often  by 
local  lesions,  such  as  the  intestinal  ulcers  of  typhoid,  or  the  glandular 
swellings  of  bubonic  plague.  The  micro-organisms  may  develop  in  the 
animal  until  its  death,  or  the  disease  may  terminate  in  recovery  and  the 
total  disappearance  of  the  microbes  from  the  body.  After  recovery  it  is 
found  that  the  patient  is  protected  from  reinfection  by  the  bacterium  which 
was  the  cause  of  the  disease,  and  this  condition  of  immunity  may  last  as 
long  as  the  patient  lives.  The  incidence  of  these  bacterial  diseases  is  not 
the  same  for  all  animals,  so  that  in  the  case  of  many  diseases  we  can  speak 
of  a  natural  immunity  of  certain  animals  for  the  diseases  in  question. 

The  pathogenic  micro-organisms  can,  in  a  number  of  cases,  be  culti- 
vated on  artificial  media  outside  the  body.  It  is  then  found;;  that  they  may 
be  divided  into  two  classes.  One  class,  of  which  the  diphtheria  and  tetanus 
bacilli  are  examples,  secrete  in  the  surrounding  culture  fluid  substances 
which  act  as  virulent  poisons  when  injected  into  animals.  Other  bacteria 
do  not  form  such  extracellular  toxins,  but  in  their  case  it  is  found  that  if 
the  bodies  of  the  bacilli  be  broken  up  the  injection  of  the  contents  of  the 

1030 


THE  CHEMICAL  MECHANISMS  OF  DEFENCE  1031 

bacteria  is  attended  with  poisonoUvS  effects.     The  bacteria  may  be  thus 

classified  according  as  they  produce  extracellular  or  intracellular  toxins. 

We  may  deal  first  with  the  manner  in  which  the  body  reacts  to  the  toxins 

excreted  by  the  first  clasK.     If  a  culture  of  diphtheria  or  tetanus  bacilli  be 

filtered,  the  clear  filtrate  free  from  bacilli  is  found  to  exercise  as  poisonous 

results  as  if  the  culture  itself  of  the  living  bacilli  had  been  employed.     The 

toxins  contained  in  these  fluids  are  extremely  potent.     Thus  five-millionths 

of  a  gramme  of  tetanus  toxin  is  a  fatal  dose  for  a  mouse,  and  -00023  grm. 

would  kill  a  man.     These  weights  apply  to  the  mixture  obtained  by  the 

evaporation  of  the  solution  of  toxin,  so  that  the  pure  toxin  must  be  even 

more  powerful  than  is  represented  in  these  figures.     We  have  at  present  no 

means  of  preparing  a  toxin  in  a  pure  condition,  nor  do  we  know  to  what  class 

of  compounds  it  should  be  assigned.     The  toxin  is  an  unstable  bodv  and  is 

destroyed   by   heating  to   65°  C.     Similar  toxins  are   widely  distributed 

throughout   the   vegetable   and   animal  kingdoms.     Thus   they   form   the 

active  constituent  of  snake  venom  and  of  the  poison  of  scorpions  and 

spiders.     They  also  occur  in  the  seeds  of  castor  oil  and  of  jequirity,  the 

toxins  of  which  seem  to  be  of  protein  character  and  are  known  as  ricin  and 

ahrin.     There  is  a  great  variability  in  the  reaction  of  different  animals  to 

these  toxins.     Thus  to  the  poison  of  tetanus  the  rabbit  is  weight  for  weight 

two  thousand  times  and  the  hen  twenty  thousand  times  more  resistant 

than  the  guinea-pig.     As  in  the  case  of  infection  by  bacteria  themselves, 

a  certain  incubation  time  is  necessary  after  the  introduction  of  the  toxin 

before  its  effects  arc  displayed.     There  is  a  striking  difference  in  this  respect 

between  the  action  of  these  complex  bodies  and  the  action  of  drugs,  such  as 

strychnine  or  morphine.     Thus  by  increasing  the  dose  of  strychnine  it  is 

possible  to  kill  an  animal  within  half  a  minute.     The  period  of  survival 

after  the  injection  of  a  dose  of  toxin  cannot  be  reduced  beyond  a  certain 

limit,  however  much  toxin  be  injected.     Thus  a  lethal  dose  of  diphtheria 

toxin  kills  a  guinea-pig  in  fifteen  hours.     If  ninety  thousand  such  doses  be 

injected  into  a  guinea-pig  it  is  not  possible  to  reduce  the  time  of  survival 

below  twelve  hours.     Another  characteristic  of  these  toxins  is  the  specificity 

of  their  action.     One  kind  of  toxin  may  act  chiefly  on  the  central  nervous 

system,  another  on  the  peripheral  nerves,  another  on  the  red  blood-corpuscles. 

In  this  respect  of  course  they  resemble  ordinary  drugs.     Associated  with. 

however,  and  apparently  a  necessary  condition  of.  this  specific  action  is  the 

actual  combination  which  occurs  between  the  toxin  and  the  organ  on  which  it 

exerts  its  eft'ect.     Thus  tetanus  toxin  has  a  specific  affinity  for  the  central 

nervous  system,  and  may  be  removed  from  a  solution  by  shaking  the  latter 

up  with  an  emulsion  of  brain.     In  spite  of  the  excessively  fatal  character  of 

these  toxins  it  is  possible  to  render  an  animal  immune  to  their  action. 

If  a  dose  of  diphtheria  or  tetanus  toxin  which  is  smaller  than  the  fatal  dose 

be  injected  into  an  animal,  the  latter  may  show  signs  of  injury  from  which 

it  recovers.     When  recovery  is  complete  it  is  found  that  three  or  four  times 

the  fatal  dose  may  be  injected  without  producing  any  evil  effects,  and  this 

process  of  injection  of  toxin  may  be  repeated  in  continually  increasing  doses 


1032  PHYSIOLOGY 

until  the  animal  is  able  to  withstand  a  dose  one  hundred  thousand  times 
as  large  as  that  which  would  have  been  fatal  to  it  in  the  first  instance. 
When  a  condition  of  immunity  has  been  produced  in  this  way  it  is  found 
that  the  blood-serum  of  the  animal  has  the  power  of  neutralising  the  toxin. 
Thus  if  the  blood-serum  from  a  horse  which  has  been  treated  with  large 
doses  of  diphtheria  toxin  be  mixed  with  an  equal  quantity  of  the  toxin  itself, 
the  mixture  may  be  injected  into  susceptible  animals  without  the  produc- 
tion of  any  efiect.  It  is  possible  in  this  way  to  get  a  serum  1  c.c.  of  which 
will  neutrahse  many  fatal  doses  of  the.  toxin,  and  the  antitoxic  serum  may 
be  injected  into  a  susceptible  animal  and  used  to  confer  an  artificial  immunity 
on  the  latter,  or  may  be  injected  into  a  diseased  animal  and  used  thus  as  a 
curative  agent.  Antitoxin  thus  plays  a  great  part  in  modern  therapeutics, 
especially  of  diphtheria.  In  the  case  of  tetanus  the  toxin  has  a  specific 
affinity  for  the  nervous  system  and  apparently  travels  up  the  axis  cylinders 
of  the  nerves  to  the  central  nervous  system.  By  the  time  that  it  has  arrived 
at  the  central  nervous  system,  and  the  spasms  typical  of  tetanus  have  broken 
out,  the  toxin  is  already  so  firmly  bound  to  the  reacting  tissue  that  the  in- 
jection of  antitoxin  into  the  blood-stream  has  little  or  no  effect  on  the 
course  of  the  disorder.  The  use  of  the  tetanus  antitoxin  is  therefore  chiefly 
as  a  prophylactic  agent. 

The  question  of  the  manner  in  which  the  antitoxin  is  able  to  combine 
with  and  neutralise  the  toxin  is  one  of  considerable  practical  importance. 
In  this  process  we  have  relations  presenting  marked  analogies  with  the 
neutrahsation  of  acids  by  bases.  If  we  define  a  unit  of  toxin  as  that  amount 
which  possesses  a  certain  power,  i.e.  which  will  kill  a  guinea-pig  in  so  many 
days,  or  will  cause  the  complete  haemolysis  of  1  c.c.  of  blood  in  two  and  a 
half  hours,  we  can  find  the  amount  of  anti-body  which  is  just  sufficient  to 
neutralise  this  effect,  and  this  amount  of  anti-body  can  be  regarded  also  as 
one  unit.  If  instead  of  one  unit  of  each  we  take  100  units,  the  neutralisation 
is  effected  in  the  same  way.  The  process  is  found,  however,  to  be  more 
complex  when  we  take  100  units  of  toxin  or  lysin  and  attempt  to  neu- 
tralise them  by  the  fractional  addition  of  antitoxin.  In  the  case  of  a  strong 
acid  and  strong  alkah  we  know  that  if  100  c.c.  of  alkali  are  just  sufficient  to 
neutralise  100  c.c.  of  acid,  the  addition  of  50  c.c.  of  alkali  will  leave  half  the 
acid  unneutrahsed.  If,  however,  we  try  the  same  experiment  in  the  case  of 
mixtures  of  toxin  and  antitoxin,  it  will  be  found  that  the  addition  of  50  units 
of  antitoxin  will  neutralise  much  more  than  half  of  the  toxin,  and  the  same 
applies  to  other  bodies  of  this  class.  Ehrlich  has  attempted  to  explain  this 
result  by  assuming  that  in  any  toxin  there  is  a  mixture  of  substances,  some 
having  a  strong  affinity  for  the  antitoxin,  and  others,  which  he  calls  toxones, 
possessing  only  a  shght  affinity.  In  the  50  units  of  toxin  first  added  the 
toxins  would  satisfy  all  their  combining  powers,  whereas  the  toxones  would 
not  begin  to  combine  until  they  were  present  in  large  excess.  Arrhenius 
and  Madsen  have  drawn  an  analogy  between  the  neutralisation  of  toxin  by 
antitoxin  and  the  neutralisation  of  a  weak  acid,  such  as  boracic  acid,  by  a 
weak  base,  such  as  ammonia.     They  show  that  in  this  case  the  general 


THE  CHEMICAL  MECHANISMS  OF  DEFENCE  1033 

course  of  events  would  be  similar  to  that  observed  by  Ehrlich.  At  no  time 
would  there  be  complete  neutralisation,  owing  to  the  fact  that  hydrolysis 
constantly  occurs,  so  that  when  equivalent  quantities  of  each  substance  had 
been  added,  the  fluid  would  still  contain  a  certain  amount  of  free  base 
alongside  of  free  acid,  in  addition  to  the  salt  produced  by  the  combination 
of  the  two.  It  is  impossible,  however,  to  account  for  all  the  phenomena 
presented  in  the  neutrahsation  of  toxin  by  antitoxin  in  this  simple  manner. 
Thus  seventeen  parts  of  ammonia  would  neutralise  exactly  an  equivalent 
quantity  of  boracic  acid,  whether  these  substances  were  dissolved  in  10  c.c. 
or  in  100  c.c.  of  water.  If,  however,  it  be  found  that  1  c.c.  of  antilysin 
exactly  neutraUses  1  c.c.  of  lysin,  these  two  substances  will  no  longer  be  in 
equilibrium  when  the  whole  is  diluted  up  to  10  c.c.  with  water.  If  a  neutral 
mixture  of  lysin  and  antilysin  be  taken  and  filtered  under  pressure  through 
a  gelatin  filter,  no  lysin  or  antilysin  passes  through  the  filter,  so  that  the 
residue  on  the  filter  becomes  concentrated.  On  examining  this  residue  it  is 
found  that  it  has  a  strong  haemolytic  action,  and  the  same  is  true  of  the 
substance  which  may  be  obtained  by  melting  the  gelatin  out  of  the  pores  of 
the  filter.  It  is  evident  that,  even  in  a  neutralised  mixture,  both  free  lysin 
and  free  antilysin,  or  free  toxin  and  free  antitoxin,  are  present,  and  it  needs 
only  the  alteration  of  the  physical  condition  of  the  mixture  in  order  to 
display  the  action  of  one  or  other  of  these  bodies.  How  then  are  we  to 
regard  this  combination  of  toxin  with  antitoxin  ?  Craw  has  pointed  out 
that  the  combination  is  in  all  respects  comparable  to  that  which  occurs 
between  absorbing  surfaces  and  many  dyestuft's.  If  we  place  some  filter 
paper  in  a  solution  of  fuchsin  or  Congo  red,  the  filter  paper  will  take  up  the 
dye  substance.  The  amount  taken  up  by  the  paper  will  increase  with 
increase  in  concentration  of  the  solution.  There  will,  however,  be  a  ten- 
dency to  the  formation  of  false  equilibrium  points,  as  in  the  case  of  the 
reaction  of  toxin  and  antitoxin.  Thus  if  two  solutions  of  fuchsin  be  made 
and  to  each  a  sheet  of  filter  be  added,  but  in  one  case  the  paper  be  added  at 
once,  and  in  the  other  case  in  three  parts  at  intervals  of  twelve  hours,  at 
the  end  of  thirty-six  hours  the  paper  which  has  been  added  in  parts  will 
have  removed  more  dyestuff  from  the  solution  than  is  the  case  where  the 
whole  amount  of  paper  was  added  at  once.  In  the  same  way,  when  treating 
a  suspension  of  bacilli  Avith  an  agglutinating  serum,  it  is  found  that  the 
successive  addition  of  the  bacillary  suspension  to  the  serum  removes  more 
agglutinin  from  the  solution  than  when  the  addition  is  made  at  one  time. 

The  interactions  therefore  between  these  bodies  must  be  looked  upon  as 
special  examples  of  the  group  of  phenomena  known  as  adsorption,  such  as 
the  adsorption  of  iodine  from  solutions  by  charcoal,  of  iodine  from  water  by 
starch,  or  of  ammonia  by  charcoal.  The  exact  adsorption  which  takes  place 
must  be  a  function  of  the  chemical  configuration  of  the  substance  forming  the 
surface,  since  otherwise  it  would  be  impossible  to  account  for  the  extremolv 
specific  character  of  the  interaction  between  toxins  and  their  corresponding 
antitoxins.  The  interaction  must  therefore  be  assigned  to  that  special 
class,  in  which  we  have  already  placed  the  action  of  ferments,  which  is  not 

33* 


1034  PHYSIOLOGY 

entirely  chemical  nor  entirely  physical,  but  depends  for  its  existence  on  a 
co-operation  of  both  chemical  and  physical  factors. 

How  are  we  to  accomit  for  the  production  of  the  antitoxin  as  a  result 
of  the  injection  of  toxins  into  the  body,  a  production  which  is  proportional 
to,  but  far  transcending  in  amount,  the  toxin  injected  ?  In  all  the  specula- 
tions on  the  mode  of  production  and  action  of  antitoxins  an  important 
part  has  been  played  by  a  conception  put  forward  by  Ehrhch  in  1885  of  the 
nature  of  the  living  protoplasmic  molecule.  According  to  this  conception, 
which  is  spoken  of  as  the  '  side  chain  theory,'  each  unit  of  living  matter 
consists  of  a  centrally  placed  protein  group  with  a  number  of  side-chains 
attached  to  it,  on  the  analogy  of  the  hypothetical  configuration  of  the 
benzene  ring,  to  each  corner  of  which  may  be  attached  an  aliphatic  chain. 
To  explain  the  phenomena  of  nutrition  and  oxidation  Ehrlich  regarded  some 
of  these  side-chains  as  corresponding  to  unoxidised  food  substances,  while 
others  of  the  side-chains  had  a  strong  affinity  for  oxygen  and  might  be 
regarded,  when  fully  saturated  with  this  substance,  as  peroxide  in  character. 
Activity  in  such  a  unit  would  be  associated  with  interaction  between  these 
two  sets  of  side-chains.  As  a  result  the  food  chain  would  be  converted  to 
carbon  dioxide  and  an  affinity  left  unsaturated  until  it  could  take  up  another 
food-molecule.  In  the  same  way  the  oxygen  side-chain,  having  lost  the 
greater  part  of  its  oxygen,  would  have  a  strong  affinity  for  this  element  and 
would  re-satarate  itself  at  the  expense  of  the  oxygen  brought  to  it  by  the 
blood.  Ehrlich  regards  the  toxins  as  partaking  essentially  of  the  same 
character  as  the  protoplasmic  molecule,  as  being  in  fact  protoplasmic 
fragments  difiering  only  from  the  protoplasm  of  the  cell  in  the  greater 
simphcity  of  arrangement  of  their  side-chains.  According  to  him  the  central 
group,  or  nucleus,  of  the  toxin  possesses  two  side-chains,  one  of  which  by  its 
stereomeric  configuration  is  peculiarly  adapted  to  fit  on  to  the  organ  or  cell 
of  the  body  which  the  toxin  or  active  body  attacks,  and  is  known  as  the 
haptophore  group,  and  another  side-chain,  the  toxophore  group,  which  is 
responsible,  when  the  toxin  is  once  anchored,  for  the  destructive  changes 
wrought  by  the  toxin  on  the  cell  of  the  body.  The  antitoxins  or  antilysins 
are  thus  supposed  to  act  in  virtue  of  their  adaptation  to  the  haptophore 
group,  so  as  to  combine  with  the  toxin  or  lysin  and  prevent  these  from 
exercising  their  injurious  effects  on  the  body.  Ehrlich  has  shown  that  in 
many  toxins  the  toxophore  can  undergo  weakening  or  destruction  without 
any  alteration  of  the  haptophore  group  ;  such  modifications  he  designates 
as  '  toxoids.'  They  have  the  same  combining  power  for  antitoxins  as  is 
possessed  by  the  ordinary  toxins,  but  are  either  without  physiological  effect, 
or  their  poisonous  characters  are  only  a  fraction  of  that  possessed  by  ordinary 
toxin. 

The  formation  of  antitoxins  is  accounted  for  (or  rather  described)  on  this 
hypothesis  in  the  following  manner.  When  a  receptor  side-chain  of  the  cell 
is  occupied  by  becoming  attached  to  the  haptophore  group  of  the  toxin, 
this  side-chain  is,  so  to  speak,  shut  out  from  the  normal  activities  of  the  cell. 
A  defect  is  thus  produced  in  the  cell  which  the  latter  endeavours  to  adapt 


THE  CHEMICAL  MECHANISMS  OF  DEFENCE 


1035 


itself  to  by  the  production  of  other  side-chains  of  the  same  character.  It 
may  be  regarded  as  a  general  rule  in  living  tissues  that  a  reaction  tends  to 
be  an  over-reaction,  so  that  the  compensation  by  the  cell  should  more  than 
made  good  the  defect  produced  by  the  attachment  of  the  toxin.  We  thus 
get,  not  one,  but  a  number  of  side-chains  produced  of  the  same  character 
as  that  occupied  by  the  toxin  molecule,  and  therefore  able  also  to  act  as 
receptors  for  the  haptophore  group  of  the  toxin.  These  new  receptor  side- 
chains,  being  produced  in  excess,  are  supposed  by  Ehrlich  to  be  thrown  off 


Fig. 


483.  Schematic  representation  of  formation  of  antitoxin  as  side-chains  of  pro- 
toplasmic molecule.  The  black  bodies  are  the  toxin  molecules  which  fit  by 
their  haptophore  end  on  to  the  side-chains  of  the  cell.     (Ehrlich.) 


from  the  cell  and  to  circulate  in  the  body-fluids  (Fig.  483,  4).  A  number 
of  protoplasmic  fragments  are  thus  set  free  which  have  a  specific  power  of 
uniting  with  the  toxin,  and  it  is  this  excess  of  side-chains  thro\Ani  off  from 
the  cell  which  represents  the  antitoxin  molecules  found  circulating  in  the 
blood  after  the  injection  of  toxins.  It  will  be  noted  that  this  theory,  though 
chemical  in  form,  is  really  purely  biological.  It  does  not  explain  the 
phenomena  by  reference  to  the  known  laws  of  chemistry,  but  is  a  manner  of 
viewing  the  biological  phenomena  which  facilitates  their  description  and 
discussion  and  enables  us  to  classify  the  very  complex  phenomena  of 
immunity  in  a  more  or  less  imperfect  fashion. 

The  property  of  giving  rise  to  anti-bodies  on  injection  into  an  animal 


1036  PHYSIOLOGY 

is  not  confined  to  toxins,  a  large  number  of  substances,  e.g.  egg  albumin, 
serum,  proteins,  ferments,  albumoses,  partaking  of  the  same  property.  All 
such  substances  are  classed  together  as  antigens.  Thus  human  serum 
injected  into  a  rabbit  produces  in  the  rabbit's  serum  some  body  which  will 
give  a  precipitate  when  mixed  with  human  serum  even  in  minute  traces. 
This  precipitin  formation  is  specific,  so  that  it  may  be  used  as  a  test  for  the 
origin  of  any  unknown  specimen  of  serum.  In  the  same  way  rennet  fer- 
ment when  injected  gives  rise  to  the  production  of  an  anti-rennin  which  will 
neutralise  the  action  of  this  ferment  on  milk.  Antigens  are  all  colloidal  in 
character  and  probably  optically  active.  Ordinary  drugs  do  not  give  rise 
to  the  formation  of  anti-bodies,  a  necessary  condition  being  apparently 
some  similarity  in  the  molecular  structure  of  the  antigen  to  the  proto- 
plasm of  the  animal  on  which  it  acts  and  to  which  it  becomes  linked  by 
its  haptophore  group. 

CYTOLYSINS.  The  bacteria  of  tetanus  and  diphtheria  cannot  exist  in 
the  body,  infection  by  them  being  limited  to  a  surface  or  abscess  cavity. 
When  a  disease  involves  infection  of  the  tissues  themselves  by  living  micro- 
organisms, somewhat  more  complicated  mechanisms  are  brought  into  play 
for  the  defence  of  the  organism.  We  have  already  seen  that  normal  blood- 
serum  may  exert  a  paralytic  or  destructive  action  on  bacteria.  Light  has 
been  thrown  on  the  factors  involved  in  this  destruction  by  a  study  of  the 
phenomenon  of  hcemolysis,  i.e.  the  destruction  of  red  blood- corpuscles. 
Normal  goat's  serum  may  be  mixed  with  the  red  blood-corpuscles  of  the 
sheep  without  any  injury  to  the  latter.  If,  however,  sheep's  corpuscles, 
previously  washed  in  normal  sahne,  be  injected  at  intervals  of  a  few  days 
into  a  goat,  the  goat's  serum  is  found  to  have  acquired  the  power  of  rapidly 
dissolving  the  red  blood-corpuscles.  This  hsemolytic  power  is  obvious,  since 
it  is  only  necessary  to  mix  the  serum  and  the  washed  blood-corpuscles 
together  and  allow  the  mixture  to  stand  in  a  narrow  tube.  The  corpuscles 
rapidly  sink  to  the  bottom,  leaving  the  colourless  serum  above,  unless 
haemolysis  has  occurred,  in  which  case  the  serum  will  be  of  a  transparent 
red  colour.  If  the  heemolytic  serum  be  heated  to  55°  C.  it  is  found  to  have 
lost  its  power  of  dissolving  sheep's  corpuscles.  This  power  is  at  once  restored 
if  to  the  heated  serum  be  added  any  normal  blood-serum,  even  of  the  sheep 
itself.  It  seems  therefore  that  two  substances  are  involved  in  the  haemolysis, 
namely,  (a)  a  substance  present  in  most  normal  sera  which  is  destroyed  at 
a  temperature  of  60°  C.  and  has  been  called  the  complement,  and  (6)  a 
substance  present  in  the  serum  only  as  a  result  of  the  previous  injection  of 
some  species  of  red  blood-corpuscle,  which  is  resistant  to  the  action  of  heat, 
and  is  called  the  amboceptor.  The  reason  for  these  names  will  be  at  once 
apparent  from  the  following  experiment.  Haemolytic  goat's  serum  is 
mixed  with  sheep's  red  blood-corpuscles  and  the  whole  mixture  kept  at  0°  C, 
at  which  temperature  haemolysis  is  indefinitely  delayed.  After  some  time 
the  corpuscles  are  separated  by  means  of  the  centrifuge.  On  testing  the 
supernatant  fluid  it  is  found  to  have  no  action  on  sheep's  corpuscles,  though 
it  still  possesses  the  power  of  activating  another  specimen  of  serum  which 


THE  CHEMICAL  MECHANISMS  OF  DEFENCE  1037 

has  been  lieated.  The  serum  separated  from  the  corpuscles  has  thus  Ujst  the 
amboceptor,  but  retained  the  complement.  The  amboceptor  is  found  to  have 
attached  itself  to  the  red  blood-corpuscles.  If  these  be  washed  and  then 
added  to  normal  sheep's  serum,  i.e.  serum  containing  the  complement,  they 
are  rapidly  dissolved.  When  solution  has  taken  place  both  complement  and 
amboceptor  are  found  to  have  disappeared.  The  function  of  the  amboceptor 
thus  seems  to  be  to  enable  the  complement  already  present  in  normal  serum 
to  act  upon  the  red  blood-corpuscles.  We  may  regard  the  amboceptor 
therefore  as  having  two  haptophore  groups,  one  of  which  anchors  on  to  the 
red  blood-corpuscle,  while  the  other  attaches  itself  to  the  complement 
CFig.  484,  7).     The  amboceptor  'plus  the  complement  thus  comes  to  resemble 


Fig.  484.     Diagram  to  show  the  relation  of  amboceptor  and  complement 
to  the  animal  cell  (7)  and  to  red  cor})uscles  (8).     (Ehklich.) 

the  toxin  molecule,  having  a  free  haptophore  group  at  one  end  and  a  toxo- 
phore  group  (the  complement)  at  the  other  end.  The  reaction  to  the  injec- 
tion of  the  red  blood-corpuscles  consists  in  the  formation  of  the  amboceptor, 
which  is  essentially  the  anti-body  of  the  red  blood-corpuscle  (Fig.  484,  8). 
Similar  specific  anti-bodies  effecting  the  dissolution  of  cells  or  organisms 
may  be  produced  by  the  injection  of  various  species  of  bacterium  or  of 
animal  cells,  such  as  leucocytes,  spermatozoa,  liver-cells,  &c.,  and  there  can 
be  no  doubt  that  bacteriolytic  substances  play  a  considerable  part  in  acquired 
immunity. 

OPSONINS,  in  some  cases  the  antibodies  produced  by  the  injection 
of  living  or  dead  micro-organisms  do  not  bring  about  actual  destruction  of 
the  bacteria,  but  alter  them  in  such  a  way  as  to  make  them  more  susceptible 
to  the  action  of  the  phagocytes.  If  washed  white  blood-corpuscles  be  mixed 
with  micrococci,  such  as  those  found  in  an  ordinary  boil,  they  are  found  to 
take  up  the  micro-organisms  in  considerable  numbers.  The  numbers  taken 
up  are  much  increased  in  the  presence  of  serum  derived  from  an  individual 
who  has  received  repeated  minute  injections  of  the  dead  micrococci  in 
question.  To  the  substances  in  the  serum  which  thus  prepares  the  micrococci 
for  ingestion  by  the  phagocytes  Wright  has  given  the  name  of  opsonins. 


1038  PHYSIOLOGY 

The  opsonic  index  of  the  leucocytes  of  any  individual  in  reference  to  a  given 
species  of  microbe  is  determined  by  observing  the  number  of  the  microbes 
taken  up  by  the  leucocytes  after  treatment  with  the  serum  of  the  individual 
and  comparing  it  with  the  number  taken  up  by  the  same  leucocytes  when  the 
bacteria  have  been  treated  with  the  serum  of  an  average  individual. 

We  thus  see  that  immunity,  whether  innate  or  acquired,  is  extremely 
complex  in  character  and  may  depend  on  one  or  more  of  many  factors. 
The  immunity  of  an  animal  to  any  given  infection  may  be  determined  by 
the  absence  of  receptor  groups  in  his  body  for  the  toxin  excreted  by  the 
microbe  responsible  for  the  infection,  or  by  the  fact  that  the  receptor  groups 
are  present  but  are  confined  to  tissues  on  which  the  toxophore  group  can 
have  no  influence.  Thus,  e.g.,  an  attachment  of  the  tetanus  toxin  to  a 
connective- tissue  cell  would  be  without  effect  on  the  health  of  the  body. 
Again,  immunity  may  be  due  to  the  efficacy  of  the  phagocytes,  either  of  the 
fluids  or  the  connective  tissues,  in  ingesting  and  destroying  the  micro- 
organism, and  this,  as  we  have  seen,  may  again  be  dependent  on  the  presence 
or  absence  in  the  body-fluids  of  substances  which,  while  not  destroying  the 
micro-organisms,  render  them  more  accessible  to  the  action  of  the  phago- 
cytes. In  those  cases  where  the  infecting  organism  secretes  a  specific  toxin, 
the  main  line  of  defence  and  the  main  factor  in  the  production  of  immunity 
is  the  formation  of  specific  antitoxins  to  the  poison  in  question.  Finally 
there  may  be  produced  as  a  result  of  the  excess  of  micro-organisms  substances 
such  as  the  amboceptors,  which  render  the  micro-organisms  susceptible  to. 
destruction  by  the  complements  or  cytases  normally  present  in  the  circu- 
lating fluids  and  possibly  themselves  derived  from  the  activity  or  destruction 
of  the  leucocytes  and  other  phagocytes  of  the  body. 

In  this  short  description  we  have  only  been  able  to  touch  upon  the  most 
salient  features  of  the  immunity  problem.  The  question  enters  strictly  into 
physiology  since,  as  we  have  seen,  it  involves  adaptations  on  the  part  of 
the  organism  to  change  in  itself  or  its  environment.  For  the  practical 
application  of  these  facts,  as  well  as  the  consideration  of  the  minuter  details 
and  exceptions,  we  must  refer  the  student  to  works  especially  dealing  with 
the  subjects  of  infectious  diseases  and  immunity. 


CHAPTER  XVI 
RESPIRATION 

SECTION  I 

THE  MECHANICS  OF  THE  RESPIRATORY  MOVEMENTS 

In  unicellular  animals  the  interchange  of  gases,  i.e.  the  intake  of  oxygen  and 
the  output  of  carbon  dioxide,  is  as  a  rule  carried  out  by  processes  of  diffusion 
occurring  at  the  surface  of  the  cell.  With  increased  size  of  the  organism 
the  surface  becomes  insufficient  for  this  purpose,  and  special  organs  make 
their  appearance  for  presenting  a  large  extent  of  surface  to  the  surrounding 
medium.  In  the  multicellular  animals  the  actual  process  of  tissue  respira- 
tion is  carried  out  between  the  internal  medium,  lymph,  blood,  &c.,  and 
the  individual  cells,  and  the  use  of  the  special  organ  of  respiration  is  to  bring 
the  circulating  internal  medium  in  intimate  relation  over  a  large  area  with 
the  surrounding  fluid,  whether  air  or  water.  In  insects  we  find  a  large 
branched  system  of  tubes,  the  tracheae,  which  contain  air  and  are  distributed 
to  the  finest  tissues,  renewal  of  the  air  in  the  tubes  being  provided  for  by 
special  respiratory  movements.  In  most  water  animals  the  respiratory 
organ  is  known  as  the  gills,  and  presents  a  large  surface  well  supplied  with 
circulating  blood  over  which  a  continual  stream  of  the  surrounding  water 
is  kept  up.  In  all  these  animals  therefore  we  can  distinguish  two  processes, 
viz.  (1)  the  interchange  of  gases  between  the  tissue-cells  and  the  surrounding 
lymph,  '  internal  respiration  '  ;  (2)  the  interchange  of  gases  between  the 
circulating  fluid  and  the  external  medium,  '  external  respiration.'  In  all 
air-breathing  vertebrates  the  organs  of  external  respiration,  the  lungs, 
arise  as  paired  diverticula  of  the  anterior  part  of  the  alimentary  canal. 
The  renewal  of  the  air  in  the  air-sacs  formed  from  these  diverticula  is 
effected  by  alternate  increase  and  diminution  in  their  size  caused  by  the 
movements  of  respiration,  while  a  rapid  circulation  of  blood  is  carried  out 
through  a  fine  meshwork  of  capillaries  just  underneath  the  surface  of  the 
sacs.  In  man  the  organs  of  external  respiration,  the  lungs,  are  built  up  in  the 
following  way  : 

The  trachea  or  windpipe,  a  wide  tube  about  \\  inches  long,  divides 
below  into  two  main  branches — bronchi;  and  these  subdivide  again  and 
again,  becoming  gradually  smaller.  The  terminal  ramifications  or  bron- 
chioles open  into  rather  wider  parts — the  injundibula,  the  walls  of  which  are 

1039 


1040 


PHYSIOLOGY 


beset  with  a  number  of  minute  cavities,  the  alveoli.  The  larger  tubes  are 
kept  patent  by  rings  or  plates  of  cartilage  in  their  walls.  The  smaller  tubes 
have  no  cartilage,  their  walls  being  composed  of  fibrous  and  elastic  tissue  and 
a  coating  of  unstriated  muscular  fibres,  which  are  able  by  their  contraction 
to  occlude  the  passage.  The  whole  system  of  tubes  is  Hned  with  a  layer  of 
epithehum — cihated  columnar  in  the  trachea,  bronchi,  and  bronchioles,  and 
cubical  over  the  parts  of  the  infundibulum  not  occupied  by  air-cells.  The 
alveoU  are  the  special  respiratory  parts  of  the  lung.  Their  walls  are  com- 
posed of  connective  tissue  containing  a  large  number  of  elastic  fibres,  and 
are  covered  internally  by  a  single  layer  of  extremely  thin  large  flattened 

cells.  The  alveoh  are  closely  packed  together, 
so  that  in  a  section  of  the  lung  an  alveolus  is 
seen  to  be  in  contact  with  others  on  all  sides. 
Immediately  below  the  squamous  epithehum 
ramify  blood-capillaries  derived  from  the  pul- 
monary artery.  These  form  a  close  network, 
and  the  blood  in  them  is  in  proximity  to  air  on 
two  sides,  being  separated  from  the  air  in  the 
alveoli  only  by  the  thin  endothelial  cells  of  the 
capillary  wall  and  the  flattened  cells  lining  the 
alveoli. 

The  lungs  in  their  development  grow  out 
from  the  fore  part  of  the  ahmentary  canal  into 
the  front  part  of  the  body- cavity  on  each  side — 
the  pleural  cavity.  The  surrounding  body- walls 
become  strengthened  by  the  formation  of  the 
ribs,  so  that  the  lungs  are  suspended  in  a  bony 
cage-work,  the  thorax.  Their  outer  surface  is 
covered  with  a  special  membrane,  the  pleura, 
which  is  reflected  on  to  the  wall  of  the  thorax 
from  the  roots  of  the  lungs,  and  completely  hnes 
the  cavity  in  which  they  he.  The  surface  of  the 
pleura  facing  the  pleural  cavity  is  hned  with  a  continuous  layer  of  flattened 
endothelial  cells,  and  is  kept  moist  by  the  secretion  of  lymph  into  the 
cavity.  Thus,  being  attached  to  the  thorax  only  where  the  bronchi  and 
great  vessels  enter,  the  lungs  are  able  to  glide  easily  over  the  inner  surface 
of  the  thorax,  with  which  under  normal  circumstances  they  are  in  intimate 
contact. 

A  constant  renewal  of  the  air  in  the  lungs  is  secured  by  movements  of 
the  thorax,  which  constitute  normal  breathing.  With  inspiration  the  cavity 
of  the  thorax  is  enlarged,  and  the  lungs  swell  up  to  fill  the  increased  space. 
The  capacity  of  the  air-passages  of  the  lungs  being  thus  increased,  air  is 
sucked  in  through  the  trachea.  The  movement  of  inspiration  is  followed 
by  that  of  expiration,  which  causes  diminution  of  the  capacity  of  the  thorax 
and  expulsion  of  air.  At  the  end  of  expiration  there  is  normally  a  slight 
pause.     The  number  of  respirations  in  the  adult  is  about  17  or  18  a  minute. 


Fig.  485.  Diagrammatic  re- 
presentation of  the  struc- 
ture of  the  lungs.  The 
trachea  branches  into  two 
bronchi,  which  subdivide 
again  and  again  before 
ending  in  the  infundibula. 
(From  Yeo.) 


MECHANICS  OF  RESPIRATORY  MOVEMENTS  1041 

This  is,  however,  much  influoiiced  by  various  coiulitious  of  the  body,  and 
also  by  the  age  of  the  individual.  Thus  a  new-born  child  breathes  about  44 
times  a  minute,  a  child  of  five  about  2(5  times,  a  man  of  twenty-five  about  16, 
and  of  fifty  about  18.  The  frequency  is  increased  by  any  muscular  efiort, 
so  that  even  standing  up  increases  the  number  of  respirations.  These 
movements  are  much  affected  by  psychical  activity  ;  they  are  to  a  certain 
extent  under  the  control  of  the  will,  although  they  can  occur  in  an  animal 
deprived  of  its  brain,  and  are  normally  carried  out  without  any  special  act 
of  volition.  We  can  breathe  fast  or  slow  at  pleasure,  and  can  even  cease 
breathing  for  a  time.  It  is  impossible,  however,  to  prolong  this  respiratory 
standstill  for  more  than  a  minute  ;  the  need  of 
breathing  becomes  imperative,  and  against  our 
will  we  are  forced  to  breathe. 

With  every  inspiration  the  cavity  of  the  thorax 
is  enlarged  in  all  dimensions,  from  above  down- 
wards by  the  contraction  of  the  diaphragm,  and 
in  its  transverse  diameters  by  the  movements  of 
the  ribs.* 

The  diaphragm  is  a  sheet  separating  the  cavity 
of  the  chest  from  that  of  the  abdomen.  It  con- 
sists of  a  central  tendon  which  forms  an  arched 

double  cupola,  to  the  circumference  of  which  are     ^^^-  -l^^.    Diagram  show- 
,      ,  ,      „,  mi       T      1  •  1  iog  movements  of   dia- 

attached  muscle-fibres.    1  he  diaphragmatic  muscles        phragm  in  respiration, 
present  two  main  divisions,  namely,  (1)  the  spinal        i?',  inspiratory  position ; 
or  crural  part,  the  fibres  of  which  arise  from  the     fyEo  V^^^^^  ^^^  ^°^^  ^°"" 
upper  three  or  four  lumbar  vertebrae  and   from 

the  arcuate  ligaments  and  are  inserted  into  the  posterior  margin  of 
the  central  tendon ;  and  (2)  the  sterno- costal  part,  which  arises  by  a 
series  of  digitations  from  the  cartilages  and  adjoining  bony  parts  of 
the  lower  six  ribs  and  from  the  back  of  the  ensiform  process.  These  latter 
fibres  pass  backwards  as  they  ascend.  In  the  cavity  of  the  larger  dome  on 
the  right  side  lies  the  liver,  while  the  smaller  dome  on  the  left  side  is  occupied 
by  the  spleen  and  stomach.  These  viscera  in  the  normal  condition  are 
pressed  against  the  under-surface  of  the  diaphragm  by  the  elasticity  of  the 
abdominal  walls.  The  central  part  of  the  diaphragm  is  thus  pressed  up  into 
the  chest,  partly  by  the  intra-abdominal  pressure  and  partly  by  the  elastic 
traction  of  the  distended  lungs.  The  upper  surface  of  the  central  tendon  is 
united  to  the  pericardium.  This  part,  during  expiration,  is  the  deepest  part 
of  the  middle  portion  of  the  diaphragm.  Towards  the  back  of  the  pericardial 
attachment  the  central  tendon  is  pierced  for  the  passage  of  the  inferior  vena 
cava.  In  expiration  the  lateral  muscular  zone  of  the  diaphragm  lies  in 
contact  mth  the  lower  part  of  the  thoracic  wall.  During  inspiration  the 
muscle  fibres  contract  and  draw  the  central  tendon  do\\niwards,  so  that  the 

*  The  student  is  advised  to  consult  the  article  by  Keith  on  the  '  Mechanism  of 
Respiration  in  Man '  for  a  fuller  account  of  this  subject  (L.  Hill's  '  Further  Advances 
in  Physiology,'  1909). 


1042  PHYSIOLOGY 

lower  siu'face    of  the   lungs  descends.      The   enlargement  of    the    lungs 
at  the  lower  part  of  the  thorax  is  aided  by  the  abduction  of  the  floating  ribs, 
produced  by  the  contraction  of  the  quadratus  lumborum  and  deep  costal 
muscles.     In  this  contraction  the  diaphragm  presses  on  the  contents  of  the 
abdomen,  so  that  the  abdomen  swells  up  with  each  inspiratory  movement. 
The  middle  of  the  central  tendon,  where  the  heart  lies,  moves  less  than  the 
two  domes,  and  the  part  where  the  vena  cava  passes  through  the  tendon 
is  practically  stationary  during  normal  respiration.     In    deep  inspiration, 
however,  both  this  part  as  well  as  the  rest  of  the  pericardial  attachment  is 
forcibly  depressed  towards  the  abdomen.     In  quiet  breathing,  when  ob- 
served by  the  Rontgen  rays,  the  mean  descent  of  the  right  dome  in  inspiration 
has  been  found  to  be  about  12-5  mm.,  and  of  the  left  dome  12  mm.     We  may 
say,  roughly,  that  the  average  descent  of  the  diaphragm  during  normal 
respiration  is  about  half  an  inch.     The  viscera  and  the  intra-abdominal 
pressure  play  an  important  part  in  determining  the  movement  of  the  dia- 
phragm, and  especially  in  preserving  the  abduction  of  the  lower  ribs  and  so 
furnishing  a  fixed  point  for  the  muscular  fibres  of  the  diaphragm.     If  the 
contents  of  the  abdomen  are  removed  from  a  living  animal  the  ribs  are  drawn 
inwards  every  time  the  diaphragm  contracts.     In  children  with  weak  chest 
walls  and  with  respiratory  obstruction  we  may  often  see  a  depression  round 
the  lower  part  oi  the  chest  corresponding  to  the  lower  border  of  the  lungs. 
It  corresponds  to  the  line  at  which  the  diaphragm  leaves  the  chest  wall,  so 
that  the  distending  force  of  the  abdominal  pressure  on  the  bony  walls  of  the 
thorax  abruptly  gives  place  to  the  pull  of  the  distended  lung.     The  con- 
traction of  the  diaphragm  lasts  four  to  eight  times  longer  than  a  simple 
contraction  or  muscle-twitch.     It  may  be  regarded  therefore  as  a  short 
tetanus. 

The  enlargement  in  the  other  diameters  is  effected  by  an  elevation  of  the 
ribs.  Each  pair  of  corresponding  ribs,  which  are  articulated  behind  with 
the  spinal  column  and  in  front  with  the  sternum,  forms  a  ring  directed 
obliquely  from  behind  downwards  and  forwards.  With  each  inspiratory 
movement  the  ribs  are  raised,  the  obliquity  becomes  less,  and  the  horizontal 
distance  between  sternum  and  spinal  column  is  therefore  increased.  More- 
over the  ribs  from  the  first  to  the  seventh  increase  in  length  from  above 
downwards,  so  that  when  they  are  raised,  the  sixth  rib,  for  instance,  occupies 
the  situation  previously  taken  by  the  fifth,  and  the  transverse  diameters  of 
the  thorax  at  this  height  are  increased.  With  each  inspiration  there  is  a 
rotation  of  the  ribs.  In  the  expiratory  condition  they  are  so  situated  that 
their  outer  surfaces  are  directed  not  only  outwards  but  also  downwards. 
As  they  are  raised  by  the  inspiratory  movements,  they  rotate  on  an  axis 
directed  through  the  fore  and  hind  ends  of  the  rib,  so  that  their  outer 
surfaces  are  turned  directly  outwards.  In  this  way  a  certain  enlargement 
of  the  thoracic  cavity  is  produced.  As  the  thorax  is  raised  there  is  always 
some  stretching  of  the  rib-cartilages. 

In  expiration  the  processes  are  reversed,  and  the  cavity  of  the  thorax 
is  diminished  in  all  three  dimensions. 


MECHANICS  OF  RESPIRATORY  MOVEMENTS  1043 

The  movements  of  the  thorax  are  effected  by  means  of  muscles.  Inspira- 
tion is  performed  by  the  following  muscles  : 

The  diaphragm,  which  is  the  most  important,  and  almost  suffices  alone 
to  carry  out  quiet  respiration. 

The  external  intercostal  muscles,  which  shorten  and  so  raise  the 
ribs. 

The  serratus  posticus  superior. 

It  is  probable  that  an  important  part  is  played  even  under  normal 
circumstances  in  the  respiratory  movements  by  the  extension  of  the  spinal 
column.  This  movement,  which  is  specially  marked  at  the  upper  part  of 
the  thorax,  causes  an  increase  in  all  three  diameters  of  this  cavity.  The 
levatores  costarum,  which  are  often  included  in  inspiratory  movements,  are 
so  inserted  into  the  ribs  as  to  be  unable  to  influence  their  movements. 
They  are  concerned,  not  in  respiration,  but  in  lateral  movements  of  the 
spine. 

These  muscles  are  the  only  ones  normally  engaged  in  carrying  out  in- 
spiration. When,  in  consequence  of  muscular  exertions  or  from  any  other 
cause,  the  inspiratory  efforts  become  more  forcible,  a  large  number  of 
accessory  muscles  are  brought  into  play.     These  are  : 

The  scaleni, 

Sterno- mastoid. 

Trapezius, 

Pectoral  muscles. 

Rhomboids,  and 

The  serratus  anticus. 

Normal  expiration  is  chiefly  effected  passively.  When  the  inspiratory 
muscles  cease  to  contract,  the  lungs,  which  were  stretched  by  the  previous 
inspiration,  contract  by  virtue  of  the  elastic  tissue  they  contain,  and  the 
thorax  itself  sinks  by  its  own  weight,  and  by  the  elastic  reaction  of  the 
stretched  costal  cartilages. 

It  must  be  remembered,  however,  that  in  a  position  of  rest  the  elasticity 
of  the  thorax  is  opposed  to  the  elasticity  of  the  lungs.  Elasticity  of  the 
chest  wall  would  therefore  tend  to  produce  inspiration.  This  factor  would 
tend  to  make  inspiration  easier  at  its  onset,  but  would  also  present  an 
impediment  to  the  carrying  out  of  expiration,  so  that  towards  the  end  of  this 
act  there  is  need  for  the  active  co-operation  of  muscular  contractions.  It 
seems  possible  that  more  or  less  muscular  activity  of  the  expiratory  muscles 
is  alternated  with  that  of  the  inspiratory  muscles.  In  fact  Sherrington's 
results  on  the  co-ordination  of  muscular  movements  would  tend  to  make  us 
assume  inhibition  of  the  tone,  e.g.  of  the  abdominal  muscles,  during  inspira- 
tion, and  active  augmentation  of  their  tone  during  expiration.  Where  the 
tone  of  the  muscles  is  entirely  lost,  e.g.  in  the  condition  of  viscero-ptosis, 
it  has  been  observed  that  the  diaphragm  is  thrown  out  of  action,  breathing 
being  chiefly  carried  out  by  an  elevation  of  the  upper  part  of  the  thorax. 
Probably  under  normal  circumstances  the  internal  intercostal  muscles 
also  contract  with  each  expiration. 


1044 


PHYSIOLOGY 


Although  the  action  of  the  intercostal  muscles  has  been  a  subject  of  debate,  physio- 
logical experiments  serve  on  the  whole  to  confirm  the  view  first  put  forward  byHamberger 
and  based  on  a  coasideration  of  the  direction  of  the  fibres.  The  external  intercostals 
pass  from  one  rib  to  the  next  below  downwards  and  forwards.  Hence  if  a  pair  of  ribs  be 
isolated  from  the  rest  of  the  chest  wall,  leaving  the  vertebral  and  costal  attachments 
intact,  contraction  of  these  muscles  will  cause  a  rise  of  both  ribs.  This  result  will  be 
evident  from  a  consideration  of  Fig.  487,  where  ab  is  a  fibre  of  the  external  intercostal 
muscles,  passing  from  the  rib  vs  to  be  attached  to  the  rib  v's'  at  b.  When  ab  contracts, 
the  tension  it  exerts  on  its  two  attachments  can  be  resolved  into  two  components  ac  acting 


Fig.  488. 


downwards  and  bd  acting  upwards,  bd,  however,  acts  at  the  end  of  the  long  lever  bv\ 
whereas  ac  acts  at  the  end  of  the  short  lever  av.  Hence  the  raising  effect  will  overcome 
the  depressing  effect,  and  both  ribs  will  rise. 

The  fibres  of  the  internal  intercostals  run  in  the  opposite  direction  to  the  external 
muscles,  and  from  a  consideration  of  Fig.  488  it  is  evident  that  their  effect  will  be  to 
depress  any  pair  of  ribs,  thus  acting  as  expiratory  muscles. 

Owing  to  the  fact  that  the  costal  cartilages  make  an  angle  with  the  bony  ribs,  the 
fibres  of  prolongation  of  the  internal  intercostals,  musculi  inter  car  tilaginei,  have  the 
same  relation  to  their  attachments  that  the  external  intercostals  have  to  the  bony  ribs. 
Their  action  therefore  must  be  to  raise  the  cartilages  and  flatten  out  the  angle  between 
the  cartilaginous  and  bony  ribs  so  that  they  must  act  with  the  external  intercostals  as 
inspiratory  muscles. 

In  forced  expiration  a  large  number  of  muscles  may  take  part — such  as 
the  serratus  posticus  inferior,  and  the  muscles  forming  the  wall  of  the 
abdomeU;  i.e.  the  rectus,  obliquus,  and  transversus  abdominis  muscles. 

As  the  lungs  are  distended  with  each  inspiration  their  position  changes 
in  relation  to  the  thoracic  wall.  All  parts  are  not  equally  distensible  in  the 
normal  position  of  the  lungs.  There  are  three  areas  which  are  in  contact 
with  the  nearly  stationary  parts  of  the  thoracic  wall  and  cannot  therefore 
be  directly  expanded.  These  are  (1)  the  mediastinal  surface  in  contact  with 
the  pericardium  and  structures  of  the  mediastinum  ;  (2)  the  dorsal  surface  in 
contact  with  the  spinal  column  and  with  the  spinal  segments  of  the  ribs  ; 
(3)  the  apical  surface  lying  in  contact  with  the  deep  cervical  fascia  at  the 
root  of  the  neck.  The  roots  of  the  lungs  move  with  inspiration  somewhat 
forwards  and  downwards.  The  front  parts  of  the  lungs  move  downwards 
and  inwards,  so  that  their  inner  borders  in  front  approach  one  another. 
The  extent  and  boundaries  of  the  lungs  can  be  easily  ascertained  in  the 
living  subject  by  means  of  percussion.  On  tapping  the  finger  laid  on  the 
chest  a  sound  is  emitted  which  varies  with  the  nature  of  the  subjacent  tissues. 
If  this  is  lung-tissue  filled  with  air,  a  clear-resonant  tone  is  obtained  ;  where 
it  is  solid  tissue,  such  as  the  heart,  or  a  lung  consolidated  with  inflammatory 


MECHANICS  OF  RESPIRATORY  MOVEMENTS  1045 

products,  or  the  liver,  a  dull  sound  is  obtained.  It  is  easy  to  show  that  the 
resonant  area  of  the  chest  increases  with  each  inspiration.  The  apices  of 
the  lungs  extend  about  one  inch  above  the  clavicle  anteriorly  and  behind 
reach  as  high  as  the  seventh  spinous  process.  During  moderate  expiration 
the  lower  margin  of  the  lungs  extends  in  front  from  the  upper  border  of  the 
sixth  rib  at  its  insertion  to  the  sternum,  and  runs  obliquely  downwards  to 
the  level  of  the  tenth  rib  at  the  back  of  the  chest.  During  the  deepest 
inspiration  the  lungs  descend  in  front  to  the  seventh  intercostal  space 
and  behind  to  the  eleventh  rib,  while  during  deepest  possible  expiration  the 
lower  margins  of  the  lungs  are  elevated  almost  as  much  as  they  descend 
during  inspiration.  In  the  front  of  the  chest  a  triangular  space  can  be 
always  marked  out  over  the  heart  where  the  note  obtained  on  per- 
cussion is  dull.  This  space  is  bounded  on  the  right  by  the  left  border  of 
the  sternum  and  extends  out  as  far  as  the  cardiac  apex,  being  bounded 
above  by  the  fourth  costo-sternal  articulation  and  below  by  the  sixth  costal 
cartilage. 

BREATH  SOUNDS.  If  the  ear  be  apphed  to  the  chest  wall,  either 
directly  or  through  the  medium  of  a  stethoscope,  each  inspiration  is  found 
to  be  accompanied  by  a  fine  rustHng  sound,  the  '  vesicular  murmur.'  It  is 
thought  to  be  caused  by  the  sudden  dilatation  of  the  air- vesicles  during 
inspiration  or  perhaps  by  the  current  of  air  passing  from  the  narrow  terminal 
bronchioles  into  the  wider  infundibula.  It  is  important  to  remember  that 
this  sound  is  heard  only  during  inspiration  and  over  healthy  lungs.  On 
listening  over  the  larger  air-passages,  i.e.  the  larynx,  trachea,  and  bronchi, 
we  hear  a  much  louder  sound  which  accompanies  both  expiration  and 
inspiration  and  may  be  compared  to  a  sharp  whispered  hah.  This  is  kno^^^l 
as  the  '  bronchial  murmur.'  It  can  be  heard  also  at  the  back  of  the  chest 
between  the  scapulae  at  the  level  of  the  fourth  dorsal  vertebra,  where  the 
trachea  bifurcates.  In  all  other  parts  of  the  chest  the  healthy  lung  prevents 
the  propagation  of  this  sound  to  the  chest  wall.  If,  however,  the  lung  is  solid, 
as  occurs  in  pneumonia,  it  conducts  the  sound  easily  from  the  large  air-tubes 
to  the  chest  wall.  Bronchial  breathing  at  any  part  of  the  chest  other  than 
that  immediately  over  the  air-tubes  is  therefore  a  distinctive  sign  of  con- 
solidation of  the  lung.  Absence  of  breath  sounds  at  any  part  of  the  chest 
implies  either  that  air  is  not  entering  that  part  of  the  lung,  or  that  the  lung 
is  separated  from  the  chest  wall  by  effused  fluid. 

INTRATHORACIC  PRESSURE.  Even  at  the  end  of  expiration  the  lungs 
are  in  a  stretched  condition.  This  is  shown  by  the  fact  that  if  in  an  animal 
or  in  the  corpse  an  opening  be  made  into  the  pleural  cavity,  air  rushes  into  the 
opening  and  the  lungs  collapse,  diiving  a  certain  amount  of  air  out  through 
the  trachea.  Since  the  lungs  are  always  tending  to  collapse,  it  is  evident  that 
they  must  exert  a  pull  on  the  thoracic  wall.  This  pull  of  the  lungs  gives  rise 
to  a  negative  pressure  in  the  pleural  cavity.  If  wo  connect  a  mercurial 
manometer  with  the  pleural  cavity,  we  find  that  the  pull  of  the  lungs  amounts 
in  the  corpse  to  G  mm.  of  mercury.  If  the  lungs  are  fully  distended,  as  after 
full  inspiration,  the  elastic  forces  are  more  brought  into  play,  and  the  negative 


1046  PHYSIOLOGY 

pressure  in  the  pleura  may  amount  to  30  mm.  Since  the  lungs  are  always 
tending  to  collapse,  respiration  becomes  impossible  directly  free  openings 
are  made  into  the  pleural  cavities  on  both  sides.  With  each  inspiratory 
movement  air  rushes  in  through  these  openings,  so  that  the  thoracic  move- 
ments can  no  longer  exert  any  influence  on  the  volume  of  the  lungs.  The 
negative  pressure  in  the  thorax  is  diminished  by  any  factor  decreasing  the 
elasticity  of  the  lung- tissue.  Thus  in  an  old  man,  where  the  elastic  tissue  is 
degenerated  and  the  alveoK  are  enlarged,  giving  rise  to  the  condition  known 
as  emphysema,  the  lungs  may  collapse  only  shghtly  or  not  at  all  on  opening 
the  chest.  The  lungs  do  not  collapse  on  making  an  opening  in  the  chest 
of  a  new-born  mammal  ;  but  this  is  owing  to  the  fact  that  they  completely 
fill  the  thorax  in  the  expiratory  position,  and  it  is  only  later  that,  with  the 
growth  of  the  ribs,  the  thorax  gets,  so  to  speak,  too  large  for  the  lungs,  which 
are  therefore  stretched  to  fill  it. 

The  force  exerted  by  the  inspiratory  muscles  is  nearly  all  spent  in  over- 
coming the  elastic  resistance  of  the  lungs  and  costal  cartilages.  A  free  access 
of  air  is  provided  for  by  contractions  of  certain  accessory  muscles  of  respira- 
tion. With  each  inspiration  the  glottis  is  widened  by  abduction  of  the  vocal 
cords.  When  the  glottis  is  observed  by  means  of  the  laryngoscope,  a 
rhythmical  separation  and  approximation  of  the  vocal  cords  are  observed, 
synchronous  respectively  with  inspiration  and  expiration  (Fig.  255,  p.  524). 
When  inspiration  is  laboured,  the  alee  nasi  are  dilated  by  the  action  of  the 
dilatator  nasi.  This  movement  of  the  nostril,  which  is  constant  in  many 
animals,  becomes  very  marked  in  children  suffering  from  any  respiratory 
trouble. 

If  a  manometer  be  connected  with  one  of  the  nostrils,  so  as  to  register  the 
pressure  in  the  air- cavities,  it  is  found  that  there  is  a  negative  pressure  of 
— 1  mm.  Hg.  with  inspiration,  and  a  positive  pressure  of  2  or  3  mm.  with 
expiration.  With  forced  inspiration  the  negative  pressure  may  amount 
to  —  57mm.  Hg.,  and  with  forced  expiration  there  may  be  a  positive  pressure 
of  +  87  mm. 

PULMONARY  VENTILATION.  Under  no  circumstances  can  we  by 
forced  expiration  empty  the  lungs  of  air.  At  the  end  of  the  most  forcible 
expiration,  if  the  pleura  were  perforated,  the  lungs  would  collapse  and  drive 
more  air  through  the  trachea.  When  breathing  quietly  a  man  takes  in  and 
gives  out  at  each  breath  about  500  c.c.  of  air,  measured  dry  and  at  0°  C.  If 
measured  moist  and  at  the  temperature  of  the  body,  viz.  37°  C,  the 
volume  would  be  about  600  c.c.  This  amount  is  known  as  the  tidal  air. 
By  means  of  a  forcible  inspiratory  effort  it  is  possible  to  take  in  about  1500 
c.c.  more  {complemental  air).  At  the  end  of  a  normal  expiration  a  forcible 
contraction  of  the  expiratory  muscles  will  drive  out  about  1500  c.c.  more 
{supplemental  air).  These  three  amounts  together  constitute  the  '  vital 
capacity  '  of  an  individual.  This  total  may  be  determined  by  means  of  the 
instrument  known  as  the  spirometer,  which  is  merely  a  small  gas-meter  with 
a  gauge  by  which  the  amount  of  air  in  it  can  be  at  once  read  off.  The  person 
to  be  tested  fills  his  lungs  as  full  as  possible,  and  then  expires  to  the  utmost 


MECHANICS  OF  RESPIRATORY  MOVEMENTS  1047 

into  the  spirometer.     The  air  left  in  the  lungs  after  the  most  vigorous 
expiration  is  known  as  the  residual  air. 

The  residual  air  may  be  determined  by  letting  a  person  expire  to  the  utmost  extent 
and  then  connecting  with  his  mouth  or  nose  a  bag  of  known  capacity  filled  with  hydrogen. 
The  subject  of  the  experiment  then  inspires  and  expires  into  the  bag  two  or  three  times, 
ending  in  the  same  state  of  forced  expiration  as  he  began.  Any  diminution  of  the  total 
volume  of  gas  in  the  bag  will  represent  the  gas  lost  during  the  experiment  by  diffusion 
into  the  blood-vessels.  By  analysis  of  the  gaseous  mixture  in  the  bag,  it  is  possible  to 
determine  the  amount  of  air  in  the  lungs  at  the  beginning  of  the  experiment.  Supposing, 
for  example,  the  bag  held  4000  c.c.  hydrogen,  after  two  respirations  the  total  volume  is 
unaltered,  but  the  gas  is  found  to  consist  of  3000  c.c.  hydrogen  and  1000  c.c.  oxygen, 
nitrogen,  and  COo.  i-e.  pulmonary  gases.  Since  the  gas  in  the  lungs  must  have  the  same 
composition  and  1000  c.c.  hydrogen  have  disappeared  from  the  bag,  it  is  evidenf'that  the 
lungs  will  contain  1000  c.c.  hydrogen  and  — yr^,  i-e.  330  c.c.  pulmonary  gases.  Thus  the 
total  volume  of  gas  left  in  the  lungs  at  the  end  of  the  forced  expiration  was  1330  c.c, 
which  is  the  residual  volume  for  the  individual. 

The  above  example  is  purely  imaginary.  As  a  result  of  actual  deter- 
minations carried  out  we  may  assume  the  residual  air  in  the  lungs  as  some- 
thing between  600  and  1200  c.c. 

Of  the  500  c.c.  of  tidal  air  taken  in  at  each  inspiration,  only  a  certain 
part  reaches  the  alveoli,  part  being  required  to  fill  the  air-tubes,  trachea, 
bronchi,  and  bronchioles  which  lead  to  the  air-cells.  The  volume  of  the 
ail-tubes  has  been  reckoned  to  amount  to  140  c.c,  so  that  of  the  500  c.c.  about 
360  c.c.  reach  the  alveoli.  For  the  same  reason  the  expired  air  represents 
the  air  from  the  alveoh  (360  c.c.)  diluted  with  140  c.c.  of  air  which  has 
remained  in  the  air-tubes  and  undergone  very  little  change,  other  than  the 
elevation  of  temperature  and  saturation  with  aqueous  vapour.  We  have 
therefore  to  allow  for  this  air  contained  in  the  so-called  '  dead  space  '  of  the 
lungs  when  we  seek  to  arrive  at  the  composition  of  alveolar  air  from  an 
analysis  of  expired  air. 

THE  BRONCHIAL  MUSCULATURE 

Both  the  large  and  smaller  air-tubes  have  a  coating  consisting  of  un- 
striated  muscle-fibres  which  in  the  bronchioles  is  complete.  Contraction 
of  these  fibres  must  have  the  following  effects  :  (1)  a  constriction  of  the 
bronchi  and  bronchioles  ;  (2)  a  diminution  of  the  air  space  of  the  lungs  and 
therefore  of  the  volume  of  the  lung ;  (3)  an  increased  resistance  to  the 
passage  of  the  air  into  and  out  of  the  alveoli.  Changes  in  the  condition  of 
contraction  of  these  muscle-fibres  may  be  studied  in  two  ways.  In  the  first 
method  artificial  respiration  is  carried  out,  a  constant  volume  of  air  being 
blown  in  and  sucked  out  at  each  respiration.  Any  diminution  in  the 
calibre  of  the  bronchioles  must  increase  the  resistance  to  the  incoming 
current  of  air  and  so  cause  a  rise  of  pressure  in  the  tracheal  tube.  Einthoveu 
in  investigating  this  subject,  has  made  use  of  an  arrangement  by  means  of 
which  a  n\ercurial  manometer  is  connected  A\*ith  the  trachea  for  a  brief 
space  of  time  during  one  part  of  the  inspiratory  phase.  Any  resistance 
to  the  current  of  air  raises  the  pressure  during  the  whole  inspiration  and 


1048 


PHYSIOLOGY 


therefore  at  the  moment  at  which  the  manometer  is  put  into  connection 
with  the  tracheal  tube,  and  a  rise  of  the  mercury  in  the  manometer  is  there- 
fore produced.  By  this  method  was  obtained  the  tracing  shown  in  Fig.  489. 
By  the  second  method  artificial  respiration  at  a  constant  pressure  is  made 
use  of.  Any  changes  in  the  bronchioles  will  in  this  case  affect  the  volume 
of  air  entering  the  lungs  at  each  stroke  of  the  pump,  and  can  be  measured 
by  recording  either  the  passive  respiratory  movements  of  the  chest  or  the 
changes  in  volume  of  a  lobe  of  the  lung  enclosed  in  a  plethysmograph 


Fig.  489.  Tracings  of  blood -pressure  (middle  curve)  and  of  intratracheal  pressure 
(upper  curve)  taken  by  Einthoven's  differential  manometer.  Between  Q  and  Q' 
the  peripheral  end  of  one  vagus  was  stimulated.     Time  markings  seconds. 

(Brodie  and  Dixon).  By  both  these  methods  it  has  been  shown  that 
stimulation  of  the  peripheral  end  of  either  vagus  causes  constriction  of  the 
bronchioles  {vide  Figs.  490  and  491).  As  a  rule  there  is  little  tonic  action  of  the 
vagi,  section  of  both  vagi  leaving  the  respiratory  pressure  curve  unaltered 
or  lowering  it  shghtly  by  2  to  10  mm.  HgO.  It  is  very  easy  to  bring  about 
a  vagus  tonus  by  allowing  the  animal  to  inhale  air  containing  3  to  4  per 
cent.  Carbon  dioxide.  A  peripheral  tonus  may  also  be  produced  by  ad- 
ministration of  muscarine  or  pilocarpine.  In  the  latter  case  Brodie  and 
Dixon  have  shown  that  stimulation  of  the  vagus  may  cause  relaxation 
of  the  bronchioles,  so  that  this  nerve  appears  to  contain  both  motor  and 
inhibitory  fibres  to  the  bronchioles. 

THE  EFFECTS  OF  BRONCHIAL  CONSTRICTION  :  ASTHMA.  Under 
the  influence  of  vagal  stimulation  or  of  carbon  dioxide,  the  pressure  neces- 
sary to  drive  the  normal  amount  of  air  into  the  lungs  may  be  raised  in  the 
dog  from  125  to  300  mm.  HgO.  We  should  therefore  expect  that,  in  cases 
where  bronchial  constriction  is  present,  there  would  be  difficulty  both  in 
inspiration  and  expiration.  There  is,  however,  a  difference  in  the  mechanical 
conditions  of  the  bronchi  during  the  two  phases  of  a  respiratory  move- 
ment. Normally  the  elastic  structure  of  the  lungs  is  drawing  upon  the 
bronchial  wall,  tending  to  maintain  it  patent,  and  so  opposing  the  action  of 


MECHANICS  OF  RESPIRATORY  MOVEMENTS  1049 

the   bronchial   muscle.     During  inspiration   this   expanding   force   is   in- 
creased, so  that  in  the  presence  of  bronchial  constriction  the  access  of  air 


Fig.  490.  Tracings  of  the  volume  changes  of  the  lung,  with  constant  variations  of 
trachea] pressure.  ( Be o die  and  Dixon.)  T.  P.  tracheal  pressure.  L.V.  lung 
volume.  B.  P.  blood-presure  (Zero  B.  P.  17  mm.  below  time  marker).  Showing 
constriction  of  bronchial  musculature  as  a  result  of  vagus  excitation. 


Fig  491.     Tracing  showing  inhibitory  effect  of  vagus  on  the  bronchial  tonus  pro- 
duced by  001  grm.  pilocarpine. 

is  rendered  the  easier,  the  more  powerful  the  contraction  of  the  inspiratory 
muscles.  In  expiration  all  parts  of  the  lung  collapse,  drawing  with  them 
the  chest-wall ;   the  pull  of  the  lung  tissue  on  the  bronchial  wall  is  lessened, 


1050  PHYSIOLOGY 

but  is  still  present.  If,  however,  the  expiratory  muscles  contract  vigorously, 
the  intrapleural  pressure  becomes  positive,  and  the  pull  of  the  lung-tissue 
on  the  bronchial  walls  is  changed  into  a  pressure  tending  to  obliterate  their 
lumen  and  so  impede  the  out  flow  of  air. 

It  is  evident,  therefore,  that  in  the  presence  of  a  spasmodic  contraction 
of  the  bronchial  muscles  the  inspiration  will  be  forcible  and  rapid,  but  all 
contractions  of  muscles  must  be  avoided,  so  far  as  possible,  during  expiration, 
which  must  be  left  to  the  elastic  reaction  of  the  lungs,  and  becomes  slow 
and  prolonged.  Moreover,  it  will  be  of  advantage  to  keep  the  lung  as 
nearly  as  possible  in  the  inspiratory  position,  so  as  to  reinforce  the  elastic 
forces  which  dilate  the  bronchioles  and  aid  expiration.  We  thus  get  the 
typical  breathing  which  occurs  in  man  in  cases  of  spasm  of  the  bronchial 
muscles,  known  as  asthma  nervosum.  This  type  of  breathing  is  often 
described  as  being  marked  by  expiratory  dysfnobSi.  This  description  is, 
however,  erroneous.  The  muscles  which  in  these  cases  are  contracted  to 
their  uttermost,  are  the  inspiratory  muscles  ;  the  expiratory  muscles,  such 
as  the  abdominal,  will  be  found  to  be  quite  flaccid  even  during  expiration. 


SECTION   II 

THE   CHEMISTRY   OF   RESPIRATION 

The  energy  of  the  body  is  derived  almost  entirely  from  the  oxidation  of  the 
carbon  and  hydrogen  of  the  food-stuffs.  An  adult  man  during  the  twenty- 
four  hours  produces  on  the  average  250  c.c.  of  carbon  dioxide  per  kilo  per 
hour.  A  man  of  60  kilos  will  therefore  excrete  250  X  60  x  24  =  360,000  c.c. 
carbon  dioxide  in  the  course  of  twenty-four  hours.  During  sleep  the  output 
of  carbon  dioxide  is  lowered  with  the  diminution  in  all  the  metabolic  pro- 
cesses of  the  body  and  amounts  to  only  160  c.c.  per  kilo  per  hour.  If  we 
assume  that  eight  hours  of  the  twenty-foui  are  given  to  sleep,  this  will  leave 
295  c.c.  per  kilo  per  hour  as  the  average  excretion  of  carbon  dioxide  during 
the  waking  hours.  Since  the  access  of  oxygen  to  the  body  and  the  removal 
of  carbon  dioxide  is  effected  by  the  pulmonary  ventilation,  the  expired  air 
will  differ  from  the  inspired  air  in  containing  more  carbon  dioxide  and  less 
oxygen.  The  oxygen  intake  is  not,  however,  absolutely  proportional  to 
the  carbon  dioxide  output.  This  is  owing  to  the  fact  that  carbon  is  not 
the  only  element  which  leaves  the  body  in  an  oxidised  condition.  Fats,  for 
example,  contain  a  number  of  unoxidised  atoms  of  hydrogen,  which  in  the 
metabolic  processes  of  the  body  are  fully  oxidised,  to  be  excreted  as  water. 
Oxygen  will  also  leave  the  body  in  combination  with  carbon  and  nitrogen 
in  the  urine,  so  that  a  certain  amount  of  oxygen  w^hich  is  taken  in  does  not 
reappear  as  carbon  dioxide  in  expired  air.  There  is  thus  an  absolute 
diminution  in  the  volume  of  expired  air  as  compared  with  that  of  inspired 
air.  This  diminution,  due  to  loss  of  oxygen,  is  greater  in  carnivora,  whose 
food  consists  mainly  of  proteins  and  fats,  than  in  herbivora,  which  feed 
principally  on  carbohydrates,  and  depends  on  the  respiratory  quotient,  i.e. 

COo  expired. 

the  ratio  - — : : — — 

0.,  mspired. 

In  man  the  average  respiratory  quotient  can  be  taken  as  0-85.     On  this 

basis  the  amount  of  oxygen  which  wall  be  taken  in  during  the  waking  hours 

will  be  347  c.c.  per  kilo  per  hour.     Taking  round  figures,  we  may  say  that, 

when  awake,  a  man  takes  in  350  c.c.  oxygen  and  gives  out  3(X)  c.c.  carbon 

dioxide  per  kilo  per  hour.     From  these  figures  we  can  calculate  the  normal 

composition  of  expired  air  when  a  man  is  breathing  quietly.     Under  these 

conditions  tlie  tidal  air  amounts  to  50()  c.c.     If  he  breathes  seventeen  times 

a  minute  the  total  pulnionai y  ventilation  dui'ing  the  hour  will  be  500  X  17 

X  60  =  510,000  c.c.  per  hour.    This  will  contain  300  x  70  c.e.=  21.000  c.c. 

lOol 


1052  PHYSIOLOGY 

carbon  dioxide.  Hence  the  percentage  of  carbon  dioxide  in  the  expired 
air  will  be  4-1  per  cent.  In  the  same  way  we  can  reckon  the  percentage  of 
oxygen  in  the  expired  air  at  16-4  per  cent.  Exact  experiments  have  shown 
that  the  volume  of  nitrogen  is  michanged  during  respiration,  this  gas 
taking  no  part  in  the  ordinary  metabohc  processes  of  the  body.  We  may 
therefore  compare  the  ordinary  composition  of  inspired  and  expired  air  as 
follows  : 

Inspired  Am 

Oxygen  .  .  .  .  .  .  .20-96  vols,  per  cent. 

Nitrogen  and  argon .  .  .  .  .     79'00       ,,  „ 

Carbon  dioxide         .....       0*04      „  „ 

Expired  Air 

Oxj'gen  .  .  .  .  .  .  .     16-4  vols,  per  cent. 

Nitrogen 79-5       „  „ 

Carbon  dioxide         .....       4*1       „  „ 

The  increase  in  the  figure  for  nitrogen  refers  of  course  only  to  the  per- 
centage amount,  since  the  total  volume  of  air  breathed  is  decreased  by  the 
disappearance  of  a  certain  amount  of  oxygen  without  the  production  of  a 
corresponding  amount  of  carbon  dioxide,  so  that  the  relative  amount  of 
nitrogen  is  shghtly  increased.  These  figures  for  the  composition  of  inspired 
and  expired  air  refer  to  dry  air  at  a  temperature  of  0°  C.  and  a  pressure  of 
760  mm.  Under  normal  circumstances  inspired  air  contains  a  variable 
amount  of  aqueous  vapour  and  has  a  variable  temperature  corresponding 
with  the  time  of  year.  Expired  air  is  fully  saturated  with  aqueous  vapour 
and  has  the  temperature  of  the  body,  37°  C.  The  aqueous  vapour  at  this 
temperature  is  by  no  means  neghgible.  Its  tension  amounts  to  50  mm.  Hg. 
Thus  when  a  man  is  breathing  dry  air  at  a  pressure  of  760  mm.  Hg.,  the 
pressure  of  the  mixture  of  gases  in  the  alveoU  of  his  lungs  will  be  only 
760  -  50,  i.e.  710  mm.  Hg. 

Only  a  certain  percentage  of  the  500  c.c.  of  tidal  air  reaches  the  alveoli, 
100  to  140  c.c.  being  required  to  fill  the  trachea  and  bronchial  tubes.  Hence 
the  alveolar  air  must  contain  more  carbon  dioxide  and  less  oxygen  than  the 
tracheal  air ;  and  it  is  found  that,  if  we  take  the  air  from  the  alveoli  instead 
of  that  expired  through  the  mouth  or  nose,  the  differences  between  it  and  the 
inspired  air  are  much  more  pronounced. 

A  sample  of  alveolar  air  may  be  obtained  for  analysis  in  the  following  way  (Haldane) : 
A  piece  of  india-rubber  tubing  is  taken  of  about  1  inch  diameter  and  4  feet  long.  Into 
one  end  (Fig.  492)  is  fitted  a  mouthpiece,  the  other  being  left  open  or  comiected  with  a 
spirometer.  About  2  inches  from  the  mouthpiece  is  fixed  a  gas  sampling- bulb,  which  is 
provided  with  three-way  taps  at  the  upper  and  lower  ends.  Before  an  experiment  the 
bulb  is  filled  with  mercury,  if  the  lower  end  is  open,  or  else  it  is  completely  exhausted. 
The  subject  of  the  experiment,  after  breathing  normally  a  few  times,  at  the  end  of  a 
normal  inspiration  puts  his  mouth  to  the  tube,  expires  quickly  and  deeply,  and  closes 
the  mouth-piece  with  his  tongue.  The  tap  of  the  sampling-bulb  is  then  turned,  and  the 
air  last  expelled  from  the  lungs  (which  is  therefore  pure  alveolar  air)  rushes  into  the  bulb. 
The  tap  of  the  bulb  is  then  turned  off,  and  the  gas  may  be  removed  for  analysis.  A 
similar  sample  is  then  taken,  in  which  the  subject  expires  deeply  at  the  end  of  a  normal 


THE  CHEMISTRY  OF  RESPIRATION 


1053 


expiration.  This  sample  will,  of  course,  contain  more  CO2  and  less  Og  than  that  obtained 
at  the  end  of  inspirat  ion.  The  mean  of  the  two  samples  is  taken  as  the  average  composi- 
tion of  alveolar  air. 

The  difference  between  the  composition  of  expired  air  and  alveolar  air 
is  determined  by  the  dilution  of  the  alveolar  air  wdth  that  contained  in  the 
dead  space.  Hence  with  shallow  breathing  there  will  be  a  large  difference, 
but  this  will  decrease  w^th  increased  depth  of  respiration.  Thus,  if  the 
alveolar  air  contained  6  per  cent.  CO 2  and  the  dead  space  amounted  to 
150  c.c,  the  expired  air  would  only  contain  3  per  cent.  CO2  when  the  person 
was  taking  in  only  300  c.c.  at  each  respiration.     If,  however,  he  was  breath- 

""  fyfo(/r/^-p/£C£. 


Sj1mpi/a/g  tube. 


Fig.  492. 

ing  slowly  and  deeply  so  as  to  raise  the  tidal  air  to  1500  c.c,  only  one-tenth 
of  this  would  be  represented  by  the  dead  space,  and  the  expired  air  would 
contain  nine-tenths  as  much  COg  as  the  alveolar  air,  i.e.  54  per  cent. 

The  changes  in  the  composition  of  alveolar  air  with  respiration  are  by 
no  means  so  marked  as  those  produced  in  the  tidal  air,  since  the  latter 
forms  only  a  small  proportion  of  the  total  air  in  the  lung  alveoli.  Thus 
at  the  end  of  a  normal  expiration  the  alveoH  still  contain  2500  c.c.  of  gases. 
In  inspiration  360  c.c.  atmospheric  air  is  taken  into  this  space  and  mixed 
with  the  2500  c.c.  already  there.  The  '  ventilation  coefficient '  in  quiet 
breathing  is  therefore  only  one-seventh,  and  the  change  in  the  oxygen  and 
carbon  dioxide  content  of  the  alveolar  air  produced  by  this  access  of  360  c.c. 
will  amount  to  less  than  one-half  per  cent.  This  is  illustrated  by  the  follow- 
ing figures  from  Haldane,  giving  the  alveolar  content  in  carbon  dioxide  at 
the  end  of  inspiration  and  at  the  end  of  expiration  respectively. 

Alveolar  CO.,  Tensions. 


Individual 

Alveolar  COj  at  end  of 
inspiration.     (Mean  of 
twelve  observations) 

COj  at  end  of 
expiration 

Mean 

J.  S.  H. 
J.  G.  P. 

5-54 
6-17 

5-70 
6-39 

5-62 

6-28 

We  can  thus  speak  of  an  average  composition  of  alveolar  air  which  in 
spite  of  the  constant  ventilation,  differs  from  the  external  air  in  containing 
an  excess  of  carbon  dioxide  and  a  relative  lack  of  oxygen.  Lavoisier,  who 
was  the  first  to  study  the  chemical  changes  in  respiration  accurately,  regarded 
the  lungs  as  the  seat  of  the  formation  of  carbon  dioxide  and  the  consump- 
tion of  oxygen.  This  view  was  generally  accepted  until  it  was  shown  by 
Magnus,  in  Heidenhain's  laboratory,  that  the  blood  passing  to  the  lungs 
contained  more  carbonic  acid  gas  and  less  oxygen  than  that  passing  away 


1054 


PHYSIOLOGY 


from  the  lungs.  The  effects  of  this  discovery  were  to  transfer  the  chief  seat 
of  oxidation  to  the  tissues  of  the  body,  and  to  show  that  the  blood  acts 
simply  as  a  carrier  of  the  oxygen  from  the  lungs  to  the  tissues,  and  of  the 
carbon  dioxide  from  the  tissues  to  the  lungs.  We  thus  learnt  to  distinguish 
between  external  and  internal  respiratory  processes.  A  consideration  of  the 
chemical  mechanisms  involved  in  the  process  of  external  respiration  in- 
cludes therefore  an  investigation  of  the  manner  in  which  gases  are  held  by 


^^^00^:=== 


Fig.  493.     Barcroft's  modification  of  the  Topler  pump. 

the  blood  and  of  the  factors  which  are  responsible  for  the  transfer  of  oxygen 
and  carbon  dioxide  from  blood  to  alveolar  air,  and  from  alveolar  air  to  blood. 
If  blood  be  exposed  to  a  Torricellian  vacuum  at  the  ordinary  temperature, 
the  whole  of  its  contained  gases  is  given  off.  For  the  purpose  of  extracting 
the  blood  gases  a  great  variety  of  pumps  have  been  devised.  In  every  case 
a  glass  vessel  is  evacuated  by  means  of  the  mercury  pump,  and  is  then  put 
into  connection  with  a  reservoir  containing  bloOd  which  has  been  defibrinated, 
or  has  been  prevented  from  clotting  by  the  addition  of  oxalate  or  citrate. 
In  all  these  pumps  the  main  difficulty  arises  in  the  exclusion  of  atmospheric 
air,  and  it  is  therefore  important  to  dispense  so  far  as  possible  with  taps. 


THE  CHEMISTRY  OF  RESPIRATION  1055 

One  of  the  best  modifications  of  the  Topler  mercury  pump  is  that  employed 
by  Barcroft  (Fig.  493),  which  differs  little  from  the  pump  devised  by  Bohr. 

The  construction  of  the  pump  is  shown  in  the  diagram.  The  actual  pump  consists 
of  the  parts  a,  b,  c,  d.  The  bulb  b  is  prolonged  below  by  a  wide  tube  dipping  into  the 
mercury  in  the  Woulf  bottle  a.  The  upper  part  of  the  bottle  is  filled  with  water  and 
connected  by  two  taps  at  w  with  the  water-supply  and  with  a  sink.  The  water  being 
turned  on,  mercury  is  forced  up  into  B  ;  as  it  rises  into  y  it  carries  before  it  a  glass  valve 
which  prevents  its  further  passage,  so  that  it  can  onty  escape  by  the  tube  c,  driving 
before  it  all  the  air  previously  contained  in  b.  The  water-supply  is  now  turned  oif,  and 
the  tap  to  the  sink  turned  on.  The  mercury  runs  back.  Air  cannot  enter  by  c,  since 
this  tube  is  sealed  by  mercmy.  The  valve  y  therefore  sinks  and  allows  the  air  in  the 
blood  receivers  G,  G  and  the  rest  of  the  apparatus  to  escape  into  B.  The  process  is  re- 
peated many  times  until  a  high  vacuum  is  produced  in  the  whole  apparatus.  A  measured 
quantity  of  blood  is  now  let  into  the  lower  bulb  G.  f  is  a  condenser  through  which  cold 
water  is  constantly  flowing  (to  prevent  all  the  blood  boiling  away),  while  warm  w'ater 
circulates  round  the  bulbs  G,  G  to  facilitate  the  giving  off  of  the  blood  gases.  The  blood 
boils  in  the  vacuum,  and  the  gases  escape  into  B,  and  may  be  driven  off  and  collected 
over  mercury  in  a  cylinder  d  by  raising  the  mercury  in  B.  The  process  of  exhaustion  is 
repeated  until  no  more  bubbles  rise  into  d  on  filling  the  bulb  B  with  mercury.  E  is  a 
sulphuric  acid  chamber  for  drying  the  gases  as  they  pass  from  the  blood  to  the  bulb  B. 

In  this  way,  from  100  c.c.  of  blood,  about  60  c.c.  of  mixed  gases  may  be 
obtained,  consisting  of  oxygen,  carbon  dioxide,  nitrogen,  and  argon.  Argon 
is  present  only  in  insignificant  quantities,  about, rO-l  volume  per  cent.  The 
nitrogen  also  forms  only  between  one  and  two-  vqlumes  per  cent,  and  is 
present  in  the  same  proportion  in  both  arterial  and  venous  blood.  The 
amounts  of  oxygen  and  carbon  dioxide  in  these  two  kinds  of  blood  differ, 
however,  wathin  wide  limits.  The  following  Table  represents  the  average 
composition  of  the  gases  obtained  from  an  artery  and  a  vein  of  the  dog  : 

From  100  vols.  May  be  obtained 


Of  oxygen         Of  carbon  dioxide       Of  nitrogen 
Of  arterial  blood      .  .     20  vols.        .     40  vols.      .      1  to  2  vols. 

Of  venous  blood      .  8  to  12  vols.    .     46     „        .         „         „ 

Measured  at  760  mm.  and  0°  C 

The  principle  introduced  by  Haldane  {vide  p.  859)  for  the  determination  of  the 
oxygen  combined  in  the  form  of  oxyhsemoglobin  may  be  successfully  applied  to  small 
quantities  of  blood,  such  as  1  c.c.  or  even  O-lc.c,  and  in  the  same  sample  of  blood  the 
carbon  dioxide  may  also  be  determined.  In  this  way  it  becomes  practicable  to  make 
blood-gas  analyses  in  a  patient,  or  in  experiments  on  small  organs  where  it  is  desired 
to  determine  their  gaseous  metabolism  by  comparing  the  arterial  with  the  venous 
blood.     Barcroft's  apparatus  for  dealing  with  1  c.c.  of  blood  is  shown  in  Fig.  494  a. 

The  apparatus  consists  of  two  bottles  of  identical  size  (about  30  c.c.)  attached  to  a 
manometer,  the  tubing  of  which  is  1  mm.  bore.  The  manometer  is  filled  with  clove  oil 
of  known  specific  gravity.  To  fill  it  take  out  the  centre  tube,  put  in  clove  oil  at  a,  put 
in  the  centre  tube  with  tlie  glass  tube  B  open  and  some  pressure  on  the  rubber  tube  c. 
The  oil  should  stand  about  half  way  up  each  tube  ;  seal  B  in  a  flame.  The  constant 
of  the  apparatus  must  be  determined,  viz.  the  capacity  of  the  bottles  and  with  their 
connections. 

It  is  determined  by  finding  what  rise  of  pressure  in  the  apparatus  is  jjroduced  by 
the  liberation  of  a  known  volume  of  oxygen  from  hydrogen  peroxide,  which  is  jjlaced  in 
the  bottle,  the  liberation  being  effected  by  the  addition  of  potassium. 


1056 


PHYSIOLOGY 


To  determine  the  oxygen  capacity  of  a  sample  of  blood.  Place  2  c.c.  of  ammonia  solution 
(made  by  adding  4  c.c.  of  strong  NH3  to  a  litre  of  water)  in  one  of  the  bottles  and  add 
1  c.c.  of  blood.  Thoroughly  lake  the  blood.  Put  vaseline  on  the  large  and  small  stoppers. 
Put  0-2  c.c.  of  a  saturated  solution  of  potassiiun  ferricyanide  in  the  small  tube  contained 
in  the  stopper  of  the  bottle  containing  the  blood  (this  is  best  done  with  a  fine  pipette 
which  goes  down  these  tubes).  Put  in  the  small  stopper.  Place  the  apparatus  on  the 
side  of  a  large  water  bath  (such  as  a  pail)  with  both  taps  open.  In  about  five  minutes  close 
the  tap  on  the  side  of  the  blood  and  rotate  the  bottle  on  the  stopper  till  the  ferricyanide 
trickles  into  the  laked  blood.  Shake  thoroughly,  replace  in  the  bath,  and  repeat  this 
several  times  till  a  constant  difference  of  level  is  obtained.     By  means  of  the  screw  clamp 


A 


B— I 


SAIRD  6.   TfiTLOrK 
(LONDON  1  L\? 


Fig.  494.     Barcroft's  blood-gas  apparatus. 
A,  for  1  c.c.  ;  B,  for  0-1  c.c.  blood. 

bring  the  column  of  oil  on  the  side  of  the  blood  to  its  original  level,  and  then  measure 
the  difference  of  level  between  the  two  sides.  Let  this  difference  of  level  be  y  mm.  ; 
let  p  be  the  height  of  the  barometer  in  millimetres  of  clove  oil,  and  x  the  volume  of 

oxygen  given  off  in  cubic  millimetres  ;  then  x  =  y  i—y     Except  in  the  most  exact  work 

p  may  be  taken  as  10,000  mm.,  in  which  case  the  expression  —  may  be  determined  once 

for  all  and  called  C,  the  constant  of  the  apparatus  :   then  x  =  y  x  C 

To  determine  the  gaseous  contents  of  a  given  blood.  If  we  wish  to  determine  the  actual 
amount  of  oxygen  as  oxyhsemoglobin  in  the  sample,  the  blood  must  be  carefully  intro- 
duced so  as  to  lie  below  the  ammonia  and  not  to  come  in  contact  with  tlie  air.  The 
stopper  is  then  replaced  in  the  bottle  and  immersed  in  the  bath,  with  both  taps  open 
until  it  has  attained  a  constant  temperature.  The  tap  is  then  closed  and  the  height  of 
the  column  of  oil  noted.  The  blood  is  then  laked  by  rotating  the  apparatus,  and  after 
allowing  five  minutes  for  complete  laking  the  ferricyanide  is  run  in.  The  rest  of  the 
determination  is  carried  out  as  above. 

The  carbon  dioxide  may  be  determined  in  the  same  sample  of  blood  by  running  in 
tartaric  acid  in  the  same  way  as  potassium  ferricyanide  was  previously  run  in.  It  is 
necessary  always  to  determine  the  oxygen  before  the  carbon  dioxide,  since  the  mere 
acidification  of  the  blood  causes  the  evolution  of  a  certain  amount  of  oxygen.  The 
results  obtained  for  carbon  dioxide  are  not  so  accurate  as  those  for  the  oxygen,  owing  to 
the  larger  error  introduced  by  the  increased  solubility  of  this  gas  in  watery  media. 
The  same  apparatus  may  be  used  as  a  differential  blood-gas  vmnometer,  where  it  is 


THE  CHEMISTRY  OF  RESPIRATION 


1057 


desired  to  compare  the  oxj^gen contents  of  two  samples  of  blood,  e.g.  of  arterial  and  venous 
blood.  For  this  purpose  1  c.c.  of  the  arterial  blood  is  introduced  into  one  bottle  and  1  c.c. 
of  the  venous  blood  into  the  other  bottle,  in  each  case  under  1 J  c.c.  of  weak  ammonia.  The 
bottles  are  then  placed  on  the  apparatus  and  immersed  in  the  water  bath  until  no  change 
occurs  in  the  height  of  the  column  of  oil.  The  two  taps  are  then  closed  and  the  apparatus 
is  vigorously  shaken.  The  blood  on  each  side  is  laked,  and  in  contact  mth  the  air  in 
the  bottles  becomes  completely  saturated  with  oxj^gen.  No  carbon  dioxide  is  given  off, 
since  tliis  combines  with  the  weak  ammonia.  If  the  two  bloods  contain  the  same  amount 
of  oxyhsemoglobin  no  difference  will  be  produced  in  the  level  of  the  oil  in  the  two  tubes. 
If,  however,  one  be  arterial  and  the  other  venous,  the  venous  blood  will  absorb  more 
oxygen  from  its  bottle  than  the  arterial  blood  from  its  side  of  the  apparatus,  so  that  the 
oil  will  rise  in  the  tube  on  the  side  of  the  venous  blood.  From  the  amount  of  rise  the 
difference  in  the  amount  of  oxygen  taken  up  by  the  blood  on  the  two  sides  can  be  reckoned 
and  this  figm-e  \vill  express  the  relative  satm-ation  of  the  hsemoglobin  in  the  two  samples 
of  blood. 

For  clinical  purposes  it  is  possible  to  work  with  0-1  c.c.  of  blood.  Fig.  49i  B  repre- 
sents the  form  of  ajjparatus  de\Tsed  by  Barcroft  for  dealing  with  these  minute  quantities. 
The  principle  of  the  apparatus  is  the  same  as  that  of  the  larger  type. 

The  condition  of  the  gases  in  the  blood  can  be  judged  by  the  amoimt  of 
gas  which  the  blood  will  take  up  when  exposed  to  different  pressures  of  the 
gas.  If  a  gas  is  in  simple  solution  the  amount  of  it  dissolved  varies  directly 
with  the  pressure.  Thus,  if  water  takes  up  a  certain  bidk  of  a  gas  at  a  given 
temperature  and  pressure,  it  will  take  up  twice  as  much  if  the  pressure  of 
the  gas  be  doubled.  Since  the  volume  of  a  gas  varies  inversely  as  the 
pressure,  we  may  say  that  a  fluid  will  dissolve  the  same  volume  of  gas 
whatever  the  pressure.  The  absorption  coefficient  of  a  hquid  for  a  gas  is 
expressed  by  the  number  of  cubic  centimetres  of  gas  which  will  be  taken 
up  at  0°  C.  by  1  c.c.  of  the  liquid  when  the  gas  is  at  a  pressure  of  760  mm. 
Hg.  The  absorption  coefficient  diminishes  with  rise  of  temperature.  The 
following  Table  represents  the  absorption  coefficients  for  oxygen,  carbon 
dioxide,  carbon  monoxide,  and  nitrogen,  in  water  at  various  temperatures 
between  0°  and  40°  C.  : 


Temperature 

Oxygen 

Carbon  dioxide 

Carbon  nionoxidr 

Xitrogen 

0 

0-0489 

1-713 

0-0354 

0-0239 

10 

0-0380 

M94 

0-0282 

00196 

20 

0-0310 

0-878 

0-0232 

00164 

30 

00262 

0-665 

0-0200 

0-0138 

40 

00231 

0-530 

0-0178 

0-0118 

From  this  Table  we  see  that  100  c.c.  of  water  at  0°  C.  will  absorb 
4-89  c.c.  oxygen  at  760  mm.  Hg.,  i.e.  at  one  atmosphere.  If  the  pressure  be 
raised  to  two  atmospheres  the  volume  of  gas  absorbed  will  be  the  same,  but 
if  these  gases  be  measured  at  the  original  pressure,  i.e.  at  one  atmosphere, 
the  amount  dissolved  will  be  9-78  volumes.  If  therefore  we  plot  out  the 
absorption  of  the  gas  on  a  curve  of  which  the  ordinates  represent  the  amount 
of  gas  dissolved  and  the  abscissa  the  different  pressures  of  the  gas,  we  shall 
find  that  the  curve  is  a  straight  line.     The  relation  between  the  amount 

34 


1058  PHYSIOLOGY 

absorbed  is  not  altered  by  the  presence  of  other  gases  at  the  same  time.  The 
pressure  of  the  whole  atmosphere  is  760  mm.  Since  the  atmosphere  con- 
sists roughly  of  four  parts  of  nitrogen  with  one  part  of  oxygen,  the  atmo- 
spheric pressure  is  due  as  to  one-filth  to  the  oxygen  and  as  to  four-fifths  to  the 
nitrogen.  If  we  shake  up  water  at  0°  C.  with  the  atmospheric  air  at  the 
ordinary  pressure,  100  c.c.  of  water  will  absorb  4-89  c.c.  x  i  of  oxygen,  and 
of  nitrogen  2  -39  c.c.  X  4.  We  may  therefore  extend  our  statement  as  to  the 
solubihty  of  gases  in  fluids  and  say  that  the  amount  of  gas  dissolved 
in  a  fluid  is  proportional  to  the  partial  pressure  of  the  gas. 

When  water  is  shaken  up  with  a  gas  until  it  will  take  up  no  more,  i.e. 
until  it  is  saturated  for  that  pressure,  a  state  of  equihbrium  exists  between 
the  gas  dissolved  in  the  fluid  and  the  gas  in  contact  with  the  fluid.  In 
this  state  of  equihbrium  the  number  of  molecules  of  the  gas  entering  the 
fluid  is  exactly  equal  to  the  number  of  molecules  of  the  gas  leaving  the 
fluid.  If  we  remove  the  hquid  after  saturation,  say,  at  one  atmosphere,  to  a 
vessel  where  it  is  in  contact  with  gas  at  a  pressure  of  half  an  atmosphere,  the 
Hquid  will  give  off  gas  until  the  amount  left  in  solution  is  diminished  to  one- 
half.  The  gas  dissolved  in  a  hquid  thus  has  a  pressure  or  tension  which 
tends  to  make  it  escape  from  the  hquid.  The  only  way  in  which  we  can 
measure  this  tension  is  by  finding  what  pressure  of  gas  is  in  exact  equihbrium 
with  the  hquid.  Thus  if  we  take  some  water  containing  carbon  dioxide  in 
solution,  divide  it  into  two  parts,  and  shake  up  one  part  with  a  gaseous 
mixture  containing  4  per  cent,  of  carbon  dioxide  and  the  other  part  with  a 
mixture  containing  5  per  cent,  of  carbon  dioxide,  and  find  that  the  solution 
loses  gas  to  the  former  and  takes  up  carbon  dioxide  from  the  latter,  we 
may  conclude  that  the  tension  of  carbon  dioxide  in  the  original  fluid  was 
something  between  4  and  5  per  cent,  of  an  atmosphere.  It  is  by  some  such 
means  that  the  tensions  of  gases  in  the  blood  are  measured,  the  instruments 
for  this  purpose  recei\dng  the  name  of  aerotonometers. 

The  solvent  power  of  water  for  gases  is  diminished  if  the  water  contains 
other  sohd  substances  in  solution.  Blood-plasma  or  blood- corpuscles  will 
therefore  have  a  smaller  solvent  power  for  gases  than  has  pure  water.  It 
has  been  shown  by  Bohr  that  the  depression  of  solubihty  caused  by  the 
presence  of  proteins  or  salts  in  solution  is  the  same  for  all  gases.  The  absorp- 
tion coejficient  of  blood-plasma  for  gases  is  reduced  to  97-5  per  cent,  of  pure 
water,  and  of  blood  to  92  per  cent.,  that  of  the  blood-corpuscles  being  as  low 
as  81  per  cent.  We  may  thus  reckon  the  absorption  coefficient  of  blood- 
plasma,  blood,  and  blood- corpuscles,  for  oxygen,  nitrogen,  and  carbon 
dioxide. 

From  the  following  Table  we  see  that  100  volumes  of  blood  at  38°  C.  might 
contain  2-2  c.c.  of  oxygen  in  solution  if  the  blood  had  been  exposed  to 
oxygen  at  a  pressure  of  one  atmosphere.  The  blood  in  the  lungs  is,  however, 
exposed  to  air  which  contains  only  about  one- sixth  of  its  volume  of  oxygen, 
so  that  the  total  amount  of  oxygen  present  in  arterial  blood  in  solution 
cannot  be  more  than  one-sixth  of  2-2,  i.e.  about  0'36  c.c.  per  cent.  Since 
arterial  blood,  or  blood  saturated  with  oxygen  by  shaking  with  air,  will 


THE  CHEiMISTRY  OF  RESPIRATION 


1059 


yield  as  much  as  twenty  volumes  per  cent,  of  oxygen  to  a  Torricellian 
vacuum,  the  oxygen  cannot  be  in  simple  solution,  but  must  be  in  some  form 
of  combination  with  some  of  the  constituents  of  the  blood.  Of  this  oxygen 
practically  the  whole  is  contained  in  the  red  blood-corpuscles  in  combina- 
tion with  haemoglobin,  the  plasma  containing  no  more  than  could  be 
accounted  for  by  simple  solution. 


Ox} 

gen 

Xitr 

jgen 

Carbon  dioxide 

15° 

38° 

15° 

38° 

15° 

.38° 

Blood-plasma    . 

Blood 

Blood-corpuscles 

0-033 
0-031 
0-025 

0023 
0-022 
0-019 

0-017 
0-016 
0-014 

0-012 
0-011 
0-010 

0-994 
0-937 
0-825 

0-541 
0-511 
0-450 

One  gramme  of  crystallised  hsemoglobin  can  absorb  1-3-1  c.c.  of  oxygen. 
If  a  solution  of  oxyha3moglobin  be  subjected  in  an  air-pump  to  gradually 
diminishing  pressure  at  the  temperature  of  the  body,  very  little  oxygen 
is  given  off  until  the  partial  pressure  of  the  oxygen  is  diminished  to  about 
30  mm.  Hg.  (Fig.  496).  At  this  point  a  large  evolution  of  gas  begins, 
and  continues  at  falling  pressure  until  at  0  mm.  pressure  all  the  oxy- 
haemoglobin  is  dissociated  and  converted  into  hsemoglobin.  The  same 
observation  may  be  made  in  a  reverse  direction.  If  a  solution  of  reduced 
haemoglobin  be  exposed  to  gradually  increasing  pressures  of  oxygen,  it  will 
be  found  that  the  greatest  absorption  takes  place  between  0  and  30  mm.  Hg. 
After  this  point  the  oxygen  is  more  slowly  absorbed  up  to  the  point  of 
complete  saturation. 

Since  there  is  no  direct  proportion  between  the  partial  pressure  of  the 
oxygen  and  the  amount  absorbed,  it  is  evident  that  the  oxygen  combines 
with  haemoglobin  to  form  an  unstable  chemical  compound,  and  that  this  is 
not  a  mere  question  of  solution.  This  is  further  proved  by  the  fact  that 
we  can  displace  the  oxygen  (Og)  from  the  oxyhaemoglobin  by  equivalent 
amounts  of  CO  or  NO.  Haemoglobin  is  also  supposed  to  form  an  unstable 
combination  with  carbon  dioxide,  since  it  takes  up  much  more  of  this  gas 
than  the  corresponding  bulk  of  water  or  salt  solution  would  do.  Although 
carbon  dioxide  combines  with  haemoglobin,  it  does  not  displace  oxygen  from 
the  oxyhasmoglobin  molecule.  Thus  we  may  have  haemoglobin  saturated 
at  the  same  time  with  oxygen  and  with  carbon  dioxide.  The  presence  of 
carbon  dioxide  does,  however,  alter  the  case  with  which  oxyhaemoglobin 
dissociates. 

The  relation  between  the  partial  pressure  of  oxygen  and  the  amount 
of  oxyhaemoglobin  formed  under  var}ang  conditions  can  be  investigated  in 
the  following  way  (Barcroft)  : 

A  large  glass  globe  with  a  stop-cock  at  one  or  both  ends  (Fig.  495)  is  filled  with  a 
gaseous  mixture  of  kno\\ii  composition  containing  oxygen.  Into  it  are  int  roduced  2  or  3  c.c. 
of  blood  or  of  hiemoglobin  solution.      It  is  then  tightly  stoppered  and  immersed  in  a 


1060  PHYSIOLOGY 

horizontal  position  in  a  pail  of  water  kept  at  a  constant  temperature.  In  the  pail  it  is 
suspended  between  its  two  ends,  so  that  it  can  be  slowly  revolved  by  means  of  a  piece  of 
string  passing  round  its  neck.  In  this  way  the  blood  is  continually  spread  in  a  thin  layer 
over  the  sides  of  the  vessel.  At  the  end  of  a  quarter  to  half  an  hour  it  will  have  attained 
equilibrium  with  the  gaseous  mixture.  It  is  then  turned  into  an  erect  position  so  that 
the  fluid  can  run  down  into  the  neck  closed  by  a  stop-cock,  whence  1  c.c.  may  be  drawn 
ofE  for  analysis  in  a  Barcroft  apparatus.  A  further  portion  of  the  same  blood  may  be 
shaken  up  with  air  so  as  to  saturate  it  completely,  and  the  saturation  of  the  two  samples 
may  be  compared  in  the  differential  gas  apparatus. 

Barcroft  has  shown  that  the  dissociation  curve  of  ha3moglobin  is  largely 
altered  by  shght  variations  in  the  fluid  in  which  the  haemoglobin  is  dissolved. 
The  most  important  of  these  conditions  are  (1)  the  saline  content  of  the 


Fig.  495.     Barcroft's  apparatus  for  determining  the  curve  of  absorption  of 
oxygen  by  haemoglobin. 

fluid,  (2)  the  reaction  of  the  fluid.  Under  this  latter  heading  must  be  classed 
the  amount  of  carbon  dioxide  present,  since  its  action  on  the  dissociation 
curve  is  similar  to  that  produced  by  the  presence  of  weak  acids  such  as 
lactic  acid.  The  influence  of  dissolved  salts  on  the  dissociation  curve  is 
shown  in  Fig.  496. 

It  is  interesting  to  note  that  the  differences  between  the  dissociation 
curve  of  blood  and  of  haemoglobin  solution,  as  well  as  between  bloods  of 
different  animals,  have  been  shown  by  Barcroft  and  Camis  to  be  dependent 
on  the  different  saline  content  of  the  solution  in  the  various  cases.  Thus 
human  haemoglobin  solution,  with  a  concentration  of  salts  similar  to  that 
of  dogs'  blood,  gives  the  same  dissociation  curve  as  normal  dogs'  blood. 

More  important  is  the  effect  of  reaction,  since,  as  we  shall  see,  it  is  the 
reaction  of  the  blood,  controlled  especially  by  carbon  dioxide  tension,  that 
determines  the  activity  of  the  respiratory  centres.  In  Fig.  497  is  repre- 
sented the  influence  of  varying  tensions  of  carbon  dioxide,  and  in  Fig.  498 
the  effect  of  slight  additions  of  lactic  acid  on  the  dissociation  curve.  It 
will  be  seen  that  the  more  acid  the  blood,  or  the  greater  tension  of  carbon 
dioxide  it  contains,  the  more  readily  does  it  undergo  dissociation.  This  is 
especially  marked  at  the  very  high  tension  of  420  mm.  carbon  dioxide.  It 
plays  an  important  part  in  the  lower  tensions,  such  as  40  and  80  mm.  Hg. 


THE  CHEMISTRY  OF  RESPIRATION 


1061 


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Fig.  496.     Dissociation  curve  of  hsemoglobin  in  various  solvents. 
I,  in  water  ;  II,  in  0-7  per  cent.  NaCl ;  III,  in  0-9  per  cent.  KCl. 
(Barcroft.) 


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Fia.  497.  Effect  of  varying  tensions  of  COg  on  the  dissociation  curve  of  oxyhapmo- 
globin.  The  lowest  curve  is  the  dissociation  at  a  COo  tension  of  420  mm.  Hg.  from 
observations  by  Barcroft.     (Bohr.) 


1062 


PHYSIOLOGY 


carbon  dioxide,  .  It  inust  be  remembered  tKat  40  mm.  carbon  dioxide  repre- 
sents approximately  the  normal  carbon  dioxide  tension  in  the  blood.  It  is 
true  that  at  150  mm.  oxygen  pressure  the  blood  is  practically  saturated 
with  oxygen  whatever  (within  physiological  hmits)  the  pressure  of  the  carbon 
dioxide.  At  lower  pressures  of  oxygen,  however,  the  pressure  of  carbon 
dioxide  makes  a  considerable  difference.  Thus  at  an  oxygen  pressure  of 
20  mm.  Hg.  the  amount  of  oxyhsemoglobin  formed  is  67-5  per  cent,  at  a 
carbon  dioxide  pressure  of  5  mm.,  whereas  at  a  pressure  of  carbon  dioxide 
of  40  mm.  the  amount  of  oxyhsemoglobin  is  only  29-5  per  cent.  -  In  con- 


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Fig.  498.     Dissociation  curve  of  sheep's  blood. 

1,  normal  blood  ;  2,  blood  containing  0-04  per  cent,  added  lactic  acid ; 

3,  blood  containing  0-08  per  cent,  added  lactic  acid. 

sequence  of  this  fact,  in  the  tissues,  where  the  carbon  dioxide  tension  is  high, 
the  oxyhasmoglobin  will  be  dissociated  with  greater  ease,  so  that  oxygen 
will  be  set  free  where  it  is  most  wanted. 

We  are  now  in  a  position  to  understand  how  the  oxygen  is  taken  up 
by  the  blood  as  it  circulates  round  the  pulmonary  alveoli.  Arterial  blood, 
such  as  that  which  fills  the  pulmonary  veins  and  the  systemic  arteries,  is 
very  nearly  {i.e.  about  90  per  cent.)  saturated  with  oxygen,  and  will  only 
take  up  about  2  volumes  per  cent,  more  on  shaking  it  with  air  at  the  body 
temperature.  Venous  blood  requires  8  to  10  volumes  per  cent,  of  oxygen  to 
saturate  it ;  but  we  have  already  mentioned  that,  at  a  tension  of  30  mm. 
oxygen,  the  blood  becomes  nearly  saturated.  The  tension  of  oxygen  in 
the  alveoli  is  considerably  above  this.  In  the  trachea  the  tension  of  oxygen 
is  about  \  of  an  atmosphere  (since  the  air  here  contains  16  volumes  per 
cent.),  and  the  tension  in  the  alveoli  will  be  a  little  lower  than  this. 
If  we  take  the  oxygen  tension  in  the  alveoli  at  \  of  an  atmosphere,*  it  will 
still  be  something  over  100  mm.  Hence  the  venous  blood  brought  to  the 
alveoli  by  the  pulmonary  artery  will,  on  there  coming  into  intimate  contact 

*  The  oxygen  tension  in  the  alveoli  has  been  reckoned  at  about  12*6  per  cent,  to 
13*5  per  cent,  of  an  atmosphere. 


THE  CHEMISTRY  OF  RESPIRATION  1063 

with  the  atmosphere,  take  up  oxygen  from  it  to  saturation,  or  to  a  point 
not  far  removed  from  it. 

The  blood,  thus  laden  with  oxygen,  travels  to  the  left  side  of  the  heart, 
and  from  there  is  sent  through  the  arteries  to  all  parts  of  the  body.  It 
must  be  remembered  that  neither  in  the  lungs  nor  in  the  tissues  does  the 
haemoglobin  come  in  actual  contact  wath  the  source  of  the  oxygen,  nor 
with  the  cells  which  it  is  to  supply.  In  both  cases  the  interchange  is  effected 
through  the  intermediation  of  the  plasma  and,  in  the  tissues,  of  the  lymph 
as  well.  Since  the  tissue-elements  are  constantly  using  up  oxygen,  they 
absorb  any  oxygen  that  is  present  in  the  surrounding  lymph.  There  is,  in 
consequence,  a  descending  scale  of  oxygen  tensions  from  red  blood-corpuscle 
through  plasma,  vessel  wall,  lymph,  and  tissue-element.  The  cell  draws  from 
the  lymph,  and  the  lymph  from  the  plasma,  so  that  the  oxygen  tension  in  the 
plasma  sinks.  This  has  the  same  efEect  as  if  we  put  the  red  corpuscles  in  a 
mercurial  pump  and  lowered  the  pressure  of  gas.  The  immediate  result  is  an 
evolution  of  oxygen,  which  is  taken  up  by  the  plasma,  to  be  in  turn  passed 
on  to  the  lymph  and  the  tissue-cell. 

Under  normal  circumstances  a  blood-corpuscle  never  stays  long  enough 
in  the  proximity  of  the  tissues  to  lose  its  whole  store  of  oxygen.  If,  how- 
ever, the  further  supply  of  oxygen  to  the  blood  be  prevented,  as  in  asphyxia, 
the  last  traces  of  oxygen  disappear  from  the  blood.  The  enormous  avidity 
of  the  tissues  for  oxygen  is  shown  by  the  following  experiment  (Ehrlich).  If 
a  saturated  solution  of  methylene  blue  be  injected  into  the  circulation  of  a 
living  animal  and  the  am'mal  be  killed  ten  minutes  later,  it  is  found  on  first 
opening  the  body  that  most  of  the  organs  present  their  natural  colour, 
although  the  blood  is  a  dark  blue  colour.  On  exposure  to  the  atmosphere 
all  the  organs  acquire  a  vi^^d  blue  colour.  The  a^^dity  of  the  tissues  for 
oxygen  has  been  so  great  that  they  have  been  able  to  decompose  the  methy- 
lene-blue  molecule,  with  the  formation  of  a  colourless  reduction-product, 
which  on  exposure  to  the  air  undergoes  oxidation  again  and  re-forms 
methylene  blue.  If  the  tissues  are  able  to  effect  the  reduction  of  a  com- 
paratively stable  body  Hke  methylene  blue,  it  is  easy  to  understand  their 
power  of  reducing  oxyhaemoglobin,  which  is  so  unstable  that  it  is  decom- 
posed by  simple  physical  means  such  as  exposure  to  a  vacuum. 

It  was  long  debated  whether  the  chief  processes  of  oxidation  took  place 
in  the  blood  or  in  the  tissues.  Our  experiences  with  muscle  would  alone 
serve  to  convince  us  that,  in  some  tissues  at  any  rate,  processes  of  oxidation 
take  place,  and  the  methylene-blue  experiment  shows  that  these  processes  of 
oxidation  are  intense  in  all  the  chief  organs  of  the  body.  It  has  been  found 
moreover  that  it  is  possible  to  keep  a  frog  alive  after  substituting  normal 
saline  solution  for  his  blood,  if  he  be  placed  in  absolutely  pure  oxygen,  and 
that  in  this  case  indeed  the  metabolism  of  the  animal  goes  on  as  actively  as 
before.  As  the  frog  has  no  blood,  it  is  evident  that  its  metabolic  processes, 
consisting  of  the  taking  up  of  oxygen  and  the  giving  out  of  carbon  dioxide, 
must*  have  their  seat  in  the  tissues. 

As  a  result  of  the  oxidative  changes  in  the  tissues  carbon  dioxide  is 


1064 


PHYSIOLOGY 


produced,  and  the  tension  of  this  gas  in  the  tissues  therefore  rises.  AsBarcroft 
has  pointed  out,  in  cold-blooded  animals  the  dissociation  of  oxyhsemoglobin 
with  the  setting  free  of  oxygen  must  be  largely  conditioned  by  the  rise  of 
carbon  dioxide  tension  in  the  tissues,  since  at  the  normal  temperature  of 
these  animals  the  evolution  of  oxygen  from  haemoglobin  is  extremely  slow. 
The  alteration  in  reaction  of  the  blood  caused  by  a  rise  in  COg  tension  or 
by  the  presence  of  small  amounts  of  lactic  acid,  markedly  quickens  the  rate 
at  which  oxyhsemoglobin  gives  up  its  oxygen,  as  is  shown  in  Fig.  499.     The 


Fig.  499.  Curves  showing  the  rate  at  which  arterial  blood  is  reduced  on  bubbling 
through  a  gas  free  from  oxygen,  and  the  effect  on  the  rate  of  the  presence  of 
COg  and  of  lactic  acid.  Ordinates  =  percentage  saturation  of  oxyhaemoglobin. 
Abscissae  =  time  in  minutes.     (Mathison.) 

carbon  dioxide  tension  in  the  tissues  may  be  approximately  measured  by 
taking  the  tension  of  this  gas  in  fluids  such  as  the  bile  or  urine.  Here  it  may 
amount  to  8  or  10  per  cent,  of  an  atmosphere,  and  since  the  carbon  dioxide 
in  venous  blood  is  rarely  above  6  per  cent,  of  an  atmosphere,  there  is  a  descend- 
ing scale  of  tensions  from  tissue  to  blood,  just  as  there  is  an  ascending  scale 
in  the  case  of  oxygen.  This  gas  therefore  passes  from  the  tissues  through 
the  lymph  into  the  blood  by  a  simple  process  of  diffusion. 

The  carbon  dioxide  carried  by  the  blood  is,  Hke  the  oxygen,  chiefly  in  a 
state  of  chemical  combination.  From  dogs'  venous  blood  we  may  obtain  by 
means  of  the  pump  about  50  c.c.  of  carbon  dioxide  per  100  c.c.  blood.  Water 
at  the  temperature  of  the  body,  if  shaken  up  with  an  atmosphere  of  carbon 
dioxide  at  a  pressure  of  760  mm.  Hg.,  would  take  up  about  50  per  cent,  of  the 
gas,  and  the  plasma  as  a  mere  solvent  would  take  up  shghtly  less.  The  tension 
of  carbon  dioxide  in  the  blood  is,  however,  much  less  than  1  atmosphere. 


THE  CHEMISTRY  OF  RESPIRATION 


1065 


Shaken  up  with  pure  carbon  dioxide  at  a  pressure  of  1  atmosphere,  the 
blood  would  take  up  as  much  as  150  per  cent.  If  we  determine  the  tension 
of  the  carbon  dioxide  in  the  blood  by  one  of  the  methods  to  be  described 
later,  we  find  that  in  venous  blood  this  gas  is  at  a  pressure  of  only  about 
5  to  6  per  cent,  of  an  atmosphere  (about  40  mm.  Hg.).  Taking  the  pressure 
of  the  carbon  dioxide  as  -^^^jof  an  atmosphere,  and  kno\ving  that  at  a  pressure 
of  1  atmosphere  the  blood 


50 


IS 


might  dissolve 
per    cent.,     it 
that   at  ^g    of 
sphere    the     blood 


an 


volumes 

evident 

atmo- 

would 

only  dissolve  |  {}  volumes  per 
cent.,  i.e.  about  2|-  volumes. 
All  the  rest  of  the  carbon 
dioxide  in  the  blood  must 
therefore  be  in  combination 
(cp.  Fig.  500). 

The  carbon  dioxide  is 
contained  chiefly  in  the 
plasma,  though  a  certain 
amount  is  also  in  combina- 
tion in  the  corpuscles.  Part 
of  the  carbon  dioxide  must 
be  in  combination  with 
some  constituent  common 
to  both  plasma  and  cor- 
puscles. When  blood- 
plasma  is  calcined,  the  ash 
is  found  to  be  distinctly 
alkahne  and  to  contain  an 
amount  of  sodium  greater 
than  is  necessary  to  com- 
bine with  the  other  acid 
radicals,   e.g.   CI,   SO4,   and 


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50  60  70  80 

COl    vrv     nvTM.   9Ca. 

Fig.  500.  Curve  of  CO2  tension  in  blood. 
(Christiaijsen,  Douglas  and  Haldajse) 
This  curve  shows  the  influence  of  the  saturation  of 
the  haemoglobin  with  oxygen,  on  the  amount  of  CO2 
taken  up  by  the  blood  at  various  pressures.  Upper 
curve  =  absorption  of  COo  by  human  blood  in 
presence  of  hydrogen  and  COo.  Middle  curve  = 
absorption  of  CO2  by  human  blood  in  presence  of 
air  and  C02.  Lower  curve  =  absorption  of  COo  in 
blood  of  ox  and  dog  in  presence  of  air ;  the  tluck 
line  A-B  represents  the  absorption  of  COo  by 
human  blood  within  the  body  (supposing  the  blood 
is  completely  deoxj'gcnated  in  the  tissues).  It  is 
evident  that  an  increase  of  15  c.c.  per  cent,  of  COo 
in  the  blood  as  it  passes  through  the  tissues  would 
raise  the  tension  of  this  gas  in  the  blood  onlj' 
22  mm  Hg  (from  40  to  62).  Under  normal  con- 
ditions the  rise  of  COo  pressure  in  the  blood  on 
passing  through  the  tissues  is  not  more  than 
5-7  mm.  Hg. 


90 


PO4,  and  this  excess  becomes 
greater  if  we  consider  that  a 
great  part  of  the  PO4  and  SO4 
is  derived  from  the  oxidation 
of  the  sulphur  and  phos- 
phorus present  in  organic  combination  in  the  plasma.  We  may  therefore 
conclude  that  a  considerable  part  of  the  carbon  dioxide  exists  in  the  plasma 
as  sodium  carbonate  or  sodium  bicarbonate.  In  the  same  way  a  certain  pro- 
portion of  the  carbon  dioxide  which  is  held  by  the  corpuscles  is  probably  in 
combination  with  sodium.  Haemoglobin  also  has  the  power  of  combining 
with  carbon  dioxide,  and  unstable  compounds  may  be  formed  between 
carbon  dioxide  and  the  proteins  of  the  plasma  itself.     According  to  Loewy 

34* 


1-9  c.c. 

6-8  \ 
12-0  j  ~ 

18-8  c.c 

7-5  \ 
11-8/ 

19-3  c.c 

1066  PHYSIOLOGY 

one  hundred  cubic  centimetres  of  arterial  blood  from  the  dog  would  yield 
normally  about  40  c.c.  of  carbon  dioxide.  These  40  c.c.  would  be  divided 
as  f  oUows  : 

In  simple  solution  in  the  plasma  and  corpuscles   . 

,  .      ,        ,     f(a)  in  corpuscles     . 
As  sodium  bicarbonate  {  ,y.  .      i 

y(o)  m  plasma 

In  organic  combination  with  haemoglobin  in  corpuscles 

In  organic  combination  with  proteins  of  the  plasma 

It  will  be  noted  that  although  we  are  deahng  here  with  arterial  blood, 
in  which  the  tension  of  carbon  dioxide  is  comparatively  low,  the  carbon 
dioxide  is  stated  to  be  in  combination  as  bicarbonate.  This  is  on  account 
of  the  fact  that  in  no  case  is  the  alkalinity  of  the  blood  equal  to  that  of  a 
solution  of  sodium  carbonate.  On  the  other  hand,  if  we  expose  blood 
to  a  vacuum  the  whole  of  the  carbon  dioxide  is  given  off.  If  sodium  bicar- 
bonate be  exposed  to  a  vacuum,  only  half  of  the  carbon  dioxide  is  evolved, 
sodium  carbonate  itself  not  undergoing  any  decomposition  in  vacuo.  If 
we  attempt  to  extract  the  carbon  dioxide  from  blood-serum  or  blood- 
plasma,  we  may  obtain  nearly  all  the  carbon  dioxide  present,  the  last  5  per 
cent.,  however,  requiring  the  addition  of  a  weak  acid  such  as  oxalic  or 
phosphoric  acid  in  order  that  it  may  be  given  off.  How  are  we  to  explain  the 
difference  between  the  behaviour  of  blood  and  the  behaviour  of  a  solution  of 
sodium  bicarbonate  ? 

We  may  artificially  make  a  fluid  which  behaves  to  carbon  dioxide  in 
the  same  way  as  blood,  by  mixing  together  sodium  carbonate  and  sodium 
hydrogen  phosphate  Na2HP04.  From  such  a  mixture  the  whole  of  the 
carbon  dioxide  may  be  given  off  when  exposed  to  a  vacuum.  On  the  other 
hand,  a  large  amount  of  carbon  dioxide  will  be  taken  up  with  a  very  small 
difference  in  tension  of  the  gases.  The  behaviour  of  the  mixture  is  due  to  an 
interaction  which  occurs  between  the  acid  radicals  PO4  and  CO3.  When  the 
mixture  is  exposed  to  a  vacuum  any  sodium  bicarbonate  present  will  undergo 
dissociation,  carbon  dioxide  being  given  off  and  the  carbonate  NagCOs 
formed.  This  then  reacts  with  the  sodium  phosphate  in  the  following 
way  : 

2NaH2P04  +  NagCOg  =  2Na2HP04  +  COg  +  H2O. 

In  this  way  the  whole  of  the  sodium  enters  into  combination  with  the  PO4 
and  the  carbon  dioxide  previously  combined  is  given  off.  On  exposing 
the  mixture  to  an  atmosphere  containing  carbon  dioxide,  the  reverse  change 
takes  place,  and  we  get  once  again  sodium  hydrogen  phosphate  and  sodium 
carbonate,  and  finally  sodium  bicarbonate.  It  was  formerly  thought  that  in 
the  blood- plasma  phosphates  were  an  important  factor  in  the  evolution  of 
the  carbon  dioxide.  Blood-plasma,  however,  contains  the  merest  trace  of 
phosphates,  and  the  role  of  a  weak  acid  competing  with  the  carbon  dioxide 
for  the  sodium  is  played  chiefly  by  the  proteins  of  the  plasma.  We  can  in 
fact,  by  adding  proteins  to  a  solution  of  sodium  carbonate  and  exposing  the 
mixture  to  a  vacuum,  obtain  the  evolution  of  practically  all  the  carbon 


THE  CHEMISTRY  OF  RESPIRATION 


1067 


dioxide  previously  in  combination  with  the  sodium.  In  the  corpuscles  both 
haemoglobin  and  proteins  play  the  part  of  a  weak  acid.  When  plasma 
is  exposed  to  a  vacuum  it  is  necessary,  as  we  have  seen,  to  add  a  httle  acid 
in  order  to  obtain  the  last  traces  of  carbon  dioxide  from  the  fluid.  Instead 
of  adding  a  weak  acid,  haemoglobin  or  red  blood-corpuscles  may  be  employed. 
In  the  latter  case  it  seems  probable  that  the  action  on  the  carbonates  of  the 
plasma  is  due  not  so  much  to  the  haemoglobin  as  to  an  interchange  of  acid 
radicals  between  the  corpuscles  and  the  plasma.  If  carbon  dioxide  be 
passed  into  defibrinated  blood  the  alkalinity  of  the  plasma  increases 
while  the  chlorides  diminish,  and  it  is  probably  the  reverse  interchange 
of  radicals  between  corpuscles  and  plasma  which  is  responsible  for  the 
evolution  of  carbon  dioxide  on  the  addition  of  corpuscles  to  plasma  in 
vacuo. 

THE  ALKALINITY  OF  BLOOD.  Blood-plasma  is  generally  described  as 
shghtly  alkahne,  and  its  alkahnity  is  measured  in  terms  of  deci-  or  centi- 
normal  acid.  The  term  alkahnity  is  relative.  Caustic  alkali  owes  its 
alkahnity  to  the  presence  of  OH  ions.  The  neutrahty  of  distilled  water  is 
due  to  the  presence  of  practically  equal  amounts  of  H  and  OH  ions  in  the 
fluid.  We  may  measure  the  concentration  of  H  or  OH  ions  in  a  fluid 
electrically.*  If  this  electrical  method  be  apphed  to  blood  or  blood-plasma 
it  reveals  either  of  these  fluids  as  practically  neutral,  i.e.  there  is  httle  or  no 
greater  concentration  of  H  or  OH  ions  in  blood  than  in  distilled  water.     The 

*  By  the  use  of  diflferent  indicators  we  may  arrive  at  some  conclusion  as  to  the 
approximate  concentration  of  hydi'ogen  ions  in  any  given  liquid.  In  the  following 
Table  are  set  out,  from  a  paj>er  by  Roaf,  the  colours  of  a  number  of  different  indicators, 
and  the  degree  of  acidity  which  is  sufficient  to  change  their  colours  : 


Indicator 

Acid  colour 

Transitional 
colour 

Alkaline  colour 

Hydrogen  ion  concentra- 
tion at  whicli  colour 
change  begins 

Dimethylamido- 
azobenzol 

[-      Red 

Orange 

Yellow 

1   X  10-3 

Congo  red 

Blue       1 

Purple  and 
brown 

1      Red 

1   X  10* 

Vesuvin  brown  . 

Brown 

— 

Yellow 

1   X  10-" 

Gallein      . 

Colourless 

Pink 

Red 

1   X  10-" 

Na  alizarine 
sulphonate 

1     Yellow 

Orange 

Red 

1  X  10-* 

Lacmoid  . 

Red 

Purple 

Blue 

1   X  10-"  -  1   X  10-8 

Rosolic  acid 

Yellow 

Orange 

Red 

1   X  10-6 

Litmus 

Red 

Purple 

Blue 

1   X  10-5  _  1   X  10-8 

Neutral  red 

Red 

Orange 

Yellow 

1   X  10-8 

Alizarine  . 

Yellow 

Orange 

Red 

1   X  10-8 

Phenolphthalein 

Colourless 

Pink 

Red 

1      X    10      9 

It  should  be  remembered  that  in  distilled  water  of  the  highest  state  of  purity  the 
concentration  of  H  and  OH  ions  respectively  is  about  1  x  10-'. 


1068  PHYSIOLOGY 

reaction  of  blood  as  normally  taken  depends  as  a  matter  of  fact  on  the 
indicator  whicti  is  used.     Thus  blood-plasma  is  acid  to  phenolphthalein, 
but  alkaline  to  htmus.     On  the  other  hand,  the  carbon  dioxide  and  proteins 
in  combination  with  the  sodium  may  be  easily  replaced  by  stronger  acid 
radicals,  and  if  the  carbon  dioxide  be  allowed  to  escape,  very  little  change 
in  the  reaction,  i.e.  in  the  concentration  of  H  or  OH   ions  respectively, 
will  be  produced.     We  may  thus  speak  of  blood-plasma  as  actually  neutral, 
though  potentially  alkahne  in  that  it  can  neutralise  a  considerable  amount 
of   acid.     This   potential   alkalinity  is   more   important  than  the   actual 
alkahnity,  since  on  it  depends  the  power  possessed  by  the  blood  of  carrying 
carbon  dioxide  from  the  tissues  to  the  lungs.     By  adding  a  fixed  acid  to  the 
blood  we  may  use  up  this  potential  alkahnity  and  finally  arrive  at  a  point  at 
which  each  addition  of  acid  makes  a  proportionate  increase  in  the  actual 
acidity,  i.e.  in  the  concentration  of  H  ions.     From  this  time  forward, 
however,  the  plasma  has  lost  its  power  of  binding  carbon  dioxide  and  can 
carry  this  gas  only  in  simple  solution.     On  exposure  of  such  plasma  to  carbon 
dioxide  the  tension  of  the  gas  rapidly  rises  in  the  fluid,  which  becomes 
saturated  when  only  a  relatively  small  amount  of  gas  has  entered  into  the 
fluid.     Any  diminution  of  the  so-called  alkalinity  of  the  blood  or  blood- 
plasma  will  seriously  impair  the  function  of  the  blood  in  respiration.     An 
example  of  such  a  condition  is  the  acidosis  which  occurs  in  diabetes,  or  in 
any  other  form  of  carbohydrate  starvation. 

EXCHANGE  OF  GASES  IN  THE  LUNGS 

A  fluid  gives  off  gas  to  or  takes  up  gas  from  any  other  medium  with  which 
it  is  in  contact,  according  to  the  relative  pressures  of  the  gas.  The  question 
arises  whether  the  physical  conditions  in  the  lungs  are  such  as  to  account  for 
the  absorption  of  oxygen  and  the  evolution  of  carbon  dioxide  by  the  blood  in 
its  passage  through  these  organs.  In  order  to  answer  this  question  we  must 
know  the  partial  pressures  or  tensions  of  oxygen  and  of  carbon  dioxide  in  the 
alveolar  air,  in  the  venous  blood  coming  to  the  lungs,  and  in  the  arterial 
blood  leaving  the  lungs.  In  the  alveoli  the  pressures  are  given  by  the  analysis 
of  alveolar  air.  The  determination  of  the  gaseous  tensions  in  the  blood 
presents,  however,  considerable  difficulty.  It  is  necessary  to  bring  the 
blood  in  contact  with  gaseous  mixtures  containing  various  proportions 
of  the  gas  whose  tension  in  the  blood  it  is  desired  to  measure.  By  making 
various  experiments  a  gaseous  mixture  will  be  found  with  which  the 
blood  is  in  equilibrium.  If  we  know  beforehand  the  amount  of  gas  in 
this  mixture,  we  know  its  tension  and  therefore  the  tension  of  the  gas  in 
the  liquid. 

Pfliiger's  aerotonometer  (Fig.  501)  consists  of  two  glass  tubes,  R  and  R,  contained  in  a 
vessel  filled  with  water  at  the  temperature  of  the  body.  The  upper  ends  of  the  tubes 
are  connected  by  the  tube  a  with  the  artery  or  vein  in  which  it  is  desired  to  estimate 
the  tension  of  the  blood-gases.  If,  for  instance,  we  wish  to  determine  the  tension  of 
CO2  in  venous  blood,  where  we  expect  the  tension  to  amount  to  about  4  per  cent,  of  an 
atmosphere,  one  tube  R  is  filled  with  a  gaseous  mixture  containing  3  per  cent.  CO2,  and 


THE  CHEMISTRY  OF  RESPIRATION 


1069 


the  other  tube  R  with  a  mixture  containing  5  per  cent.  COo.  a  is  now  connected  with 
the  distal  end  of  the  jugular  vein,  or  with  the  central  end  of  the  carotid  artery,  and 
blood  is  allowed  to  flow  in  a  thin  stream  down  the  walls  of  the  tubes  R  and  R,  thus 
presenting  a  large  surface  to  the  contained  gases.  The  blood  collects  in  the  lower 
narrower  jiortions  of  the  tubes,  and  runs  out  into  the  vessels  h,  b,  whence  after  defibrina- 
tion it  is  returned  at  intervals  into  the  veins  of  the  animal. 

Bohr's  aerotonometer  was  built  on  the  plan  of  the  Stromaiche  devised  by  Ludwig, 
and  could  be  inserted  in  the  course  either  of  an  artery  or  of  a  vein.     In  using  this  instru- 
ment it  is  advisable  to  inject  some  sub- 
stance  like   peptone  or,  better,  hirudin, 
in  order  to  prevent    coagulation   of   the 
blood. 

In  all  these  instruments  the 
main  difficulty  is  in  obtaining 
a  sufficient  surface  of  the  blood 
exposed  to  the  gaseous  mixture. 
The  interchange  of  gases  is  thus 
very  slow,  and  it  is  difficult  to  be 
certain  at  any  time  that  the  blood 
and  the  gas  with  which  it  is  in  con- 
tact are  really  in  equihbrium.  Krogh 
therefore  adopted  an  ingenious  de- 
vice of  limiting  the  volume  of  air  to 
a  small  bubble,  the  superficial  area 
of  which  is  large  in  proportion  to 
its  bulk.  This  bubble,  after  it  has 
been  in  a  stream  of  blood  for  some 
minutes,  is  transferred  to  a  special 
capillary  tube  in  which  its  analysis  can  be  carried  out  with  a  fair  degree  of 
accuracy. 

The  performance  of  a  tonometer  may  be  expressed   by  the  ratio  of  the  surface  of 
blood  exj)osed  to  the  volume  of  the  air  used.     The  '  specific  surface  '  of  an  aerotonometer 
area  in  sq.  cm. 


Fig.  501.     Pfliiger's  aerotonometer. 


is  represented  by 


The  specific  surface  of  Pfliiger's  instrument  is  only 


volume  in  c.c. 

3-3  and  of  Bohr's  only  5-2.  In  Krogh's  microtonometer  the  absolute  volume  of  air 
employed  is  reduced  to  a  bubble  of  about  2  mm.  in  diameter,  having  a  volume  of  -004  c.c. 
and  a  surface  of  0-125  sq.  cm.,  so  that  its  specific  surface  is  30.  In  such  a  bubble  the 
equalisation  of  the  tensions  takes  place  with  extreme  rapidity  and  only  a  minute 
quantity  of  fluid  is  necessary.  The  microtonometer  consists  of  the  tonometer  proper 
and  the  apparatus  for  the  microanalysis  of  the  gas  bubble.  In  the  latter  the  measure- 
ment of  the  gas  bubble  is  carried  out  in  a  capillary  tube,  the  absorption  of  carbon  dioxide 
and  of  oxygen  being  carried  out  in  the  usual  way  with  potash  and  with  pyrogallic  acid. 
The  tonometer  is  represented  in  Fig.  502.  It  is  kept  in  a  small  water-bath  at  the  tem- 
perature of  the  blood  to  be  examined.  The  tonometer  is  filled  with  saline  solution  and 
contains  the  gas  bubble  2,  which  can  be  drawn  up  by  mean.s  of  the  screw  4  into  the 
narrow  graduated  tube  3,  where  its  volume  is  measm'ed.  The  blood  from  the  artery  or 
vein,  in  which  we  wish  to  examine  the  tension  of  the  gases,  passes  by  a  cannula  through 
the  tube  1,  and  enters  the  tonometer  as  a  fine  jet.  It  forces  its  way  up  above  the  gas 
bubble,  which  is  pressed  a  little  down  by  the  current,  and  kept  oscillating  with  great 
rapidity.  From  the  tonometer  the  blood  flows  back  througii  the  tube  7  and  is  collected 
in  a  vessel  wliere  it  can  bo  measured  and  afterwards  drawn  off  and  reinjected  into  the 


1070 


PHYSIOLOGY 


animal  if  necessary.  Since  the  total  pressure  of  the  gases  in  the  blood  is  nearly  always 
negative,  it  is  necessary  to  keep  the  pressure  in  the  tonometer  also  negative.*  This  is 
accompUshed  by  means  of  a  mercury  valve  and  can  be  regulated  to  any  desired  pressure. 
During  the  comrse  of  a  tonometric  experiment  the  volume  of  the  gas  bubble  is 
measured  from  time  to  time  by  di'awing  it  up  into  the  graduated  tube,  and  the  pressure 
is  regulated  until  the  volume  of  the  bubble  remains  constant.  After  five  minutes 
gaseous  equilibrium  vdll  have  been  established  between  the  gas  bubble  and  the  surround- 
ing blood,  and  it  is  only  necessary  then  to  draw  it  up  into  the  graduated  tube  and  analyse 
it  in  order  to  determine  the  tension  of  the  gases  in  the  blood.  Clotting  of  the  blood  is 
prevented  by  the  injection  of  hirudin. 

B 


Fig.  502.     a,  Krogh's  microtonometer.     b,  upper  part  of  microtonometer  showing 
capillary  tube  into  which  the  bubble  is  returned  for  measurement  and  analysis. 

In  the  experiments  the  tension  of  the  air  in  the  alveoK  of  the  animal's 
lungs  or  in  the  bifurcation  of  the  trachea  was  determined  by  taking  samples 
of  the  air.  The  results  of  the  experiments  show  that  the  tension  of  the 
gases  in  arterial  blood  follows  closely  the  tension  of  the  corresponding  gases 
in  the  alveolar  air.  The  tension  of  carbon  dioxide  in  arterial  blood  is  either 
identical  with  or  very  shghtly  above  the  tension  of  the  gas  in  the  alveolar 
air.  The  oxygen  tension  of  the  blood  is  always  lower  than  the  alveolar 
oxygen  tension,  and  the  difference  is  generally  1  to  2 — even  3  to  4: — per  cent, 
of  an  atmosphere.  The  results  of  a  series  of  determinations  of  the  tensions 
of  the  gases  in  the  blood  and  alveolar  air  respectively  are  given  in  Fig.  503. 
In  Fig.  504  a  and  b  (Krogh)  the  composition  of  the  alveolar  air  was  artificially 
*  Otherwise  the  whole  bubble  would  gradually  go  into  solution  and  disappear. 


THE  CHEMISTRY  OF  RESPIRATION  1071 

altered  by  increasing  the  percentage  of  carbon  dioxide  and  of  oxygen 
respectively.  It  will  be  seen  in  each  case  that  there  was  a  corresponding 
alteration  of  the  tension  in  the  arterial  blood,  the  tension  of  carbon  dioxide 


30        •tO        50 


20      30      to       SO 


Fig.  503.     Tensions  of  Oo  and  CO2  in  alveoli  compared  with  those  in  arterial 

blood  of  rabbit. 
The  dotted  lines  represent  the  tensions  in  the  alveolar  air,  the  uninterrupted 
lines  the  tensions  of  the  gases  in  the  arterial  blood.     (Krogh.) 

being  higher  and  that  of  oxygen  lower  in  the  blood  than  iu  the  air  throughout 
the  experiment.  We  have  no  direct  determinations  of  the  tensions  of  the 
gases  in  the  blood  of  man,  though  an  approximate  valuation  of  these  tensions 


\kl 

^OSS 

yf7           %    O2 

1$ 

/n  inspired 

w 

;  /'' 

air 

IT 

;/ 

16 

•1 
•1 

i  '■ 

it) 

1/ 

li- 

' 

\u 

13 

\  \ 

12 

■    .-.- ^ 

V " 

11 

■ 

1 

10 

0- 

Oz 

Z 

+ — 

^23^ 

/JO     *o       io 


iO       30       *<?       50 


3filT<t 


Fig.  504.     Tensions  of  gases  in  alveolar  air  and  in  arterial  blood. 

A,  during  artificial  increase  of  oxygen  tension  in  alveoli ;  b,  during  artificial 

increase  of  CO2  tension  in  alveoli. 

can  be  obtained  by  knowing  the  degree  to  which  the  arterial  and  venous 
blood  respectively  are  saturated  with  oxygen  or  carbon  dioxide.  An  indirect 
method  may  be  employed  to  measure  the  gaseous  tensions  in  the  venous 
blood  coming  to  the  lungs.     It  is  possible,  as  Loewy  has  shown,  to  block  the 


1072  PHYSIOLOGY 

right  bronchus  in  man  by  introducing  a  catheter  through  the  larynx  and 
trachea,  so  that  the  renewal  of  air  in  the  right  half  of  the  lung  is  entirely 
stopped  for  some  time.  A  sample  of  air  in  the  blocked  lung  can  be  taken 
at  any  time  by  means  of  the  catheter.  The  interchange  of  gases  between 
alveolar  air  and  blood  will  go  on  until  the  tension  of  gases  in  the  air  is  the 
same  as  that  coming  to  the  blocked  portion  of  lung.  By  this  means  the 
tension  of  the  oxygen  in  the  venous  blood  was  found  to  be  5-3  per  cent.  —  37 
mm.  Hg.,  and  that  of  the  carbon  dioxide  6  per  cent.  =  46  mm.  Hg. 
The  tensions  in  the  alveolar  air  of  man  may  be  taken  as  follows  : 

Oxygen    ......     107  mm.  Hg. 

Carbon  dioxide .  .  .  .  .       40       „ 

As  the  venous  blood  enters  the  lungs  there  is  thus  a  difference  of  pressure 
of  107  —  37  =  70  mm.  Hg.,  which  will  tend  to  cause  a  flow  of  oxygen  from 
alveolar  air  to  blood  and  a  difference  of  46  -  40  =  6  mm.  Hg.,  tending 
to  cause  a  flow  of  carbon  dioxide  from  blood  to  alveolar  air.  Is  this  difference 
sufiicient  to  account  for  the  amount  of  gas  given  off  or  taken  up  by  the  blood 
in  its  passage  through  the  lungs  ?  In  a  state  of  medium  distension  the 
3000  c.c.  of  air  contained  by  the  lungs  have  been  estimated  to  occupy  seven 
hundred  milhon  alveoh,  each  of  which  has  a  diameter  of  0-2  mm.,  so  that  the 
total  surface  over  which  the  blood  is  exposed  to  the  alveolar  air  amounts  to 
90  square  metres.  This  is  a  minimal  figure,  since  no  account  is  taken  in  the 
calculation  of  the  augmentation  of  surface  caused  by  the  fact  that  the  capil- 
laries project  into  the  lumen  of  the  alveolus,  and  by  Hiifner  the  total  surface 
exposed  is  calculated  at  140  square  metres.  The  former  figure,  however, 
amounts  to  about  1000  square  feet  and  is  equivalent  to  the  floor-space  of  a 
room  50  feet  long  by  20  feet  wide.  It  is  important  to  realise  that  the  blood 
passing  through  the  pulmonary  artery  suddenly  spreads  out  into  a  layer 
which  is  not  more  than  one  blood- corpuscle  thick,  and  is  exposed  to  the  air 
over  this  huge  area,  whence  it  is  picked  up  again  and  collected  into  the 
pulmonary  veins.  Such  a  means  of  facihtating  rapid  interchange  of  gases 
between  the  blood  and  a  given  volume  of  air  we  cannot  possibly  imitate 
artificially.  The  thickness  of  the  tissue  separating  this  layer  of  air  from 
the  alveolar  air  is  on  the  average  -004  mm.  Loewy  and  Zuntz  have  direetly 
calculated  the  velocity  of  diffusion  of  carbon  dioxide  and  nitrous  oxide 
through  the  frog's  lung  and  have  calculated  therefrom  the  rate  at  which 
oxygen  would  diffuse  through  a  similar  layer  of  tissue,  taking  into  account 
the  much  greater  solubility  of  carbon  dioxide  as  compared  with  oxygen. 
They  calculate  that  under  a  constant  difference  of  pressure  of  35  mm.  Hg., 
6-7  c.c.  of  oxygen  would  pass  in  a  minute  through  each  square  centimetre 
of  the  alveolar  wall.  Through  the  whole  surface  of  the  lung  this  would 
amount  to  an  absorption  of  6083  c.c.  oxygen.  The  oxygen  actually  absorbed 
by  a  man  at  rest  amounts  to  about  300  c.c.  per  minute,  so  that  the  physical 
conditions  allow  an  ample  margin  for  any  increase  in  the  consumption  of 
oxygen  ;  in  fact,  a  difference  of  pressure  of  a  couple  of  milhmetres  would 
suffice  to  cause  a  passage  of  the  250  c.c.  per  minute  which  is  required  by  the 


THE  CHEMISTRY  OF  RESPIRATION  1073 

resting  man.  In  the  same  way  it  is  easy  to  account  for  the  passage  of 
carbon  dioxide  in  the  reverse  direction.  This  gas  diffuses  through  a  wet 
membrane  about  twenty-five  times  as  rapidly  as  oxygen,  so  that  a  differ- 
ence of  pressure  between  the  blood  and  the  alveolar  air  amounting  to  only 
•03  mm.  Hg.  would  suffice  to  cause  a  passage  outwards  of  the  250  c.c. 
normally  expired  per  minute. 

It  is  evident  that  the  only  hmitation  for  the  absorption  of  oxygen  is  given 
by  the  power  of  the  hsemoglobin  to  combine  with  the  oxygen  which  passes 
through  the  alveolar  wall  into  the  blood-plasma. 

If  we  look  at  the  dissociation  curve  of  the  oxy haemoglobin  in  mammaUan 
blood  given  on  p.  1061  we  see  that  the  amount  of  oxygen  which  can  be  taken 
up  by  haemoglobin  in  the  presence  of  the  normal  tension  of  carbon  dioxide, 
i.e.  40  mm.  Hg.,  begins  to  diminish  very  rapidly  when  the  pressure  of  the 
oxygen  falls  below  50  mm.  Hg.  Thus  at  40  mm.  oxygen  pressure  and  a 
carbon  dioxide  tension  of  40  mm.,  oxy haemoglobin  is  about  65  per  cent, 
saturated,  and  at  30  mm.  it  is  only  50  per  cent,  saturated.  Under  normal 
circumstances  the  blood  leaves  the  lungs  over  90  per  cent,  saturated  with 
oxygen.  If  the  saturation  falls  to  60  per  cent,  we  should  expect  to  obtain 
evidence  of  failure  of  oxygen  supply  to  the  tissues.  According  to  Loewy 
the  oxygen  tension  in  the  alveoh  can  sink  to  between  30  and  35  mm.  Hg. 
before  any  signs  of  oxygen  lack  make  their  appearance.  These  results  were 
obtained  by  exposing  a  man  in  a  state  of  complete  rest  to  reduced  pressure 
in  an  air-chamber.  Under  these  conditions  the  shghtest  muscular  exertion 
would  at  once  tend  to  cause  distress  from  deficient  oxygen  supply.  The 
exact  percentage  of  oxygen  in  the  inspired  air  which  would  give  an  alveolar 
oxygen  tension  of  30  to  35  mm.  varies  with  the  depth  of  respiration.  Thus 
with  shallow  respiratory  movements  the  pressure  may  sink  to  35  mm.  Hg, 
when  the  inspired  air  contains  as  much  as  12  per  cent,  oxygen.  If  the  move- 
ments be  deeper  the  oxygen  content  of  inspired  air  may  be  reduced  to  9  or 
10  per  cent,  before  respiratory  distress  is  observed. 

The  view  that  in  the  interchange  of  gases  in  the  lungs  the  membrane  between  the 
blood  and  the  alveolar  aii-  plays  simply  a  passive  part  was  till  recently  by  no  means 
universally  accepted.  In  Bolur's  experiments  on  the  tension  of  oxygen  and  carbon 
dioxide  in  the  blood  as  determined  with  his  aerotonometer,  oxygen  tensions  were  often 
found  considerably  higher  in  the  blood  than  in  the  air  of  the  alveoli,  and  in  the  same  way 
the  carbon  dioxide  tension  of  the  blood  leaving  the  lungs  was  found  to  be  less  than  the 
carbon  dioxide  tension  of  the  alveolar  air.  Krogh's  experiments  show  conclusively, 
however,  that  these  results  are  not  reliable,  and  that  the  difference  between  the  tensions 
in  the  alveoli  and  in  the  blood  respectively  is  always  such  as  to  allow  of  the  passage  by 
diffusion  of  oxygen  inwards  and  carbon  dioxide  outwards  from  the  blood.  Moreover, 
as  Krogh  points  out,  the  structure  of  the  pulmonary  epithelium  lends  no  support  to  the 
view  that  it  acts  as  a  secreting  membrane.  In  mammals  the  cells  are  of  two  kinds,  viz. 
small  granular  nucleated  cells  lying  in  the  interstices  of  the  capillaries,  and  larger, 
extremely  thin  structureless  plates,  irilJwiif  nuclei,  covering  the  capillaries.  In  birds, 
where  the  gaseous  exchange  is  of  all  animals  the  most  rajiid  and  efficient,  the  existence 
of  a  lung  epithelium  has  never  been  demonstrated,  and  the  ca])illaries  appear  to  be 
almost  completely  free  and  to  be  surrounded  with  air  on  both  sides. 

Bohr's  view  as  to  the  secretory  function  of  tlie  ]ndmonary  eiiithelium  was  supported 
as  concerns  tlie  intake  of  oxygen,  by  Haldane.     This  observer  has  devised  a  method  of 


1074  PHYSIOLOGY 

determining  the  oxygen  tension  of  the  blood  in  the  lungs  founded  on  the  use  of  carbon 
monoxide.  It  has  already  been  mentioned  that  carbon  monoxide  has  the  power  of  dis- 
placing oxygen  from  oxyhaemoglobin  to  form  a  much  more  stable  compound,  carboxy- 
hsemoglobin.  If  blood  be  shaken  up  with  a  mixtvu-e  of  oxygen  and  carbon  monoxide, 
the  haemoglobin  distributes  itself  between  the  two  gases.  In  order,  however,  to  get  an 
equal  distribution,  it  is  necessary  to  take  a  very  small  percentage  of  carbon  monoxide, 
owing  to  its  greater  avidity  for  haemoglobin.  Thus,  if  haemoglobin  solution  be  shaken 
up  with  air  containing  "07  per  cent,  of  CO,  the  result  is  a  mixture  of  equal  parts  of  oxy- 
and  carboxyhsemoglobin.     The  aflfinity  of  CO  for  haemoglobin  would  thus  appear  to  be 

21 
about —  =  300  times  the  affinity  of  oxygen  for  haemoglobin. 

Carbon  monoxide  is  not  destroyed  in  the  body,  so  that  if  a  mixture  containing  a 
small  proportion  of  CO  be  breathed,  this  gas  will  be  taken  up  until  a  certain  percentage 
of  haemoglobin  is  converted  into  CO-haemoglobin  and  the  tension  of  CO  in  the  tissues  and 
fluids  of  the  body  is  equal  to  that  of  the  inspired  air.  The  amount  of  haemoglobin  which 
is  converted  into  carboxyhaemoglobin  will  serve  as  a  measure  of  the  relative  tensions 
of  CO  and  oxygen  in  the  lungs.  If  the  oxygen  tension  of  arterial  blood  were  the  same 
as  that  of  the  alveolar  air,  we  should  expect  that,  with  a  given  percentage  of  CO  in  the  air 
breathed,  the  final  satm-ation  with  CO  of  the  blood  within  the  body  would  be  the  same 
as  the  saturation  of  blood  when  shaken  outside  the  body  with  air  containing  the  same 
percentage  of  CO  as  in  the  air  breathed.  It  was  found  by  Haldane,  however,  that  in  all 
cases  the  percentage  of  CO  haemoglobin  farmed  was  much  less  in  the  body  than  outside 
the  body.  Thus  in  blood  shaken  up  with  air  containing  20*9  per  cent,  oxygen  and 
•045  per  cent.  CO,  the  amount  of  carbon  monoxide  formed  was  31  per  cent,  of  the  whole 
haemoglobin.  When  the  same  mixture  was  inhaled  for  three  or  four  hours  by  a  man, 
the  percentage  of  CO  haemoglobin  in  his  blood  rose  only  to  26  per  cent.,  at  which  figure 
it  remained  stationary.  This  would  correspond  to  an  oxygen  tension  of  about  25  per 
cent,  of  an  atmosphere,  whereas  we  have  already  seen  that  the  oxygen  tension  in  the 
alveoli  cannot  be  greater  than  15  per  cent.  He  therefore  concluded  that  the  epithelial 
cells  of  the  alveoli  play  an  active  part  in  the  respiratory  interchange,  taking  up  the 
oxygen  on  one  side  at  a  tension  of  15  per  cent,  and  piling  it  up  on  the  other  until  the 
pressure  in  the  blood  is  much  higher  than  that  in  the  alveolar  air.  Theoretically  there 
is  no  reason  to  deny  the  possibility  of  such  powers  to  the  pulmonary  epitheliimi.  We 
know  that  the  secreting  cells  of  the  kidney  take  up  urea  from  the  blood  which  contains 
only  about  -02  per  cent,  of  this  substance,  and  excrete  it  into  the  renal  tubule,  into  a 
medium  containing  about  2  per  cent.  ;  and  if  the  data  given  by  Haldane  are  correct 
we  must  ascribe  an  analogous  function  to  the  pulmonary  epithelium.  These  data, 
however,  were  obtained  by  a  colorimetric  method  working  with  very  minute  quantities 
of  blood,  and  lacked  the  support  of  control  experiments.  As  a  result  of  further  experi- 
ments, Haldane  has  modified  his  position  so  far  as  to  allow  that  under  normal  conditions 
the  absorption  of  oxygen  from  the  alveolar  air  takes  place  in  accordance  with  the  differ- 
ence of  pressure,  i.e.  by  a  process  of  diffusion.  He  is  still  of  opinion  that  under  abnormal 
conditions,  when  the  oxygen  tension  in  the  alveolar  air  is  very  low,  there  is  an  active 
absorption  and  transference  of  oxygen  to  the  blood  on  the  part  of  the  pulmonary 
epithelium.  Why  animals  should  evolve  a  function  which  can  only  be  brought  into 
play  on  climbing  mountains  seems  difficult  to  understand,  and  it  does  not  seem  probable 
that  a  reinvestigation  of  the  tensions  of  oxygen  in  the  blood  under  such  conditions  by 
Krogh's  method  will  lend  any  confirmation  to  Haldane's  conclusions. 

An  analogy  has  been  drawn  between  the  processes  of  gas  interchange  in  the  lungs 
and  that  in  the  swim  bladder  of  the  fish.  Bohr  has  shown  that  the  gas  obtained  by 
punctm-ing  the  bladder  often  contains  considerable  excess  of  oxygen.  If  the  bladder 
be  punctiu-ed  and  the  fish  then  left  in  the  water,  the  gas  rapidly  reaccumulates,  and  it 
is  found,  on  tapping  a  second  time,  that  the  percentage  of  oxygen  is  largely  increased, 
and  may  amount  to  between  60  and  80  per  cent,  of  the  total  gases.  This  reaccumulation 
of  the  gases  does  not  take  place  if  both  vagi  are  cut,  and  is  therefore  ascribed  to  a  direct 
secretory  activity  on  the  part  of  the  epithelium  lining  the  swiin  bladder  under  the 
influence  o  the  vagus  nerves.     Bohr,  as  the  result  of  experiments  by  himself  and  some 


THE  CHEMISTRY  OF  RESPIRATION  1075 

of  his  pupils,  is  inclined  to  endow  the  vagus  nerves  in  the  higher  vertebrates,  including 
mammals,  with  an  analogous  regulatory  intluence  on  the  gaseous  exchanges  in  the  lungs. 
As  regards  the  evolution  of  carbon  dioxide  the  facts  elucidated  by  Haldane  himself 
would  make  one  hesitate  in  ascribing  any  special  secretory  activity  to  the  pulmonary 
epithelium.  We  find,  namely,  that  the  respiratory  centre  reacts  immediately  to  the 
slightest  increase  in  the  tension  of  the  carbon  dioxide  in  the  alveolar  air.  Since  this 
behaviour  of  the  respiratory  centre  is  independent  of  any  nervous  connections  between 
the  lungs  and  the  brain,  it  seems  to  indicate,  as  indeed  Krogh  has  found,  that  the  tension 
of  the  carbon  dioxide  in  the  blood  follows  closely  the  tension  of  the  carbon  dioxide  in 
the  alveolar  air.  If  the  carbon  dioxide  were  secreted  by  the  pulmonary  epithelium  we 
should  expect  the  Ixmgs  to  react  to  increased  carbon  dioxide  in  the  alveoli  by  simply 
increasing  their  work  so  as  to  maintain  the  tension  of  carbon  dioxide  in  the  blood  at  a 
constant  level.  This  at  any  rate  is  the  way  in  which  the  kidney  would  behave  under 
analogous  circumstances.  Moreover  there  is  no  likeness  between  the  thick  typical 
secreting  cells  of  the  '  red  gland,'  which  is  the  gas-secreting  part  of  the  swim  bladder, 
and  the  thin  structureless  plates  which  separate  the  capillaries  of  the  lungs  from  the 
alveolar  air. 


SECTION  III 

THE  REGULATION  OF  THE  RESPIRATORY 
MOVEMENTS 

Each  movemeut  of  inspiration  involves  the  co-ordinated  activity  of  a  large 
number  of  muscles.  Thus  the  diaphragm  and  the  intercostal  muscles 
must  come  into  action  at  the  same  time,  and  the  extent  to  which  they 
contract  will  determine  the  depth  of  the  inspiration.  Similarly,  they  must 
cease  to  act  simultaneously  if  the  act  of  expiration  is  to  take  place.  The 
rhythm  and  extent  of  the  alternate  contractions  and  relaxations  of  the 
respiratory  muscles  are  determined,  as  we  have  seen,  by  the  needs  of  the 
organism  as  a  whole.  These  respiratory  movements  are  regulated  so  that 
the  total  ventilation  of  the  alveoh  shall  be  sufl&cient  to  meet  the  gaseous 
exchanges  of  the  body.  Whether  the  organism  consumes  250  or  1000  c.c.  of 
oxygen  per  minute,  the  respiratory  movements  keep  the  composition  of  the 
gas  in  the  alveoU  at  a  practically  constant  level. 

The  muscles  involved  both  in  inspiration  and  expiration  can  only  be 
thrown  into  activity  by  the  intermediation  of  nerves .  Each  act  of  inspiration 
involves  a  discharge  along  a  number  of  nerves,  e.g.  the  facial  to  the  muscles 
moving  the  alse  nasi,  the  vagus  to  the  muscles  of  the  larynx,  the  branches 
of  the  cervical  and  brachial  nerves  to  the  muscles  of  the  neck,  the  phrenic 
nerves  to  the  diaphragm,  and  the  dorsal  nerves  to  the  intercostal  muscles. 
The  fibres  making  up  these  nerves  are  derived  from  nerve- cells  of  the  anterior 
horn,  situated  at  various  levels  in  the  meduUa  and  spinal  cord.  In  each  act 
of  inspiration  or  expiration  the  activities  of  all  these  groups  of  cells  must  be 
brought  into  relation  among  themselves,  as  well  as  with  the  needs  of  the 
organism  for  oxygen  and  for  the  ehmination  of  carbon  dioxide.  It  is 
conceivable  that  the  co-ordination  of  the  activities  of  the  various  motor 
nuclei  might  be  attained  by  the  provision  of  communicating  nerve-paths 
joining  the  centres  among  themselves,  and  by  a  sensibihty  of  all  these  centres 
to  the  gaseous  contents  of  the  blood  as  well  as  to  the  influence  of  afferent 
impressions  from  the  periphery.  A  much  more  efficient  co-ordination, 
however,  would  be  effected  by  the  subjection  of  these  motor  nuclei  to  the 
action  of  some  specialised  portion  of  the  central  nervous  system  which 
would  act  as  a  receiving  centre  for  afferent  impressions  from  the  lungs  and 
surface  of  the  body,  and  would  be  endowed  with  a  special  sensibility  to 
changes  in  the  composition  of  the  blood  circulating  through  its  vessels. 
Experiment  shows  that  the  latter  method  is  employed  in  the  organism  for 

1076 


EEGULATION  OF  RESPIRATORY  MOVEMENTS  1077 

the  regulation  of  the  respiratory  movements.  If  the  spinal  cord  be  cut  across, 
below  the  seventh  cervical  nerve-roots,  the  action  of  the  intercostal  and 
abdominal  muscles  in  respiration  ceases  permanently,  although  respiration 
is  still  continued  by  the  rhythmic  activity  of  the  diaphragm  and  the  other 
muscles  supphed  by  nerves  leaving  the  central  nervous  system  above  the  point 
of  section.  Division  of  the  cord  at  the  first  or  second  cervical  nerve  abolishes 
the  action  of  the  diaphragm,  though  the  movements  of  the  muscles  supplied 
by  the  facial,  vagus,  and  spinal  accessory  nerves  continue.  A  section  of  the 
brain-stem  through  the  mid-brain  leaves  the  respiratory  movements  un- 
altered, and  the  same  absence  of  effect  as  concerns  these  movements  may 
often  be  obtained  when  a  section  is  carried  across  the  upper  part  of  the 
medulla  about  the  level  of  the  stricB  acousticce.  We  must  conclude  from 
these  experiments  that  the  motor  nuclei  of  the  cord  are  subject  to 
and  normally  thrown  into  activity  by  impulses  originating  in  the 
medulla  oblongata  and  transmitted  therefrom  down  the  spinal 
cord. 

Many  experiments  have  been  made  with  the  idea  of  locating  the  position 
of  the  medullary  respiratory  centre  more  accurately.  The  first  experiments 
on  this  point  were  made  at  the  beginning  of  last  century  by  Legallois,  whose 
observations  were  confirmed  and  extended  by  Flourens.  These  observers 
described  the  respiratory  centre  as  limited  to  a  small  area  at  the  level  of  the 
apex  of  the  calamus  scriptorius,  which  they  designated  nceud  vital  on  account 
of  the  fact  that  destruction  of  this  area  was  at  once  fatal  by  paralysis  of 
respiration.  Later  experiments  have  shown  that  the  centre  is  not  quite  so 
circumscribed.  In  the  first  place,  it  is  bilateral,  each  centre  presiding  more 
especially  over  the  muscles  of  the  same  side  of  the  body,  so  that  longitudinal 
section  in  the  middle  line  does  not  destroy  the  respiratory  movements. 
Other  observers  have  located  the  centre  in  the  situation  of  the  solitary 
bundle  ('  respiratory  bundle  of  Gierke  '),  which  is  made  up  of  the  descending 
branches  of  the  vagus  nerve  after  they  have  entered  the  medulla,  while, 
according  to  Gad,  the  respiratory  centre  is  dift'used  over  a  considerable 
area  of  the  formatio  reticularis  on  either  side  of  the  medulla.  There  is  no 
doubt  that  this  centre  is  in  close  connection  \nth.  the  central  terminations  of 
the  vagus  nerves. 

From  the  centre  on  each  side  the  efferent  impulses  to  the  motor  nuclei 
of  the  respiratory  muscles  pass  down  in  the  deeper  portions  of  the  lateral 
columns  of  the  cord.  Hemisection  of  the  cervical  cord,  e.g.  on  the  right 
side,  causes  cessation  of  the  contractions  of  the  diaphragm  on  the  same  side. 
There  must,  however,  be  commissural  fibres  joining  the  motor  nuclei  on  the 
two  sides.  If  the  right  phrenic  nerve  be  di\ided,  after  hemisection  on  the 
left  side,  the  left  half  of  the  diaphragm  at  once  commences  to  contract 
rh}i^^hmically  with  each  respiraton  (Porter).  It  is  evident  that  the  cessation 
of  respiration  after  section  of  the  cord  is  not  due  to  a  condition  of  shock  of 
the  lower  spinal  centres,  since  it  is  possible  for  impulses  to  pass  down  the 
cord  and  to  cross  over  to  the  contra-lateral  diaphragm  nucleus  imniediately 
after  hemisection  of  the  cord  on  the  side  of  the  nucleus. 


1078  PHYSIOLOGY 

THE  QUESTION  OF  SPINAL  RESPIRATORY  CENTRES.  Several  physiologists 
e.g.  BrowTi  Sequard,  Langendorii,  and  Wertheimer,  have  described  respiratory  centres 
in  the  spinal  cord.  There  is  no  doubt  that  if  the  cord  be  cut  across  in  the  upper  cervical 
region,  and  artificial  respiration  maintained  for  some  time,  cessation  of  the  respiration 
may  be  followed  by  rhythmic  contractions  of  the  respiratory  muscles.  These  are 
especially  marked  in  young  animals  and  if  the  activity  of  the  cord  has  been  heightened 
by  the  injection  of  small  doses  of  strychnine.  Careful  observation  of  the  movements 
shows,  however,  that  they  cannot  be  spoken  of  as  respiratory,  since  although  rhythmic, 
they  are  not  co-ordinate.  The  diaphragm  may  contract  either  simultaneously  or  in 
alternation  with  the  intercostals,  and  muscles  which  are  essentially  expiratory  at  the 
same  time  as  those  which  we  are  wont  to  regard  as  inspiratory.  These  experiments 
show  merely  that  the  motor  centres  of  the  cord  can  enter  into  rhythmic  activity  under 
the  influence  of  asphyxial  conditions.  The  movements  affect  the  muscles  of  the  limbs 
as  well  as  those  essentially  respiratory  in  function. 

THE  AUTOMATICITY  OF  THE  RESPIRATORY  CENTRE 

We  have  now  to  inquire  what  it  is  that  keeps  the  respiratory  centre  in 
activity.  Is  the  rhythmic  discharge  of  inspiratory  impulses  from  the  centre 
due  to  rhythmic  or  continuous  stimulation  of  afferent  nerves,  or  is  the  centre 
so  constructed  that  under  the  normal  conditions  of  its  environment  the 
metabohc  activity  of  its  constituent  parts  tends,  hke  that  of  the  heart-cells, 
to  assume  a  rhythmic  character  ?  In  other  words,  is  the  activity  of  the  centre 
reflex  or  automatic  ?  It  has  been  found  by  Rosenthal  that  rhythmic  respira- 
tory movements  are  maintained  even  after  complete  section  of  the  brain- 
stem at  the  level  of  the  superior  corpora  quadrigemina,  section  of  the  cord 
at  the  level  of  the  seventh  cervical  nerve,  and  division  of  both  vagi  and  of  the 
posterior  roots  of  all  the  cervical  spinal  nerves.  It  is  true  that  if  the  sections 
of  the  brain-stem  be  placed  as  low  as  the  strice  acousticcB,  the  respiratory 
movements  are  profoundly  modified  and  give  place  to  a  series  of  inspiratory 
spasms.  We  might  argue  from  this  that  the  centre  was  capable  of  a  very 
imperfect  degree  of  automatic  action,  but  needed  the  stimulus  of  afferent 
impulses  from  the  vagi  or  from  the  higher  parts  of  the  brain  to  render  these 
actions  adequate  for  the  respiratory  needs  of  the  organism. 

In  the  above  experiment  the  centre  cannot  be  regarded  as  free  from  all 
afferent  stimuh,  since  the  mere  closure  of  the  demarcation  current  in  the 
cut  ends  of  the  nerves  would  cause  a  certain  amount  of  excitation,  and  the 
animal  does  not  survive  sufficiently  long  to  allow  this  condition  to  pass  off. 
Hering  has  shown  that  in  the  '  spinal  cord  frog  '  {i.e.  one  in  which  the  brain 
has  been  destroyed)  section  of  all  the  posterior  roots  absolutely  destroys 
all  mobihty,  the  injection  of  strychnine  being  without  effect.  A  typical 
spasm,  however,  can  be  at  once  produced  by  exposing  and  stimulating  the 
stump  of  one  of  the  cut  posterior  roots.  We  might  suppose  that  the  respira- 
tory centre  would  be  similarly  devoid  of  automatism  if  absolutely  free  from 
afferent  stimuli.  It  must  be  mentioned,  however,  that  according  to  Sherring- 
ton it  is  possible  to  excite  strychnine  or  asphyxial  spasms  in  a  dog  or  cat 
with  isolated  spinal  cord,  in  which  all  the  afferent  roots  below  the  transection 
have  been  divided  six  or  seven  hours  previously.  He  therefore  is  of  opinion 
that  in  the  mammal  the  motor  nervous  mechanism  can  be  set  into  activity 


REGULATION  OF  RESPIRATORY  MOVEMENTS  1079 

apart  from  the  incidence  of  afEerent  impressions.  The  respiratory  centre 
tends  to  respond  to  all  stimuli,  continuous  or  rhythmic,  by  means  of  rhythmic 
discharges,  and  there  can  be  no  doubt  that  if  we  take  the  medulla  in  connec- 
tion with  the  rest  of  the  hind-  and  ffiid -brain  we  are  justified  in  regarding  its 
activity  as  automatic. 

The  automatic  activity  of  the  heart  is  intimately  dependent  on  the 
saline  constituents  of  the  blood.  It  may  be  aboHshed  or  diminished  by 
modifying  these  constituents,  and  can  be  maintained  for  a  considerable  length 
of  time  by  perfusing  the  heart  with  solutions  containing  inorganic  salts  in 
the  concentration  in  which  they  exist  in  the  blood-plasma.  When  we 
speak  of  the  automatic  activity  of  the  respiratory  centre  we  imply  in  the 
same  way  that  its  activity  is  dependent  on  the  normal  composition  of  the 
blood  circulating  through  its  vessels.  In  this  case,  however,  it  is  the 
gaseous  contents  of  the  blood  which  are  of  supreme  importance.  If  the 
normal  ventilation  of  the  lungs  be  prevented,  as  by  Ugature  of  the  trachea 
or  opening  both  pleural  cavities,  the  blood  becomes  more  and  more  venous. 
As  this  venous  blood  circulates  through  the  medulla  the  activity  of  the  centre 
is  continually  increased,  until  finally  the  impulses  discharged  from  the 
centre  may  set  into  activity  practically  every  muscle  of  the  body,  producing 
asphyxial  convulsions.  On  the  other  hand,  the  activity  of  the  respiratory 
centre  can  be  diminished  or  even  abolished  if,  by  an  artificial  ventilation  of 
the  alveoh,  we  maintain  an  over-arterialisation  of  the  blood,  so  that  the 
fluid  passing  to  the  brain  contains  more  oxygen  and  less  carbon  dioxide 
than  is  the  case  under  normal  circumstances.  What  are  the  factors  involved 
in  this  chemical  regulation  of  respiration  ? 

THE  CHEMICAL  REGULATION  OF  THE  RESPIRATORY 
MOVEMENTS 

If,  the  nervous  centres  being  intact,  the  proper  aeration  of  the  respiratory 
centre  be  interfered  with  in  any  way,  the  respiratory  movements  increase  in 
strength  and  frequency,  and  if  the  disturbing  factor  be  not  removed  the 
animal  dies,  presenting  a  train  of  phenomena  which  are  classified  together 
under  the  term  '  asphyxia.' 

The  phenomena  of  asphyxia  may  be  divided  into  three  stages  : 

(1)  In  the  first  stage,  that  of  hyperpnoea,  the  respiratory  movements 
are  increased  in  ampHtude  and  in  rhythm.  This  increase  affects  at  first  both 
inspiratory  and  expiratory  muscles.  Gradually  the  force  of  the  expiratory 
movements  becomes  increased  out  of  all  proportion  to  the  inspiratory,  and 
the  first  stage  merges  into  : 

(2)  The  second,  which  consists  of  expiratory  convulsions,  in  which  almost 
every  muscle  of  the  body  may  be  involved.  Just  at  the  end  of  the  first 
stage  consciousness  is  lost  and  almost  immediately  after  the  loss  of  con- 
sciousness we  may  observe  a  number  of  phenomena  extending  to  almost  all 
the  functions  of  the  body,  some  of  which  have  been  already  studied.  Thus 
the  vaso-motor  centre  is  excited,  causing  universal  vascular  constriction. 


1080  PHYSIOLOGY 

There  is  often  also  secretion  of  saliva,  inhibition  or  increase  of  intestinal 
movements,  constriction  of  the  pupil,  and  so  on. 

(3)  At  the  end  of  the  second  minute  after  the  stoppage  of  the  aeration  of 
the  blood,  the  expiratory  convulsions  cease  almost  suddenly,  and  give  way  to 
slotv  deep  inspirations.  With  each  inspiratory  spasm  the  animal  stretches 
itself  out  and  opens  its  mouth  widely  as  if  gasping  for  breath.  The  whole 
stage  is  one  of  exhaustion  :  the  pupils  dilate  widely,  and  all  reflexes  are 
abolished.  The  pauses  between  the  inspirations  become  longer  and  longer, 
until  at  the  end  of  four  or  five  minutes  the  animal  takes  its  last  breath. 

If  we  increase  the  activity  of  the  centre,  and  therefore  its  gaseous  inter- 
changes, by  warming  the  blood  in  the  carotid  arteries,  there  may  be  a  con- 
siderable quickening  of  respiration  unaccompanied  by  any  deepening,  a 
condition  which  is  spoken  of  as  tachypncea.  On  the  other  hand,  we  may  slow 
the  respiratory  movements  by  placing  a  small  piece  of  ice  on  the  floor  of  the 
fourth  ventricle. 

In  the  production  of  the  phenomena  of  asphyxia  two  factors  must  be  at 
work.  In  the  first  place,  there  is  an  accumulation  of  carbon  dioxide  in  the 
blood  bathing  the  centre  or  an  increased  tension  of  this  gas  in  the  centres 
themselves,  either  as  a  result  of  deficient  excretion  or  increased  production. 
On  the  other  hand,  the  centre  is  deprived  of  oxygen,  either  by  failure  of 
renewal  of  the  oxygen  supply,  or  by  increased  using  up  of  this  gas  in  the  meta- 
bohsm  of  the  centre.  The  question  arises,  which  of  these  two  changes  is 
responsible  for  the  different  physiological  events  which  characterise 
asphyxia  ?  At  various  times  these  phenomena  have  been  ascribed  either  to 
the  increased  tension  of  carbon  dioxide  or  to  the  diminished  tension  of 
oxygen  in  the  centre.  The  view  that  the  normal  stimulus  to  the  respiratory 
centre  in  asphyxia  was  the  lack  of  sufficient  oxygen  and  that  the  normal 
activity  of  this  centre  was  determined  by  the  tension  of  oxygen  in  the 
blood  circulating  through  the  brain  was  first  put  forward  by  Rosenthal. 
When  sufficient  oxygen  was  present,  the  centre,  according  to  this  observer, 
would  cease  to  act,  so  that  a  condition  of  apnoea  would  be  produced.  Ac- 
cording to  Traube,  on  the  other  hand,  the  special  respiratory  stimulus  was 
the  excess  of  carbon  dioxide  in  the  blood,  and  this  view  was  supported 
strongly  by  Miescher.  The  tendency  of  recent  work,  especially  by  Haldane 
and.  his  pupils,  has  been  to  show  that  there  is  an  element  of  truth  in  both 
views — that  indeed  the  respiratory  centre  can  be  excited  either  by  excess 
of  carbon  dioxide  or  by  lack  of  oxygen,  but  that  its  sensitivity  to  carbon 
dioxide  is  by  far  the  most  important  factor  in  the  determination  of  the 
increased  respiratory  movements  in  asphyxia,  and  is  the  only  chemical 
factor  which  can  be  regarded  as  playing  any  part  in  the  regulation  of  the 
respiratory  movements  under  normal  conditions.  This  factor  is  well  brought 
out  if  we  investigate  the  effect  on  the  respiratory  movements  of  altering  the 
tensions  of  the  two  gases  in  the  air  breathed.  If  by  this  means  we  succeed 
in  altering  the  tension  of  the  two  gases  in  the  alveolar  air  we  may  assume  that 
the  tensions  of  the  gases  in  the  arterial  blood  leaving  the  lungs  are  altered  in 
the  same  ratio.     The  results  of  such  experiments  are  very  striking.     Even 


EEGULATION  OF  RESPIRATORY  MOVEMENTS 


1081 


a  slight  increase  in  the  percentage  of  carbon  dioxide  in  the  air  causes  an 
increase  first  in  the  depth  and  later  on  in  the  rhythm  of  respiration  (Fig.  505). 
This  is  shown  in  the  following  Table  by  Haldane,  which  represents  the  average 
depth  and  frequency  of  the  respirations  when  the  subject  was  breathing 
normal  air  and  air  charged  with  varying  percentages  of  carbon  dioxide. 


Fig.  505.     EfiEect  of  CO2  on  respiratory  movements  of  rabbit.     (Scott.) 
Upper  line,  tracing  of  diaphragm  slip  (Head's  method).     Lower  tracing,  carotid 
pressure.     During  the  first  period  indicated  on  the  signal  line  the  animal  breathed 
9-6  per  cent.  CO2  in  air,  and  during  the  second  period  10  per  cent.  COo  with  33  per 
cent,  oxygen.     Time  tracing  =  2  sees.     Scale  =  mm.  Hg.  blood-pressure. 

A  rise  of  carbon  dioxide  in  the  atmosphere  to  2  per  cent,  increases  the  depth  of 
respirations  by  30  per  cent.,  and  the  total  alveolar  ventilation  by  50  per  cent. 
A  rise  of  carbon  dioxide  to  3  per  cent,  increases  the  total  ventilation  of  the 
alveoli  by  126  per  cent.  An  amount  of  carbon  dioxide  equivalent  to  6 
per  cent,  increases  the  depth  of  each  respiration  by  272  per  cent.,  and  the 
total  alveolar  ventilation  by  757  per  cent. 


Percentage  CO2 
in  inspired  air 

Average  depth 
of  respirations 

Average 
frequency  of 
respirations 
per  minute 

Ventilation  of  alveoli 
with  inspired  air 
(normal  =  100) 

COj  percentage 
in  alveolar  air 

0-04 

673 

14 

100 
(6-60  litres  per  min.) 

5-6 

0-79 

739 

14 

116 

5-5 

2-02 

864 

15 

153 

5-6 

3-07 

1216 

15 

226 

5-5 

5-14 

1771 

19 

498 

6-2 

6-02 

2104 

27 

857 

6-6 

If  we  examine  the  last  column  of  figures  in  this  Table,  representing  the 
percentage  of  CO2  in  the  alveolar  air,  it  will  be  seen  that,  in  spite  of  the  very 
large  variations  in  the  air  breathed,  the  alveolar  content  in  COo  remained 
practically  constant  until  the  COo  in  the  atmosphere  was  increased  to  such 
an  extent  that  the  processes  of  compensation  were  no  longer  efficient.  We 
must  conclude  therefore  that  the  respiratory  centre  is  so  arranged  as  to 


1082 


PHYSIOLOGY 


react  to  the  slightest  increase  of  CO 2  tension  in  the  blood,  any  increase  in  this 
gas  giving  at  once  a  compensatory  increase  in  depth  and  frequency  of 
respiration,  so  that  the  alveolar  COg  content  may  be  maintained  almost 
constant. 

That  it  is  the  tension  of  CO2  in  the  alveolar  air,  and  therefore  in  the  blood 
bathing  the  centres,  and  not  the  percentage  amount  of  this  gas,  which  is  the 
determining  factor  is  shown  by  a  comparison  of  the  composition  of  the 
alveolar  air  under  different  atmospheric  pressures.  Thus,  when  the  subject 
of  the  experiments,  from  which  the  above  Table  was  derived,  was  placed  in 
an  air-chamber  compressed  to  a  pressure  of  1261  mm.,  the  mean  percentage 


f  600 


3000       2600 


22Q0        1800        MOO 
air  pressure  mm  Mg 


Fig.  506.  Effects  of  alterations  in  the  barometric  pressure  on  the  alveolar  CO2 
tension,  the  alveolar  CO2  percentage,  and  in  the  alveolar  O2  tension.  Note 
that  the  excitant  effects  of  O.  lack  are  not  seen  until  the  pressure  falls  below 
500  mm.  Hg.  (Boycott  and  Haldane.) 

of  CO  2  in  the  alveolar  air  was  342,  corresponding,  however,  to  a  tension  of 

3-42  X  -=-—  =  5-6  per  cent,  of  an  atmosphere,  a  figure  almost  identical 

with  those  given  in  the  last  column  of  the  Table  above.  At  the  top  of  Ben 
Nevis,  where  the  barometric  pressure  was  646  mm.,  the  percentage  of  CO2  in 

the  alveolar  air  was  6-6,  corresponding  to  a  tension  of  6-6  x  ,— -  =  5-2  per 

cent,  of  an  atmosphere,  i.e.  of  760  mm.  Thus  the  pressure  of  CO2  in  alveolar 
air  remains  practically  constant  with  widely  varying  limits  of  atmospheric 
pressure  and  with  very  different  percentages  of  CO2  in  the  inspired  air, 
showing  that  the  reactions  of  the  organism  are  directed  so  as  to  maintain,  by 
alterations  in  the  respiratory  depth  and  rhythm,  a  constant  tension  of  this 
gas  in  the  alveoli  and  therefore  in  the  arterial  blood. 

Very  different  are  the  phenomena  observed  on  alteration  of  the  partial 


REGULATION  OF  RESPIRATORY  MOVEMENTS  1083 

pressure  of  oxygen  (Fig.  506).  Here,  within  wide  limits,  the  partial  pressure 
of  oxygen  in  the  alveolar  air  is  determined  by  its  pressure  in  the  inspired  air. 
Thus,  if  we  take  the  same  series  of  observations  with  a  pressure  of  646  mm., 
the  percentage  of  oxygen  in  the  alveolar  air  was  13-19,  corresponding  to  a 

tension  of  13-19  x  =-—  =  10-4  per  cent.     At  an  atmospheric  pressure  of 

755  mm.  the  percentage  of  oxygen  in  the  alveolar  air  was  13-97,  corresponding 
to  a  tension  of  13-06  per  cent.,  which  we  may  take  as  the  normal  figure  at  the 


Fig.  507.     Effects  of  oxygen  lack.     (Scott.) 
During  tracing,  diaphragm  slip  ;   lower  tracing,  carotid  blood-pressure.     During 
time  indicated  by  signal,  5  per  cent,  oxygen  in  nitrogen  was  inhaled,     c  =  con- 
vulsion. 

sea-level.     In  air  compressed  to  a  pressure  of  1261  mm.  the  percentage  of 

1261 
oxygen   was   16-79,   corresponding  to   a   tension  of  16-79  x  — —  =  26-8 

<60 

per  cent,  of  an  atmosphere  of  760  mm. 

Similar  results  are  obtained  by  altering  the  percentage  of  oxygen  in  the 

air  breathed.     The  oxygen  tension  or  percentage  in  the  inspired  air  can  be 

lowered  from  its  normal  of  20-93  to  12  or  13  per  cent,  without  altering 

in  any  way  th^e  depth  or  rhythm  of  respiration,  and  in  fact  A\ithout  any 

change  being  noticed  by  the  individual  who  is  the  subject  of  the  experiment. 

A  percentage  of  13  per  cent,  of  oxygen  corresponds  to  an  alveolar  content  in 

oxygen  of  8  per  cent.,  and  with  a  further  reduction  of  the  oxygen  content 

there  is  increased  pulmonary  ventilation  (Fig.  507),  but  the  diminution  in 

oxygen  may  be  pushed  to  such  an  extent  that  the  patient  becomes  blue  from 

the  deficient  aeration  of  his  hajmoglobin,  without  any  considerable  distrees 


1084  PHYSIOLOGY 

being  caused.  lu  fact  in  many  cases  the  subject  of  such  an  experiment  may 
lose  consciousness  suddenly  before  he  has  been  aware  of  any  serious  deficiency 
in  his  aeration. 

The  difference  in  the  sensitiveness  of  the  centre  to  increase  of  carbon  dioxide  and 
lack  of  oxygen  respectively  is  "well  shown  by  an  experiment  of  Haldane's,  in  which  the 
same  person  breathed  in  and  out  of  a  bag,  in  the  first  place  allowing  the  carbon  dioxide 
produced  in  respiration  to  accumulate,  and  in  the  second  removing  the  carbon  dioxide 
by  means  of  soda  lime,  so  that  the  sole  effect  of  respiration  was  to  produce  a  continual 
diminution  in  the  percentage  of  oxygen.  In  the  first  case,  when  the  carbon  dioxide  was 
allowed  to  accmnu'ate  it  was  found  that  extreme  and  intolerable  hyperpncea  was  pro- 
duced when  the  gaseous  content  of  the  bag  consisted  of  5-6  per  cent,  carbon  dioxide 
with  14*8  per  cent,  oxygen.  When  the  carbon  diox'de  was  absorbed  it  was  possible 
to  breathe  in  and  out  of  the  bag  for  a  much  longer  period.  No  hyperpnoea  was  pro- 
duced, and  the  experiment  was  stopped  as  soon  as  the  subject  was  becoming  blue  in 
the  face  and  experienced  slight  throbbing  in  the  head.  The  pulse  frequency  had  gone 
up  from  80  to  108.  The  bag  was  found  to  contain  no  carbonic  acid  and  only  8-7  per 
cent,  oxygen.  In  another  similar  experiment  the  oxygen  had  been  reduced  to  6  7  per 
cent,  before  it  was  necessary  to  stop  the  experiment. 

We  must  conclude  that  the  respiratory  centre  possesses  a  specific  sensi- 
bility for  carbon  dioxide,  which  determines  the  normal  depth  and  rhythm 
of  the  respiratory  movements.  Although  the  respiratory  centre,  in  com- 
mon with  the  rest  of  the  central  nervous  system,  is  sensitive  to  and  can  be 
excited  by  lack  of  oxygen,  this  quahty  is  rarely  brought  into  play.  Under 
all  ordinary  circumstances  an  increased  need  for  oxygen  is  associated  with 
an  increased  production  of  carbon  dioxide  in  the  oxidative  processes  of  the 
body,  and  the  augmentation  of  respiration,  produced  by  the  excitatory 
effect  of  a  small  excess  of  carbon  dioxide  tension  in  the  blood,  suflB.ces  to. 
proAade  fully  for  the  increased  needs  of  the  organism  for  oxygen.  The 
reactions  of  the  organism  have  not  been  evolved  in  order  to  adapt  it  to 
balloon  ascents  or  experiments  in  respiratory  chambers.  As  an  example  of 
a  normal  adaptation  we  may  take  the  changes  in  respiration  which  occur 
in  an  animal  as  the  result  of  muscular  exercise.  During  their  activity  a 
large  amount  of  carbon  dioxide  is  produced  in  the  muscles.  The  blood 
passing  from  the  muscles  to  the  heart  will  not  be  able  to  get  rid  of  the  excess 
of  the  carbon  dioxide  in  passing  through  the  lungs,  and  will  reach  the 
respiratory  centre  more  highly  charged  with  this  gas,  the  tension  of  which 
will  be  raised.  The  respiratory  centre  is  thus  stimulated,  and  the  increased 
pulmonary  ventilation  thereby  produced  lowers  the  alveolar  carbon  dioxide 
pressure,  until  a  point  is  reached  at  which  an  equilibrium  is  maintained 
between  the  effect  of  the  increased  production  of  carbon  dioxide  in  raising 
the  arterial  carbon  dioxide  tension  and  that  of  the  increased  respiratory 
activity  in  lowering  it.  Under  these  circumstances  it  is  found  that  the 
increased  consumption  of  oxygen  in  the  contracting  muscles  is  more  than 
compensated,  so  that  the  oxygen  tension  in  the  alveoli  and  in  the  arterial 
blood  is  rather  above  than  below  normal. 

In  certain  experiments  Zuntz  and  Geppert  found  that  during  muscular 
exercise  the  respiratory  movements  were  increased  to  such  an  extent  as 
to  bring  the  tension  of  carbon  dioxide  in  the  arterial  blood  below  normal. 


REGULATION  OF  RESPIRATORY  MOVEMENTS         1085 

In  these  experiments  the  muscular  contractions  were  produced  by  tetanis- 
ing,  through  the  spinal  cord,  the  lower  hmbs  of  an  animal.  Under  these 
circumstances  the  activity  of  the  muscle  would  be  associated  with  a 
diminished  blood-flow,  so  that  the  contractions  would  be  carried  out  in  the 
absence  of  a  sufficient  supply  of  oxygen.  In  the  absence  of  sufficient 
oxygen  muscular  contractions  result  in  the  production,  not  of  carbon 
dioxide,  but  of  lactic  acid,  and  it  is  highly  probable  that  in  the  experiments 
in  question  there  was  a  discharge  of  acid  substances  into  the  blood,  diminish- 
ing the  alkalinity  of  this  fluid  and  therefore  lowering  its  carrying  power  for 
carbon  dioxide.  As  a  matter  of  fact,  one  can  produce  dyspnoea  by  diminish- 
ing the  alkahnity  of  the  blood  by  the  injection  of  acids,  and  attacks  of 
dyspnoea  are  observed  in  the  later  stages  of  diabetes,  when  the  alkalinity 
of  the  blood  is  decreased  in  consequence  of  the  production  of  such  bodies 
as  oxybutyric  acid.  This  dyspnoea  has  been  ascribed  to  the  fact  that  a 
diminished  carrying  power  of  the  blood  for  carbon  dioxide  will  raise  the 
tension  of  this  gas  in  the  tissues  where  it  is  formed,  so  that  a  diminished 
alkahnity  of  the  blood  may  cause  a  higher  tension  of  carbon  dioxide  around 
the  respiratory  centre.  It  has  been  shown  by  Ryfiel  that  even  a  short 
period  of  sufficiently  violent  muscular  exercise,  i.e.  one  giving  rise  to 
dyspnoea,  causes  a  subsequent  increase  of  lactic  acid  in  the  urine,  and  that 
the  blood  itself  at  the  close  of  the  period  of  exercise  contains  a  demonstrable 
amount  of  this  acid.  Thus  in  one  case  the  urine,  passed  thirty  minutes 
after  running  one-third  of  a  mile  in  two  minutes,  contained  454  mg.  lactic 
acid  as  against  a  normal  excretion  of  between  3  and  4  mg.  of  lactic  acid 
per  hour.  In  another  experiment  blood  was  obtained  from  the  fore-arm 
before  exercise,  immediately  after  exercise,  and  three-quarters  of  an  hour 
later.  The  exercise,  which  consisted  of  running  rapidly,  lasted  two  minutes 
forty-five  seconds.     The  following  Table  represents  the  results  obtained  : 

Lactic  acid  per  100  e.c. 
Blood  before  starting        ......     12-5  uig. 

Blood  immediately  after  stopping       .  .  .  .     70-8  „ 

Blood  4.5  minutes  later      ......     15-9   „ 

The  production  of  lactic  acid  during  muscular  exercise  may  thus  be 
regarded  as  a  second  line  of  defence  for  the  organism,  tending  to  maintain 
the  increased  ventilation  of  the  lungs  even  when  the  supply  of  oxygen  is 
insufficient  to  oxidise  completely  the  materials  consumed  in  the  production 
of  the  muscular  energy.  This  acid  mechanism  is,  however,  only  employed 
when  the  supply  of  oxygen  lags  behind  the  respiratory  needs  of  the  body 
(cp.  Fig.  508).  Ordinary  exercise,  even  when  considerable,  e.g.  a  twenty- 
four  hours'  track  walking  race,  does  not  cause,  as  Ryffel  has  shown,  any 
appreciable  increase  in  the  elimination  of  lactic  acid  by  the  urine.  Under 
normal  circumstances  the  depth  and  rhythm  of  respiration  depend  on  the 
carbon  dioxide  pressure  in  the  respiratory  centre,  a  rise  of  0-2  per  cent,  of 
an  atmosphere  in  the  tension  of  this  gas  in  the  alveoli  being  sufficient  to 
double  the  amount  of  alveolar  ventilation  during  rest. 


1086 


PHYSIOLOGY 


The  first  phase  in  the  phenomena  of  asphyxia  is  thus  conditioned  simply 
by  the  changes  in  the  carbon  dioxide  tension.  A  httle  later  the  gradual 
exhaustion  of  oxygen  in  the  blood  round  the  centre  begins  to  make  itself 
felt.  The  respiratory  centre  shares  with  the  rest  of  the  central  nervous 
system  a  sensitiveness  to  the  absence  of  oxygen,  deprivation  of  oxygen 
having  first  an  excitatory  and  later  a  paralytic  effect.  In  asphyxia  the 
first  centres  to  feel  this  effect  are  those  of  the  cortex,  and  during  the  first 
stage  there  is  mental  excitation  terminating  rapidly  in  abohtion  of  con- 
sciousness. During  the  second  stage  there  is  a  discharge  of  energy,  which 
spreads  throughout  the  whole  nervous  system,  beginning  in  the  bulbar 
centres  and  causing  a  great  rise  of  blood-pressure  with  slowing  of  the  heart, 


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Fig.  508.     Dissociation  curve  of  oxyhsemoglobin  in  defibrinated  cat's  bleed. 
1,  cat  I,  after  partial  occlusion  of  trachea  and  fifteen  minutes  breathing  of  gas 
of  increasing  poverty  in  oxygen  ;  4,  cat  II,  at  beginning  of  experiment ;  3,  cat  II, 
after  fifteen  minutes  gas  respiration ;  2,  after  twenty-one  minutes  ditto. 

and  extending  thence  to  all  the  spinal  centres  with  the  production  of  muscular 
spasms.  At  this  stage  too  there  is  a  discharge  of  impulses  giving  contraction 
of  the  pupil,  and  a  discharge  along  the  whole  sympathetic  system,  producing 
the  various  phenomena  of  vaso-constriction,  erection  of  hairs,  sweating, 
sahvation,  which  are  generally  brought  about  by  stimulation  of  different 
parts  of  this  system.  The  phenomena  of  the  third  stage  are  due  to  exhaus- 
tion of  the  nerve-centres,  accompanied  or  preceded  by  exhaustion  and  dilata- 
tion of  the  heart,  the  circulation  faihng  before  the  excitation  of  the  lower 
centres  has  entirely  come  to  an  end.  In  this  third  stage  it  is  impossible 
by  the  strongest  stimuh  to  evoke  any  reflex. 

Considerable  discussion  has  taken  place  as  to  the  exact  nature  of  the  stimulation 
brought  about  by  want  of  oxygen.  The  blood  of  animals  which  have  been  killed  by 
asphyxia  is  known  to  contain  reducing  substances,  so  that  oxygen  added  to  it  disappears 
and  cannot  be  recovered  in  a  vacuum.  Pfiiiger  therefore  suggested  that  it  was  these 
reducing  substances  themselves  which  were  effective  exciting  agents.  It  was  shown 
many  years  ago  by  Hoppe-Seyler  and  his  pupils  that  in  conditions  of  chronic  oxygen 


REGULATION  OF  RESPIRATORY  MOVEMENTS  1087 

starvation  there  was  an  excessive  production  of  lactic  acid  in  the  body,  and  we  have 
seen  that  the  same  is  true  for  the  isohxted  muscle  and  that  to  these  substances  has  been 
ascribed  (Zuntz  and  Geppert)  the  excitation  of  the  respiratory  centre  which  occurs  in 
violent  muscular  exercise.  Haldane  has  suggested  that  in  the  hyperpnoea  and  con- 
vulsions which  occur  as  the  result  of  breathing  mixtures  with  very  low  percentages  of 
oxygen  the  effective  stimulus  is  also  lactic  acid.  Experiments  were  carried  out  by 
Ryffel  on  individuals  who  had  been  subjected  in  a  respiratory  chamber  to  very  low 
oxygen  tensions,  sufficient  to  cause  cyanosis,  so  that  their  oxygen  alveolar  tension  was 
only  about  6  per  cent.  After  an  experiment,  lasting  four  hours,  there  was  a  definite 
increase  of  lactic  acid  in  the  blood  of  the  fore  arm  (up  to  23-6  mg.  lactic  acid  per  100  c.c). 
After  one  lasting  only  fifteen  minutes,  in  which  the  oxygen  shortage  became  very 
marked,  no  increase  could  be  detected.  When  we  expose  an  animal  such  as  a  rabbit  to 
low  percentages  of  oxygen,  the  hyperpncea  so  produced  disappears  almost  immediately 
when  a  larger  percentage  of  oxygen  is  sui)plied  to  the  animal,  whereas  that  produced  by 
carbon  dioxide  excess  dies  away  slowly  on  exjiosure  to  normal  conditions.  It  would  seem 
that  when  the  exposure  to  low  oxygen  tensions  is  of  short  duration  no  lactic  acid  is  pro- 
duced in  the  blood.  If  therefore  we  ascribe  the  hyperpnoea  to  the  production  of  lactic  ac'd 
we  must  locate  the  production  of  this  acid  in  the  respii'atory  centre  itself.  There  are  no 
inherent  improbabilities  in  such  an  assumjition,  but  it  is  difficult  at  present  to  see  how 
it  can  be  put  to  the  test  of  experiment. 

In  dealing  with  the  question  of  the  blood  alkalinity  we  defined  neutrality  as  a  con- 
dition in  which  there  were  equivalent  concentration  of  H  and  OH  ions.  In  the  blood 
the  H  ion  concentration  is  about  0-3  x  10"'^iSr.  The  alkalinity  is  expressed  by 
concentration  OH  ions 

——-: —  TT  ■ •     The  acids  and  bases  of  the  blood-serum  and  of  the  tissue-fluids 

concentration  H  ions  ^i^uo 

generally  are  in  such  proportions  as  to  maintain  the  approximate  neutrality  of  these 
fluids  even  after  considerable  additions  of  acid  or  alkali.  This  hydrochloric  acid  may 
be  added  to  the  extent  of  -025  N,  or  NaOH  to  the  extent  of  -005  X,  without  causing  any 
marked  alteration  in  the  reaction  of  the  blood.  Although,  however,  the  change  pro- 
duced by  the  addition  of  acids  or  alkalies  is  so  minute,  it  is  appreciable  by  electrical 
methods,  and  it  may  still  more  readily  be  appreciated  by  and  act  as  a  stimulus  for  the 
cells  of  the  body  themselves.  Thus  we  have  not  yet  succeeded  in  determining  electric- 
ally the  change  in  hydrogen  ion  concentration  caused  by  the  change  from  arterial  to 
venous  blood.  If,  however,  blood-serum  be  saturated  with  carbon  dioxide  at  a  full 
atmosphere,  the  concentration  of  the  hych'ogen  ions  rises  to  1  -4  x  10 "  "X,  while  after  re- 
moving the  greater  part  of  the  carbon  dioxide  from  the  same  serum  by  the  passage  of  a 
stream  of  aii',  the  concentration  of  the  hydrogen  ions  sinks  to  -008  x  10~"X.  As  the 
respiratory  centre  responds  to  such  minute  changes  of  concentration  as  would  be  ex- 
pressed by  a  difference  of  0-2  per  cent,  of  an  atmosphere  in  the  carbon  dioxide  tension 
of  the  circulating  blood,  it  must  possess  a  sensitivity  greater  than  any  of  our  physical 
means  for  measuring  the  concentration  of  hydrogen  ions  in  a  fluid.  We  may  approach 
this  delicacy  of  reaction  by  using  a  large  molecule  as  our  indicator.  Thus,  as  we  have 
seen,  the  dissociation  curve  of  haemoglobin  is  sensitive  to  the  change  in  reaction  caused 
by  raising  the  tension  of  carbon  dioxide  in  the  haemoglobin  solution  bv  10  mm.  Hg. 
(cp.  Fig.  497). 

The  regulating  factor  in  the  blood  is  jH-obably  not  carbon  dioxide  nor  any  sijecial  acid, 
but  the  concentration  of  hydrogen  ions  in  this  fluid  or  in  the  cells  of  the  centre  itself. 
Such  a  conclusion  brings  under  one  head  all  the  several  factors  which  we  know  to  act 
upon  the  resjju'atory  centre,  namely,  tension  of  carbon  dioxide,  presence  of  acids  in  the 
blood — especially  lactic — and  considerable  diminution  of  oxj'gen  supplj'  to  the  cells. 
The  resph'atory  centre  would  then  not  differ  qualitatively  from  an}'  other  pjirt  of  the 
central  nervous  system.  Its  special  function  would  be  determined  simply  by  the  evolution 
to  a  marked  degree  of  a  sensibflity  to  hydrogen  ions  which  is  already  possessed  by  the  whole 
of  the  central  nervous  system  and  indeed  by  practically  every  tissue  of  the  body. 

We  may  conclude  that  mere  lack  of  oxygen  is  not  to  be  regarded  in 
itself  as  an  excitatory  agent.     Its  influence  will  be  rather  to  paralyse  all 


1088  PHYSIOLOGY 

activity.  On  the  other  hand,  excitation  is  caused  by  the  products  of 
metaboHsm,  which  vary  according  as  the  oxygen  supply  is  ample  or  in- 
sufficient for  the  needs  of  the  cells.  In  the  former  case  activity  results 
in  the  production  of  carbon  dioxide,  in  the  latter  of  lactic  acid,  and  perhaps 
other  substances.  Both  these  are  acid  substances  and  their  production 
will  therefore  raise  the  concentration  of  the  hydrogen  ions  in  the  cells 
where  they  are  produced  as  well  as  in  the  blood.  The  nerve-centres  are 
extremely  sensitive  to  minute  changes  in  the  hydrion  concentration  either 
in  themselves  or  in  the  fliiids  surrounding  them,  and  are  thrown  into 
activity  by  excess  of  these  ions  and  inhibited,  or  put  to  rest,  by  relative 
deficiency  of  the  ions.  In  their  relation  to  H  and  OH  ions  respectively 
the  medullary  centres  have  a  sensibiHty  five  times  as  great  as  the  spinal 
centres.  The  condition  of  apnoea,  which  is  associated  not  only  with 
cessation  of  respiratory  movements  but  also  with  fall  of  blood-pressure, 
may  be  ascribed  to  relative  increase  in  the  OH  ions  or  diminution  in  the 
H  ions. 

Since  the  animal  has  developed  a  mechanism  by  means  of  which  changes 
in  the  reaction  of  the  blood  can  be  rapidly  adjusted  by  varying  the  excre- 
tion of  carbon  dioxide,  whilst  the  excretion  of  other  acids  is  relatively  slow, 
carbon  dioxide  may  be  regarded  as  the  normal  respiratory  hormone,  and 
so  far  we  may  agree  with  Henderson  in  regarding  carbon  dioxide  as  maintain- 
ing the  activities  of  the  various  nerve-centres  at  their  normal  level.  But  it  is 
the  hydrion  concentration  which  appears  to  be  the  essential  factor,  and  the 
acid  substances  produced  during  oxygen  lack  are  equally  efficacious,  but  not 
so  convenient.  Thus  their  production  is  not  a  steady  process  Hke  that  of 
carbon  dioxide,  but,  as  Mathison  points  out,  commences  suddenly  at  a  time 
when  the  executive  side  of  the  nerve-cell  is  feehng  the  effect  of  oxygen 
starvation,  so  that  the  cell  may  be  too  much  disorganised  to  respond  to 
stimulation.  "  The  broad  margin  of  safety  protecting  the  organism  against 
paralysis  of  its  cells  by  oxygen  starvation  is  assured  by  the  sensitiveness  of  the 
medullary  centres  to  hydrogen  ion  concentration  and  therefore  to  carbon 
dioxide  in  common  with  other  acids." 

On  the  other  hand,  it  must  be  remembered  that  excessive  production  of 
hydrogen  ions  may  finally  result  in  a  condition  of  paralysis,  which  in  the 
nervous  centres  is  expressed  by  narcosis.  These  effects  can  only  be  removed 
by  a  free  supply  of  oxygen.  The  concentration  at  which  these  results  occur 
varies,  as  we  have  seen,  in  different  parts  of  the  nervous  system  and  also  in 
different  tissues.  Thus  on  the  heart  a  slight  increase  in  H  ion  concentration 
causes  diminished  tone,  which  may  lead  to  dilatation  and  failure  of  this  organ. 
The  same  effect  is  produced  on  the  unstriated  muscle  fibre  of  the  blood- 
vessels. Since  in  the  heart  and  blood-vessels  the  reverse  effect  is  produced 
by  increasing  the  OH  ion  concentration,  it  is  evident  that  the  fine  of 
'  physiological '  neutrahty  at  which  neither  stimulation  nor  paralysis  is 
produced  must  vary  in  different  tissues. 

It  is  an  interesting  question  whether  the  electrical  excitation  of  nerves 
may  not  be  due  to  a  similar  alteration  in  the  hydrion  concentration  at  the 


REGULATION  OF  RESPIRATORY  MOVEMENTS  1089 

cathode  which  is  the  seat  of  stimulation.  If  this  were  so,  all  the  activities 
of  protoplasm  might  be  regarded  as  determined  by  the  relative  concentration 
of  the  H  and  OH  ions  within  the  cells  or  in  the  medium  surrounding  the 
cells. 

THE  REFLEX  NERVOUS   REGULATION  OF  RESPIRATION 

Although  the  specific  sensibility  of  the  respiratory  centre  to  COg  is  the 
most  important  factor  in  determining  the  depth  and  rhythm  of  the  respiratory 
movements,  these  movements  and  the  condition  of  the  respiratory  centre 


§^ 


Fig.  509.     Normal  tracing  of  diaphragm  slip  (Head's  method). 

itself  are  modified  in  a  large  degree  by  impulses  arriving  at  the  centre  along 
both  vagi.  Through  other  sensory  nerves  of  the  body  the  respiratory 
movements  can  be  altered  reflexly,  but  it  is  only  through  the  vagi  that  a  con- 
tinuous stream  of  impulses  passes  to  the  centre  under  normal  circumstances, 
so  that  every  respiratory  movement  is  modified  by  these  impulses. 

In  studying  the  nervous  mechanism  of  respii'ation,  it  is  necessary  to  have  some 
accurate  method  of  recording  the  respiratory  movements.  They  may  be  registered  by 
means  of  a  tambour  applied  to  the  chest,  communicating  with  another  tambour  i)rovided 
with  a  lever,  which  is  arranged  to  write  on  a  blackened  surface  ;  or  a  side  tube  to  a 
cannula  in  the  trachea  may  be  connected  with  the  registering  tambour.  In  the  first 
case  movements  of  the  thorax  are  registered  ;  in  the  second  changes  of  intra-pulmonary 
pressure.  These  methods  are  obviously  useless  when  it  is  wished  to  study  the  effects 
of  artificial  distension  or  collapse  of  the  lungs.  In  this  instance  we  may  use  the  ingenious 
method  described  by  Head.  In  the  rabbit  a  slip  of  the  diaphragm  on  either  side  of 
the  ensiform  cartilage  is  so  disposed  that  the  end  of  it  maj^  be  freed  and  attached  by  a 
thread  to  a  lever  without  injury  to  its  blood-  or  nerve-supply.  It  is  found  that  this 
slip  contracts  synchronously  with  the  rest  of  the  diaphragm,  so  that  it  serves  as  a  sample 
of  the  diaphragm,  the  contractions  of  which  may  be  recorded  uninfluenced  by  passive 
movements  of  the  chest  wall  or  artificial  increase  of  intra-pulmonary  pressure. 

If,  while  the  respiratory  movements  are  being  recorded  in  one  of  the 
afore-mentioned  ways,  both  vagi  be  divided,*  a  marked  change  in  the 
respiratory  rhythm  is  at  once  seen.  The  first  effect  is  an  increased  in- 
spiratory tonus,  but  this  rapidly  disappears,  and  the  respiratory  move- 

*  The  division  of  the  vagi  is  best  effected  by  putting  them  on  a  hooked  copper  wire, 
of  which  the  upper  end  is  inserted  in  a  freezing-mixture.  In  this  way  complete  func- 
tional division  of  the  nerves  is  obtained  without  any  excitation.  If  the  nerves  be  cut, 
a  certain  amount  of  stimulation  takes  place  in  consequence  of  tlie  closure  of  the  demarca- 
tion current  produced  bv  the  cross-section. 

'  35 


1090 


PHYSIOLOGY 


ments  become  less  frequent  and  are  increased  in  amplitude.  If  now  the 
central  end  of  one  of  the  vagi  be  stimulated  with  an  interrupted  current,  the 
respiration  may  be  quickened,  or,  as  is  more  commonly  the  case,  the  in- 
spiratory movements  may  be  increased  at  the  expense  of  the  expiratory,  so 
that  finally  a  condition  of  inspiratory  standstill  is  produced,  and  the  shp  of 
the  diaphragm  enters  into  prolonged  contraction. 

With  a  very  weak  stimulus  it  is  sometimes  possible  to  produce  augmenta- 
tion of  the  expiratory  movements  or  rather  inhibition  of  the  inspiratory,  and 

this  is  the  invariable  result  of  passage  of 
a  constant  current  through  the  vagus  in 
an  ascending  direction.  This  effect  may  be 
more  striking^ly  brought  about  by  stimu- 
lation of  the  central  end  of  the  superior 
laryngeal  nerve,  which  produces  first  an 
inhibition  of  inspiration,  so  that  the  re- 
spiratory muscles  come  to  a  standstill  in 
the  position  of  expiration,  and  then  a 
forcible  contraction  of  the  expiratory  mus- 
cles. This  illustration  of  the  presence  of 
expiratory  fibres  in  the  superior  laryngeal 
nerve  is  not  confined  to  laboratory  experi- 
ence, but  is  constantly  occurring  in  every- 
day life.  The  superior  laryngeal  nerve 
supphes  sensory  fibres  to  the  mucous 
membrane  of  the  glottis,  and  we  know 
that  the  sHghtest  irritation  of  these  fibres 
— ^the  presence  of  a  crumb  or  a  particle  of 
mucus — causes  forcible  expiratory  spasms, 
with  spasmodic  closure  of  the  glottis,  which 
we  term  a  cough.* 

So  we  see  that  the  vagus  nerve 
contains  two  kinds  of  afferent  fibres,  or 
at  any  rate  afferent  fibres  with  two 
distinct  functions.  Stimulation  of  the 
one  kind  stops  inspiration  and  produces  expiration  ;  stimulation  of  the 
other  stops  expiration  and  produces  inspiration.  Since  section  of  both 
vagi  causes  slowing  of  respiration,  impulses  which  exert  some  influence  on 
the  respiratory  centre  and  quicken  respiration  must  travel  up  the  vagi  from 
the  lungs.  The  respiratory  movements  cause  an  alternate  distension  and 
contraction  of  the  lungs,  and  it  has  long  been  thought  that  it  is  these  changes 
in  the  volume  of  the  lungs  which  start  the  accelerating  impulses  that  travel 


Fig.  510.  Effects  of  distension- 
collapse  of  lung.  Both  curves  are 
described  by  a  lever  attached  to  a 
slip  of  the  diaphragm  of  a  rabbit. 
A  contraction  of  the  diaphragm 
(inspiration)  raises  the  lever ;  dur- 
ing relaxation  of  the  diaphragm 
the  lever  falls. 

In  A,  the  trachea  is  closed  at  x, 
the  height  of  inspiration ;  *  a  pause 
follows,  during  which  the  lever  gradu- 
ally sinks  until  an  inspiration  (a  very 
powerful  one)  sets  in. 

In  B,  the  trachea  is  closed  at  the 
end  of  expiration,  x ;  there  follow 
powerful  inspirations.     (Foster.) 


*  It  mu.st  not  be  imagined  that  the  fibres  of  the  superior  laryngeal  nerves  are  con- 
cerned in  the  reflex  maintenance  of  the  normal  respiratory  rhythm.  They  are  cited  here 
merely  because  the  result  of  their  stimulation  resembles  that  which  would  be  caused 
by  stimulation  of  the  analogous  expiratory  fibres  which  run  in  the  trunk  of  the  vagus 
from  the  lungs  to  the  respiratory  centre. 


REGULATION  OF  RESPIRATORY  MOVEMENTS  1091 

up  the  vagus  nerves.  To  test  the  truth  of  this  hypothesis  it  is  necessary 
to  study  the  two  phases  of  respiration  separately  ;  that  is,  to  see  first  the 
result  on  the  respiratory  inapulses  of  distension  of  the  lungs,  and,  secondly, 
the  result  of  a  sudden  collapse  or  a  contraction  caused  by  sucking  air  out 
of  the  lungs.  The  effects  of  distension  or  collapse  of  the  lung  may  be  shown 
by  ?imply  closing  the  trachea  at  the  end  of  inspiration  or  of  expiration.  The 
results  of  such  an  experiment  are  shown  in  Fig.  510, 

A  still  more  marked  effect  is  produced  if  the  lungs,  by  means  of  a  tube 
in  the  trachea,  be  artificially  inflated  or  if  air  be  sucked  out  of  them.  The 
inflation  produces  an  instantaneous  and  complete  relaxation  of  the  dia- 
phragm (Fig.  511)  which  by  clamping  the  tracheal  tube  may  be  prolonged 


Fig.  511.     Positive  ventilation.     (Hkad.) 
Under  the  influence  of  positive  ventilation,  the  inspiratory  contractions  of  the 
diaphragm  become  less  and  less  till  they  disappear  completely. 


Xi'g.  vcutilation 
Jiuplinigm 


Fig.  512.     Negative  ventilation.     (Head.) 
At  a  negative  ventilation  was  commenced.     The  expiratorj^  relaxation  of  the 
diaphragm  is  seen  to  become  more  and  more  incomplete,  until  it  finally  enters  into 
continued  contraction, 

for  several  sconds,  while  sucking  air  out  of  the  lungs  causes  a  tonic  contrac- 
tion of  the  diaphragm  (Fig,  512),  Somewhat  similar  results  may  be  obtained 
by  repeatedly  inflating  or  deflating  the  lungs  (positive  and  negative  ventila- 
tion). The  effects  here  are  comphcated  by  the  fact  that  one  is  deahng  in 
both  cases  with  alternating  movements  of  the  lungs,  of  expansion  and  con- 
traction, both  of  which  will  have  an  influence  on  the  respiratory  centre. 
Moreover  repeated  forcible  inflation  of  the  limgs  increases  the  ventilation 
of  the  pulmonary  alveoli,  thus  lowering  the  normal  carbon  dioxide  tension 
of  the  lungs.  As  a  result  of  repeated  ventilation  we  may  obtain  a  condition 
of  respiratory  standstill.  In  this  condition,  however,  as  we  shall  see  later, 
the -determining  factor  is  rather  chemical  than  mechanical. 

These  inhibitory  and  augmentor  effects  of  changes  in  the  volume  of 
the  lung  must  also  result  from  the  normal  movements  of  these  organs  in 


1092  PHYSIOLOGY 

respiration.  Let  us  consider,  for  instance,  what  will  happen  if  the  influence 
of  the  two  vagi  could  be  suddenly  thrown  in  after  these  nerves  have  been 
divided.  (This  experiment  can,  in  fact,  be  reahsed  more  or  less  completely 
if  the  functional  division  of  the  vagi  be  effected  by  cooling  or  by  ether 
narcosis).  The  animal  would  be  breathing  slowly  and  deeply.  If  at  the 
beginning  of  an  inspiration  the  vagi  became  functional  the  expansion  of  the 
lungs  caused  by  the  inspiratory  movement  would  send  inhibitory  impulses 
up  to  the  vagus  centre,  which  would  stop  the  movement  of  inspiration. 
The  movement  of  expiration  would  then  begin,  and  the  collapse  of  the  lungs 
thereby  produced  would  itself  send  impulses  up  the  vagi  which  would  tend 
to  excite  an  inspiratory  movem.ent.  Both  inspiration  and  expiration  would 
therefore  be  shortened,  and  the  successive  movements  would  follow  one 
another  at  a  shorter  interval  than  if  the  vagi  were  not  functional.  In  this 
way,  under  normal  circumstances,  the  rhythm  of  the  respiratory  centre 
must  be  determined  reflexly  through  the  agency  of  the  vagi,  while  the  chief 
factor  in  determining  the  total  pulmonary  ventilation  is,  as  we  have  seen,  the 
carbon  dioxide  tension  of  the  blood. 

In  the  foregoing  account  we  have  spoken  of  the  expiratory  and  inspiratory  effects 
of  the  vagus  as  if  they  were  of  equal  importance.  It  seems  probable,  however,  that  the 
inhibitory  or  expiratory  impulses  started  by  the  inspiratory  movement,  the  only  or 
the  more  active  part  of  normal  respiration,  play  a  more  prominent  part  in  the  regulation 
of  respiration  than  do  the  inspiratory  impulses  ;  and  one  observer  (Gad)  goes  so  far  as 
to  deny  altogether  the  existence  of  two  kinds  of  respiratory  fibres  in  the  vagus.  Accord- 
ing to  Gad,  the  vagus,  as  regards  the  respiratory  centre,  is  a  purely  inhibitory  nerve. 
Hence  the  primary  effect  of  dividing  both  vagi  is  an  increased  inspiratory  tone.  This 
view  at  first  seems  paradoxical,  in  that  it  explains  the  final  slowing  of  respiration  after 
section  of  the  vagi  as  due  to  the  cutting  off  of  previous  inhibitory  impidses.  But  inhi- 
bition in  all  tissues  has  a  twofold  effect.  Although  the  immediate  effect  is  diminution  of 
activity,  yet  the  diminished  disintegration  necessarily  associated  with  diminished 
activity  means  an  increase  of  the  anabolic  at  the  expense  of  the  catabolic  processes  of 
the  tissues.  In  this  way  we  explained  the  diminished  excitability  occurring  in  a  nerve 
at  the  anode  of  a  constant  current,  and  it  will  be  remembered  that  the  secondary  result 
of  anelectroronus  was  increased  irritability  and  consequent  excitation  at  break  of  the 
constant  current.  The  same  sort  of  process  must  occur  in  the  respiratory  centre.  A 
continued  restraint  of  its  rhythmic  activity  must  lead  to  a  heaping  up  of  its  irritable 
material,  so  that  the  final  result  is  a  state  of  hyperexcitability  in  which  the  centre,  so  to 
speak,  boils  over  on  the  slightest  provocation. 

In  this  condition  a  cutting  off  of  the  inhibitory  impulses  must  at  first  increase  the 
activity  of  the  centre,  leading  to  the  increased  inspiratory  tonus  already  described. 
But,  unchecked  by  any  reign'ng  impulses,  the  centre  enters  upon  a  career  of  spendthrift 
activity.  Each  inspiratory  contraction  is  maximal,  but  the  centre,  exhausted  by  the 
effort,  has  to  wait  a  considerable  time  before  it  can  accumulate  sufficient  energy  for  the 
next  ;  hence  the  final  result  of  section  of  both  vagi  is  deepening  and  slowing  of  respira- 
tion. 

Although  Gad  has  rendered  great  service  in  emphasising  the  importance  of  the  in- 
hibitory or  expiratory  impulses  which  ascend  the  vagi,  there  is  no  doubt  that  he  went  too 
far  in  denying  the  existence  of  inspiratory  fibres  in  the  vagus.  This  is  shown  by  the 
following  experiment  of  Head.  According  to  Gad's  view,  collapse  of  both  lungs  implies 
simply  a  removal  of  the  normal  inhibitory  impulses  ascending  the  vagi,  and  is  therefore 
equivalent  to  division  of  these  two  nerves.  If  in  the  rabbit  the  left  vagus  be  divided,  a  tube 
can  be  introduced  into  the  left  bronchus,  and  artificial  respiration  can  be  performed  by 
alternate  inflation  and  collapse  of  the  left  lung,  without  in  any  way  affecting  the  respira- 


REGULATION  OF  RESPIRATORY  MOVEMENTS 


1093 


tory  centre,  all  connections  with  the  latter  being  destroyed  {v.  Fig.  513).  Meanwhile 
the  animal  carries  out  normal  respiratory  movements,  which  can  be  recorded  by  the 
diaphragm  slip  method.  While  the  slip  is  contracting  regularly,  the  right  pleura  is 
opened  and  the  right  lung  allowed  to  collapse.  The  effect  of  this  collapse,  carried  up  by 
the  right  vagus  to  the  centre,  is  an  extreme  contraction  of  the  diaphragm,  and  since  the 
onset  of  asphyxia  is  prevented  by  the  artificial  respiration  carried  out  on  the  left  lung, 
the  tonic  standstill  of  the  diaphragm  may  last  over  a  minute.     In  this  case  therefore 


RT  Lung. 


artif  resp  app. 


Lunc 


Fig.  513.     Diagram  to  illustrate  Head's  experiment  on  the  effect  of  collapse  of  the 
lung.     R.c,  respirator}'  centre  ;  R.v,  l.v,  right  and  left  vagi. 

the  effect  of  collapse  of  one  lung  is  enormously  greater  than  that  produced  by  section 
of  both  vagi,  showang  that  the  effect  is  due,  not  to  abolition  of  the  ordinary  tonic  inhibi- 
tory stimuli,  but  to  excitation  of  special  inspiratory  fibres  in  the  vagus  by  the  collapse 
of  the  lung. 

By  means  of  the  string  galvanometer  it  is  jiossible  to  show  definitely  that  a  collapse 
o'  1  he  lungs  does  set  up  a  nervous  impulse  travelling  up  the  vagus  nerves.  This 
impulse  must  be  inspiratory  in  character,  ?o  that  there  is  no  reason  to  deny  the  existence 
of  both  kinds  of  fibres  in  these  nerves.  The  effect  of  electrical  stimulation,  especially 
with  an  ascending  constant  current,  is  also  strong  evidence  in  the  same  direction. 

After  division  of  both  vagi  the  total  piilmouaiy  ventilation  does  not  as 
a  rule  undergo  any  marked  changes,  and  in  the  absence  of  anaesthesia  the 
aeration  of  the  blood  may  be  carried  out  almost,  if  not  quite,  as  well  as  in 
the  intact  animal.  The  importance  of  the  vagus  action  for  the  organism 
is  shown,  however,  if  we  put  an  increased  strain  on  the  respiratory  mechanism, 
as,  for  instance,  by  increasing  the  percentage  of  carbon  dioxide  in  the  air 
breathed.  In  the  intact  animal  this  procedure  leads  first  to  increased  depth 
and  later  to  increased  frequency  of  respiration,  the  total  ventilation  being 
thereby  augmented  to  such  an  extent  as  to  keep  the  alveolar  tension  of  carbon 
dioxide  almost  constant.  If  the  same  percentage  of  carbon  dioxide  be 
administered  to  an  animal  after  section  of  both  vagi  the  effect  is  deepening 
of  respiration,  but  not  (|uickeniiig  (Fig.  514).  Each  inspiratory  movement, 
however,  is  already  considerable  so  that  the  margin  by  which  increase  of 


1094 


PHYSIOLOGY 


pulmonary  ventilation  is  possible,  by  increase  of  depth  of  respiration  alone, 
is  not  so  great  as  in  a  normal  animal.  Moreover,  since  no  quickening  of 
rsspiration  takes  place,  the  increased  ventilation  rapidly  becomes  inadequate 
for  the  maintenance  of  the  normal  alveolar  carbon  dioxide  tension.     In  the 


Fig.  514.  Effect  of  10'6  per  cent.  COg  in  a  mixture  containing  23'3  per  cent.  O2  on  a 
rabbit  witli  both  vagi  divided.  The  gas  was  administered  between  the  arrows. 
Zero  line  of  blood-pressure  is  32  mm.  below  bottom  of  tracing.  Compare  this 
figure  with  Fig.  505,  p.  1081.     (F.  H.  Scott.) 

following  Table  the  total  amounts  of  pulmonary  ventilation  obtained  on 
administration  of  mixtures  containing  carbon  dioxide  to  a  rabbit  before 
and  after  section  of  the  vagi  are  compared. 


Rabbit,  3  kilos 

Respirations 
per  minute 

Vol.  of  each 
respiration 

Total  ventilation 
per  minute 

Respiration  with  air     . 

„                 4-2  per  cent.  CO2 . 
„                 8-6  per  cent.  CO2. 
„                 air     . 

72 
96 

97 

72 

c.c. 
19 
25 
29 
20 

1368 
2400 
2813 
1440 

Vagi  Divided 

Respiration  with  air      . 

„                 4-2  per  cent.  CO2 . 
„                 8-6  per  cent.  COg. 

45 
45 
42 

29 
34 
38 

1305 
1530 
1596 

Whether  we  assume  that  the  prevaihng  impulses  travelling  up  the 
vagi  are  purely  inhibitory  or  are  both  inhibitory  and  augmentor,  the  re- 
sultant effect,  by  reining  in  the  activity  of  the  centre,  is  to  economise  its 
energy  and  the  energy  of  the  respiratory  muscles.  The  result  of  the  vagal 
impulses  will  therefore  be  to  increase  the  excitability  of  the  respiratory 
centre  and  make  it  more  susceptible  to  slight  changes  in  the  carbon  dioxide 
tension  of  the  blood,  while  maintaining  a  sufficient  margin  of  energy  to 


REGULATION  OF  RESPIRATORY  MOVEMENTS  1095 

meet  the  increased  needs  thrown  on  the  respiratory  mechanism  by  aug- 
mented metabolism,  such  as  occurs  in  violent  muscular  exercise. 

The  important  part  played  by  the  vagi  in  the  regulation  of  normal 
respiration  is  shown  stiU  more  strikingly  if  the  respiratory  centre  in  the 
medulla  be  separated  from  the  higher  parts  of  the  brain  before  the  section 
of  the  vagi  is  carried  out.  Separation  of  the  medulla  from  the  higher  parts 
of  the  brain,  as  by  section  just  behind  the  corpora  quadrigemina,  has 
practically  no  influence  on  the  respiratory  rhythm.  If  now  both  vagi  be 
divided  the  normal  respiratory  movements  cease  entirely,  being  replaced 
by  a  series  of  inspiratory  spasms,  each  of  which  lasts  several  seconds  and 
is  followed  by  a  pause  of  half  to  one  minute's  duration.  These  spasms  are 
inadequate  for  the  proper  oxygenation  of  the  blood.  They  become  gradually 
less  and  less  frequent,  and  in  about  half  an  hour  the  animal  dies  of  asphyxia. 
We  must  conclude  therefore  that  the  medullary  respiratory  centre  with 
the  help  of  the  vagi  is  able  to  carry  out  normal  respiratory  movements.  If 
both  vagi  are  cut,  impulses  arrive  at  the  centre  from  the  higher  parts  of  the 
brain  regulating  its  activity,  and  enabhng  it  to  carry  out  modified  but 
sufficient  respiratory  movements.  Removed  from  both  these  sources  of 
afierent  impulses,  the  centre  discharges  only  a  series  of  spasms  which  are 
totally  inadequate  for  the  renewal  of  the  blood-gases,  so  that  the  animal 
dies. 

We  may  summarise  these  results  as  follows  : 

Respiratory  centre  with  vagi — normal  respiration. 

Respiratory  centre  wath  brain — modified  respiration. 

Respiratory  centre  alone — inadequate  spasmodic  contractions  of 
respiratory  muscles,  afid  death  of  animal. 

The  nature  of  the  suiiplemental  action  of  the  mid-brain  on  the  medullary  respiratory 
centre  has  not  yet  been  made  out.  It  is  apparently  not  dependent  on  afferent  impulses 
arriving  at  the  brain,  since  section  of  no  cranial  nerve  affects  in  any  way  the  activity  of 
the  centres.  Certain  observers  have  described  'accessory  respiraotry  centres  '  in  the 
mid-brain,  in  the  region  of  the  posterior  corpora  quadrigemina.  Stinnilation  of  this 
part  causes  increase  in  the  rate  of  inspiratory  movements  and  finally  tonic  spasm  of  the 
diaphragm.  Expiratory  effects  have  been  produced  by  stinmlalion  of  the  an  erior 
corpora  quadrigemina,  and  it  would  seem  that  a  section  has  to  pass  through  or  behind 
these  bodies  in  order  to  produce  the  results,  alieady  described,  of  cutting  off  the  higher 
centres  from  the  mednlla  oblongata  after  division  of  the  vagi.  Other  localised  spots  in 
the  brain  from  which  effects  on  respiration  have  been  obtained  are  the  inner  wall  o'  the 
optic  thalamus  and  the  root  of  the  olfactory  tract.  Further  experiments  are  necessary 
before  we  can  regard  any  of  these  centres  as  normally  involved  in  the  maintenance  or 
regulation  of  the  respiratory  movements. 

APNCEA.  If  artificial  respiration  be  maintained  so  as  to  produce  a 
somewhat  greater  ventilation  than  occurs  by  the  normal  respiratory  move- 
ments of  the  animal,  a  standstill  of  respiration  is  brought  about.  This 
condition  is  called  apnoea.  The  first  explanation  of  this  standstill  was  that 
it  was  due  to  over- oxygenation  of  the  blood.  The  fact  that  it  could  be 
produced  by  artificial  ventilation  Avith  inert  gases,  sucli  as  hydrogen  and 
nitrogen,  as  well  as  the  discovery  of  the  inhibitory  influence  of  distension 


1096  PHYSIOLOGY 

of  the  lungs  on  the  respiratory  centre,  led  Head  to  ascribe  it  to  the  summation 
of  a  series  of  inhibitory  stimuli.  In  these  experiments,  however,  the  fact 
was  forgotten  that  forced  ventilation  of  the  lungs  with  air  or  any  inert  gases 
vn\\  reduce  the  carbon  dioxide  tension  in  the  blood  circulating  round  the 
pulmonary  alveoh  and  therefore  round  the  respiratory  centre.  A  respiratory 
pause  will  therefore  ensue  and  last  until  the  increasing  accumulation  of 
carbon  dioxide  in  the  blood  raises  its  tension  to  the  normal  height,  at  which 
the  respiratory  centre  is  '  set,'  so  to  speak,  to  respond  by  a  respiratory  dis- 
charge. If  the  carbon  dioxide  content  of  inspired  air  be  increased  to  about 
4-5  per  cent.,  it  is  impossible  to  produce  an  apnoeic  pause,  however  rapidly 
the  respiratory  movements  be  carried  out.  It  would  seem  therefore  that 
ordinary  apnoea  is  entirely  due  to  deficiency  of  carbon  dioxide  tension  in  the 
respiratory  centre,  and  that  although  the  vagus  nerve  is  inhibitory  of 
respiration,  it  is  impossible  to  summate  a  series  of  vagus  inhibitions  by 
artificial  respiration  so  as  to  produce  a  lasting  cessation  of  respiratory 
movements.  The  chief  use  of  the  vagi  in  respiration  seems  to  be  for  maintain- 
ing, by  frequent  inhibitions,  the  excitability  of  the  respiratory  centre  at  a 
maximum. 

M  escher  distinguished  three  types  of  apnoea,  viz.  : 

Apnoea  vera,  due  to  the  washing  out  of  COg  from  the  lungs,  and  the  consequent  re- 
duction of  the  tension  of  this  gas  in  the  blood. 

Apncea  vagi,  a  stoppage  of  respiration  caused  by  stimulation  of  the  inhibitory  fibres 
of  the  vagi.  This  stoppage  is  limited,  as  we  have  seen,  to  the  immediate  duration  of 
the  stimulu?  (whether  electric  or  produced  by  distension  of  the  lungs). 

Apnoea  spuria.  Stoppage  of  respiration  by  stimulation  of  other  nervous  or  sensory 
surfaces.  Thus  when  a  duck  plunges  there  is  immediate  stoppage  of  respiration, 
which  may  last  four  or  five  minutes  if  the  animal  remains  so  long  under  water.  The 
same  stoppage  may  be  produced  by  pouring  water  on  the  beak. 


'  CHEYNE-STOKES  '   BREATHING 

If  a  man  desires  to  hold  his  breath  for  some  time  he  takes  first  a  series 
of  deep  breaths.  The  result  is  to  diminish  the  carbon  dioxide  tension  in  the 
alveoU  and  therefore  to  take  away  the  need  and  the  desire  to  breathe  until 
the  carbon  dioxide  tension  rises  to  normal  as  the  result  of  the  continued 
formation  of  carbon  dioxide.  By  continuing  forced  respiratory  movements 
for  a  minute  or  two  the  carbon  dioxide  tension  both  in  the  alveoli  and  in 
the  blood  may  be  brought  down  to  a  very  considerable  extent.  As  a  result 
there  is  a  prolonged  period  of  apnoea.  During  this  period  of  cessation  of 
respirations,  however,  the  oxygen  is  being  used  up,  and  the  tension  of  this 
gas  in  the  alveoli  may  fall  to  such  an  extent  that  the  respiratory  centre  is 
excited  by  lack  of  oxygen  before  the  carbon  dioxide  tension  in  the  alveoli 
has  risen  to  its  normal  value.  As  a  result  of  the  excitation  by  oxygen  lack,  a 
few  breaths  are  taken  and  the  carbon  dioxide  tension  is  once  more  lowered, 
and  the  stimulation  due  to  the  oxygen  lack,  disappears.  There  is  therefore 
again  a  cessation  of  respiration.  These  periods  of  cessation  alternate  with 
periods  of  respiration  so  that  we  get  a  condition  of  periodic  breathing 


REGULATION  OF  RESPIRATORY  MOVEMENTS 


1097 


which  is  spoken  of  as  Cheyne-Stokes  respiration.  During  the  period  of 
apnoea,  resulting  on  forced  breathing,  the  great  diminution  of  oxygen 
tension  in  the  alveoli  is  shown  by  the  fact  that  the  subject  of  the  experi- 
ment becomes  blue,  and  may  indeed  lose  consciousness.  There  are  at  the 
same  time  rhythmic  changes  in  the  blood-pressure,  which  rises  towards  the 


Fig.  515.     Forced  breathing  of  air  for  two  minutes,  followed  by  apnoea  for  two 
minutes,  and  periodic  ('  Cheyne-Stokes  ')  breathing  for  about  five  minutes. 
At  A,  sample  of  alveolar  air  contained  O2,  11-44  per  cent.  ;   CO2,  5-58  per  cent. 
Second  sample  at  b,  Og,  13-55  per  cent.  :  CO,,  5-57  per  cent.     (Douglas  and 
Hai.dane.) 

ends  of  the  periods  of  the  apnoea,  falhng  during  the  periods  of  respiration. 
The  first  respiration  after  forced  breathing  is  due  to  oxygen  lack.  The 
period  of  apnoea  may  therefore  be  considerably  prolonged,  if  the  onset  of 
oxygen  lack  be  postponed,  by  increasing  the  tension  of  this  gas  in  the  alveoli 
at  the  commencement  of  the  apnoeic  period.  By  forcibly  breathing  for  a 
period  of  two  minutes  in  an  atmosphere  of  oxygen,  men  have  succeeded  in 
holding  their  breath  for  as  long  a  period  as  eight  minutes  (Vernon). 

'  Cheyne-Stokes  '  breathing  is  almost  invariably  observed  as  one  of  the  effects  of 
exposure  to  high  altitudes,  and  is  then  especially  marked  during  sleep.  It  is  often  present 
when  the  activity  of  the  respiratory  centre  is  depressed,  as  in  cases  of  lu-ismia  or  per- 
nicious anaemia.  Under  these  circumstances  it  may  be  temporarily  removed  by 
administering  either  oxygen  or  carbon  dioxide  (in  small  percentage)  to  the  patient. 
The  oxygen  improves  the  condition  of  the  centre  ;  the  carbon  dioxide  acts  as  an  added 
stimulus  and  rouses  its  activity. 


35^ 


SECTION  IV 

THE  EFFECTS   ON   RESPIRATION   OF  CHANGES  IN 
THE   AIR  BREATHED 

We  have  already  seen  that  a  moderate  increase  in  the  carbon  dioxide  per- 
centage of  -the  air  breathed  {e.g.  up  to  4  per  cent.)  causes  a  proportional 
increase  in  the  ventilation  of  the  lungs  so  as  to  maintain  the  tension  of  this 
gas  in  the  alveoli  at  the  normal  level.  The  same  effect  is  observed  whether 
the  mixture  breathed  contains  18  or  50  per  cent,  of  oxygen,  showing  that  the 
sHght  diminution  in  oxygen  content  caused  by  mixing  the  air  with  carbon 
dioxide  is  in  no  way  responsible  for  the  effect.  If  the  amount  of  carbon 
dioxide  be  increased  to  12  or  15  per  cent,  it  becomes  almost  impossible  to 
continue  the  inhalation  owing  to  the  spasm  of  the  glottis  produced  by  the 
irritant  effects  of  the  carbon  dioxide.  If  these  high  percentages  be  ad- 
ministered to  an  animal  by  a  tracheal  tube,  violent  dyspnoea  is  produced 
which  gradually  diminishes,  and  the  animal  passes  into  a  condition  of 
narcosis  in  which  the  respiratory  movements  become  less  and  the  oxygena- 
tion of  the  blood  is  ineffectively  carried  out  even  in  the  presence  of  excess  of 
oxygen.  The  administration  of  larger  percentages,  such  as  30  or  40  per 
cent.,  causes  rapid  death  and  failure  of  the  circulation  and  respiration,  often 
preceded  by  convulsions.  Coincident  with  the  increased  respiration  brought 
about  by  moderate  percentages  of  carbon  dioxide  there  is  a  rise  of  blood- 
pressure,  determined  partly  by  vascular  constriction,  partly  by  an 
increased  output  from  the  heart.  With  high  percentages  of  carbon  dioxide 
the  curve  of  blood-pressure  obtained  resembles  that  produced  by  lack  of 
oxygen. 

Oxygen  itself  exercises  no  excitatory  effects  on  the  respiratory  move- 
ments. At  the  normal  atmospheric  pressure  the  tension  of  oxygen  in  the 
alveoli  is  about  107  mm.  Hg,  a  pressure  which,  as  we  have  seen,  is  amply 
sufficient  to  saturate  the  hsemoglobin  passing  through  the  vessels  of  the 
lungs.  Since  the  depth  and  frequency  of  respiration  are  determined  by  the 
carbon  dioxide  tension  in  the  alveoli  no  alteration  in  respiration  will  be 
produced  by  increasing  the  tension  of  oxygen  in  the  air  breathed  above  its 
normal  amount.  The  respiratory  movements  in  an  atmosphere  of  pure 
oxygen  will,  in  the  normal  individual,  remain  unchanged. 

This  statement  is  only  true  for  the  healthy  individual.  If  from  failure  of  the  heart 
and  circulation,  or  diminished  oxygen  tension,  or  severe  loss  of  blood,  the  oxygenation  of 

1098 


EFFECTS  OF  CHANGES  IN  AIR  BREATHED  1099 

the  blood  is  already  insufficient,  marked  amelioration  of  the  symptoms  may  be  produced 
by  inhalation  of  jjure  oxygen.  Especially  is  this  noticeable  where  there  is  failure  of 
the  heart.  In  these  cases  the  heart,  already  affected,  is  unable  to  keep  up  an  adequate 
circulation  and  to  supply  itself  with  sufficient  oxygen.  A  vicious  circle  is  thus  estab- 
lished in  which  the  heart  tends  to  get  steadily  worse.  By  administration  of  oxygen  an 
adequate  supply  of  this  gas  to  the  heart-muscle  is  assured  ;  the  heart-beat  therefore 
becomes  more  effective  and  the  whole  circulation  is  improved  and  therewith  the  pro- 
vision of  oxygen  to  the  body  at  large. 

If  a  warm-blooded  animal  be  immersed  in  a  chamber  and  submitted  to 
pure  oxygen  at  a  pressure  of  four  atmospheres,  it  dies  as  rapidly  as  if  it  were 
in  an  atmosphere  of  pure  nitrogen.  At  this  pressure  the  oxidative  processes 
of  the  body  as  well  as  the  intake  of  oxygen  into  the  lungs  are  absolutely 
abolished.  It  is  interesting  to  note  that  certain  other  oxidative  phenomena, 
e.g.  the  spontaneous  oxidation  of  phosphorus,  also  cease  if  the  tension  of  the 
oxygen  be  sufficiently  high.  Exposure  of  an  animal  over  a  considerable 
period  of  time  to  a  pressure  of  oxygen  of  two  atmospheres  may,  as  Haldane 
and  Lorrain  Smith  have  shown,  set  up  severe  inflammation  of  the  lungs  and 
thereby  cause  death  indirectly. 

CHANGES  IN  TENSION  OF  OXYGEN.  If  a  man  breathe  a  mixture  of 
nitrogen  and  oxygen  free  from  carbon  dioxide,  and  the  oxygen  be  gradually 
diminished,  no  feeling  of  '  want  of  breath  '  may  be  experienced.  With  per- 
centages of  oxygen  as  low  as  12  per  cent,  there  may  be  no  change  in  the 
breathing,  even  though  the  deficient  oxygenation  of  the  blood  may  be 
shown  by  the  blueness  of  the  lips  and  face.  If  the  oxygen  be  reduced  still 
lower,  a  certain  amount  of  hyperpnoea  may  occur,  but  in  many  cases  the 
individual  experimented  on  may  not  feel  any  ill  effects  until  he  suddenly 
becomes  unconscious  from  lack  of  oxygen.  If  fresh  oxygen  be  not  supplied 
this  unconsciousness  may  be  followed  by  convulsive  movements  and  death. 
If  the  administration  of  low  percentages  of  oxygen,  e.g.  about  10  to  12 
per  cent,  of  an  atmosphere,  be  continued  for  some  time,  the  subject  of  the 
experiment  may  suffer  considerable  discomfort.  One  of  the  signs  of  oxygen 
lack  is  often  severe  headache,  and  this  may  be  accompanied  by  vomiting  or 
nausea  and  by  a  feehng  of  discomfort  in  the  precordial  region.  Many 
experiments  have  been  made  both  on  animals  and  man  by  submitting  them 
to  a  lowered  atmospheric  pressure  in  chambers  specially  built  for  the 
purpose.  The  limit  to  which  the  pressure  may  be  reduced  varies  in  different 
individuals,  the  variations  being  determined  by  the  type  of  respiratory 
movement  of  the  individual  in  question,  since  on  the  depth  of  respiration 
depends  the  relation  between  the  tension  of  oxygen  in  the  alveoli  and  that 
in  the  inspired  air.  The  lowest  limit  at  which  life  is  possible  corresponds 
to  an  oxygen  tension  in  the  alveoli  of  27  to  30  mm.  Hg. 

MOUNTAIN  SICKNESS.  The  phenomena  just  described  as  ensuing  on 
exposure  of  an  animal  to  low  oxygen  tensions  in  a  respiratory  chamber  for 
some  length  of  time  are  exactly  similar  to  those  which  are  regarded  as 
characteristic  of  mountain  sickness.  The  following  Table  shows  the  diminu- 
tion in  the  atmospheric  pressure  at  varying  heights  above  the  level  of  the 
sea  : 


1100 


PHYSIOLOGY 


Height  above  sea  level, 

Barometer 

Per  cent,  of  an 

in  metres 

mm.  Hg 

atmosphere 

0 

760 

100 

1000 

670 

88 

2000 

593 

78 

3000 

524 

69 

4000 

463 

61 

5000 

410 

54 

6000 

367 

47 

7000 

320 

42 

At  a  height  of  5000  metres  the  pressure  of  the  air  is  reduced  to  little 
over  half  an  atmosphere  and  the  oxygen  tension  is  therefore  only  about  11 
per  cent,  of  an  atmosphere.  It  must  be  remembered  that  in  most  cases  of 
mountain  sickness,  in  addition  to  this  absolute  oxygen  lack,  there  is  in- 
creased consumption  of  oxygen,  owing  to  the  muscular  exercise  involved 
in  chmbing.  Moreover  a  greater  volume  of  the  alveolar  air  must  consist 
of  carbon  dioxide  if  the  tension  of  this  gas  is  to  be  kept  constant  (cp.  Fig.  506, 
p.  1082).  Since  diminished  oxygen  tension,  within  fairly  wide  hmits,  does 
not  excite  any  corresponding  increase  in  the  respiratory  movements,  there 
must,  at  these  heights,  be  an  actual  diminution  in  the  oxygen  tension  in  the 
alveoh.  This  diminution  in  tension  is  shown  by  a  series  of  observations 
carried  out  by  Zuntz  on  himself  and  fellow  workers  at  different  locahties. 
It  may  be  noted  that  on  Monte  Eosa,  where  the  oxygen  tension  in  the 
alveoh  was  reduced  to  between  37  and  57  mm.  Hg,  as  against  the  normal  101 
to  105  mm.  Hg,  all  the  members  of  the  party  were  suffering  from  mountain 
sickness. 


Height 

above  sea 

level, 

metres 

O2  tension 
of  air 

Alveolar  O2  tension 

A 

B 

c 

D 

E 

F 

Berlin    . 
Brienz    .          , 
Brienzer  Rothorn    . 
Col  d'Olen      . 
Monte  Rosa    . 

54 

500 

2130 

2900 

4560 

157 
148 
121 
110 

89 

105 

84-5 

68 

57 

101 
94 
66 

46 

80 
64 

49 

105 
88 
62 
60 
61 

103 
86 
66 
68 
37 

104 
91 

71 
68 

57 

As  a  result  of  the  oxygen  starvation  there  is  inadequate  supply  of  this 
gas  to  the  heart,  so  that  the  circulation  tends  to  fail,  especially  on  making 
the  slightest  muscular  movements.  At  the  same  time  the  oxygen  starva- 
tion of  the  brain  produces  failure  of  judgment  and  inability  to  carry  out  or  to 
co-ordinate  muscular  movements  properly.  The  symptoms  as  a  rule  do  not 
increase  until  death  results,  so  that,  although  there  is  an  oxygen  starvation 
of  the  body,  there  must  be  some  means  by  which  the  respiration  is  modified 


EFFECTS  OF  CHANGES  IN  AIR  BREATHED  1101 

so  as  to  obtain  a  sufficiency  of  this  gas  for  the  lowered  requirements  of  the 
body.  That  the  adaptation  is  effective  is  shown  by  the  fact  that  most 
individuals,  if  they  remain  at  a  height,  gradually  recover  from  the  mountain 
sickness  and  may  finally  be  able  to  carry  out  muscular  movements  with 
almost  as  gi-eat  precision  and  force  as  they  could  previously  on  the  plains. 
The  mechanism  by  which  increased  ventilation  of  the  lungs  is  attained  is  that 
already  mentioned  in  dealing  with  the  effects  of  lack  of  oxygen,  namely,  the 
production  of  acid  substances  in  the  body.  The  respiratory  centre  is  thus 
stimulated  by  these  acid  substances,  especially  lactic  acid,  as  well  as  by 
the  carbon  dioxide  tension  of  the  blood,  and  the  joint  action  of  these  two 
substances  (which  probably  co-operate  in  raising  the  hydrion  concentration  of 
the  blood)  determines  the  marked  increase  in  the  lung  ventilation.  Since 
the  carbon  dioxide  is  no  longer  the  sole  factor  responsible  for  the  ventilation, 
the  tension  of  this  gas  in  the  alveolar  air  is  diminished. 

ACAPNIA.  This  diminution  of  carbon  dioxide  tension  in  the  blood  and  alveolar  air 
has  been  regarded  by  Mosso  as  the  essential  factor  in  the  causation  of  mountain  sickness 
and  has  been  designated  acapnia.  It  may  be  absent,  however,  in  the  most  marked 
cases  of  mountain  sickness,  where  the  respiratory  centre  has  failed  to  respond  to  the 
additional  acid  stimulation,  and  may  be  present  to  a  marked  degree  in  individuals  who 
are  experiencing  none  of  the  ill  eifects  of  this  disorder. 

Another  important  means  of  rapid  adaptation  is  by  means  of  the  circula- 
tion. This  is  noticeable  even  in  the  case  of  persons  sitting  quietly  in  a 
gas  chamber  who  are  subjected  to  gradually  lower  pressures.  It  is  evident 
that  a  deficient  passage  of  oxygen  from  the  alveoli  to  the  blood  may,  so 
far  as  the  tissues  and  heart  are  concerned,  be  accommodated  for  by  increasing 
the  rapidity  of  the  circulation,  and  this  is  effected  by  a  quickening  of  the 
pulse-rate.  The  following  Table  shows  the  changes  in  the  pulse-rate  caused 
by  exposure  to  varying  pressures  in  a  gas  chamber  : 

Pulse  rff  Gas  Chamber 

Pressure  .      I'ulse 

720 64 

650 72 

424         .......         84 

This  quickening  of  the  pulse  is  to  be  observed  also  in  the  trained  mountain 
soldier,  in  individuals  in  whom  there  is  no  lowering  of  the  alveolar  carbon 
dioxide  tension,  so  that  apparently  in  such  cases  the  whole  adaptation  to 
altered  conditions  is  by  means  of  the  circulation.  In  cases  where  adaptation 
fails  it  is  in  the  circulation  that  the  failure  is  most  marked,  so  that  the 
symptoms  of  severe  mountain  sickness  resemble  closely  those  produced  by 
rapid  heart-failure.  Dilated  heart,  cyanosis,  muscular  weakness,  vomiting, 
mental  torpor,  inco-ordination,  delirium,  may  all  be  observed  in  both  cases. 
The  disturbance  of  the  central  nervous  system  is  shown  by  the  almost 
invariable  occurrence  at  great  heights  of  Cheyne  Stokes  breathing. 

If  the  animal  is  able  to  withstand  the  immediate  effects  of  exposure  to  a 
rarefied  atmosphere,  a  process  of  adaptation  comes  into  play  which  finally 


1102 


PHYSIOLOGY 


fits  him  for  discharging  his  functions  normally  even  at  the  high  altitude. 
From  the  lack  of  sensibility  of  the  respiratory  centre  to  small  changes  in 
oxygen  tension,  any  diminution  in  oxygen  tension  must  cause  a  corresponding 
diminution  in  the  degree  of  saturation  of  the  haemoglobin  of  the  blood.  This 
change  in  oxygen  saturation  is  at  once  felt  by  the  blood-forming  organs. 
As  an  immediate  effect  of  change  to  a  region  of  low  atmospheric  pressure 
there  is  a  relative  increase  in  the  blood-corpuscles  due  to  a  concentration 
of  the  blood  and  a  diminution  of  its  plasma.  Simultaneously,  however, 
the  blood-forming  organs  enter  into  a  condition  of  increased  activity,  so 
that  after  a  stay  of  four  or  five  weeks'  duration  at  a  height  both  corpuscles 
and  haemoglobin  are  considerably  increased  in  total  amount.  The  following 
Table  shows  the  average  number  of  red  corpuscles  contained  in  one  cubic 
millimetre  of  blood  from  the  inhabitants  of  regions  at  varying  altitudes  : 


Height  above  sea 

level, 

Red  corpuscles 

metres 

Christiaiiia    . 

0 

4,970,000 

Zxirich . 

412 

5,752,000 

Davos 

1560 

6,551,000 

Arosa  . 

1800 

7,000,000 

Cordilleras    . 

4392 

8,000,000 

There  is  of  course  a  limit  to  the  power  of  adaptation,  a  limit  which  varies 
in  different  individuals.  Thus  for  some  men  it  is  impossible  to  stay  any 
length  of  time  in  the  high  settlements  in  the  Andes,  while  others,  after  two 
or  three  weeks'  discomfort,  become  perfectly  inured  to  their  new  conditions. 
It  seems  doubtful,  however,  whether  any  of  the  present  race  of  men  could 
become  adapted  to  permanent  residence  at  a  height  over  5000  metres,  and 
though  for  a  certain  length  of  time  by  bringing  into  play  the  reserve 
mechanisms  already  described,  they  may  raise  themselves  to  a  height 
considerably  above  5000  metres,  it  seems  questionable  whether  without 
artificial  means,  such  as  the  inhalation  of  oxygen,  it  will  be  possible  for 
any  man  to  attaio  the  highest  points  on  the  earth's  surface,  or  at  any  rate 
to  arrive  there  by  his  own  unaided  efforts.  The  highest  summits  in  the 
Himalayas  have  a  height  approaching  that  attained  by  Tissandier  with  his 
two  companions  in  his  famous  balloon  ascent,  namely,  8600  metres.  In  this 
ascent,  although  oxygen  inhalation  was  used  (somewhat  ineffectively),  two 
of  the  party  succumbed. 

The  stimulating  effect  of  oxygen  lack  on  the  blood-forming  organs 
extends  also  to  the  muscular  system,  so  that  one  of  the  effects  of  a  residence 
in  high  altitudes  is  increased  assimilation  of  nitrogen.  For  a  time  the 
nitrogen  output  is  less  than  the  nitrogen  intake,  and  there  is  an  actual 
building  up  of  new  tissue.  The  condition  of  the  individual  is  similar  to  that 
of  a  growing  animal,  a  fact  which  may  explain  the  admirable  results  of  a 
mountain  holiday.     We  can  hardly  imagine  that  the  power  of  the  organism 


EFFECTS  OF  CHANGES  IN  AIR  BREATHED  1103 

to  react  in  this  way  was  evolved  through  generations  of  mountain  climbing. 
We  are  probably  here  making  use  of  an  adaptation  which  has  been  evolved 
for  the  purpose  of  retrieving  loss  of  blood  by  haemorrhage,  such  as  must  have 
been  of  continual  occurrence  in  the  struggle  of  individual  against  individual, 
which  has  resulted  in  the  survival  of  the  animals  of  to-day. 

ALTERATIONS  IN  THE  NITROGEN  TENSION,  The  nitrogen  of  the 
atmosphere  plays  no  part  in  the  metabohsm  of  the  body,  and  nuist  be 
regarded  as  a  purely  inert  gas.  It  is  a  matter  of  indifference  whether  under 
normal  atmospheric  pressure  we  breathe  an  atmosphere  of  pure  oxygen  or 
one  containing  one-fifth  part  of  this  gas  diluted  with  four-fifths  of  nitrogen. 
The  very  inertness  of  nitrogen  may  be  of  danger  to  the  body  under  certain 
conditions.  If  a  man  or  an  animal  be  exposed,  as  in  a  di\dng-bell,  to  a 
pressure  of  three,  four,  or  six  atmospheres,  the  respiratory  functions  are 
unaffected,  but  the  amount  of  nitrogen  dissolved  in  the  fluids  of  the  body 
is  increased  in  direct  proportion  to  the  pressure.  If  the  pressure  be  now 
suddenly  released,  the  nitrogen,  which  cannot  be  used  up  by  the  tissues,  is 
given  off  from  the  body-fluids  in  the  form  of  bubbles,  just  as  carbonic  acid 
gas  rises  in  bubbles  from  soda-water  when  the  pressure  is  removed  by  with- 
drawing the  cork  from  the  bottle.  These  bubbles  occurring  in  all  the 
capillaries  obstruct  the  flow  of  blood,  and  therefore,  if  the  evolution  of  gas  is 
sufficiently  large,  the  animal  dies  in  convulsions.  A  similar  evolution  of  gas 
may  occur  in  the  spinal  cord,  giving  rise  to  destruction  of  the  cord  and 
paralysis  ('  divers'  palsy  ').  In  order  to  prevent  this  sudden  evolution  of 
gas  it  is  necessary  that  the  change  from  the  high  pressure  to  the  ordinary 
atmospheric  pressure  should  be  carried  out  gradually,  so  as  to  give  the 
blood-plasma,  supersaturated  mth  nitrogen,  time  to  get  rid  of  its  excess  of 
nitrogen  without  the  formation  of  bubbles. 

OTHER  GASES.  Hydrogen  and  methane  are,  like  nitrogen,  indifferent 
gases.  They  may  be  respired  if  mixed  with  20  per  cent,  of  oxygen,  and 
either  of  the  gases  may  be  used  instead  of  nitrogen  to  dilute  the  oxygen  that 
we  breathe,  without  harm  or  inconvenience. 

Carbon  monoxide  is  rapidly  poisonous  by  its  action  on  the  red  corpuscles. 
It  combines  with  haemoglobin,  forming  CO-haemoglobin,  a  compound  which 
is  much  more  stable  than  oxyhaemoglobin.  The  blood  is  therefore  deprived 
of  its  oxygen  carrier,  and  the  animal  dies  of  asphyxia.  We  have  seen, 
however,  that  the  displacement  of  oxygen  by  CO  is  not  absolute,  but  only 
relative.  Hence,  although  the  avidity  of  CO  for  haemoglobin  is  140  times 
that  of  oxygen,  we  can  convert  the  CO  back  into  oxyha'moglobin  by  in- 
creasing the  mass  influence  of  the  oxygen.  This  may  be  done  by  giving  the 
poisoned  animal  pure  oxygen  to  breathe,  or  even  oxygen  under  pressure. 
In  pure  oxygen  at  a  pressure  of  two  atmospheres  an  animal  can  breathe  and 
live,  even  though  tlu>  \vh()l(>  of  its  haMuoglobin  is  converted  into  CO-haemo- 
globin,  the  amount  of  oxygen  which  is  simply  dissolved  by  the  blood-plasma 
being  sufficient  at  this  pressure  for  the  respiratory  needs  of  the  animal 
(Haldane). 

Other  gases  which   have  special  poisonous  properties  are  hydrocyanic 


1104  PHYSIOLOGY 

acid,  sulphuretted  hydrogen,  phosphuretted  hydrogen  (PH3),  arseniuretted 
hydrogen,  &c. 

IRRESPIRABLE  GASES  are  those  which  are  so  irritating  that  they  pro- 
duce spasm  of  the  glottis.  Such  are  ammonia,  chlorine,  sulphur  dioxide, 
nitric  oxide,  and  many  others. 

VENTILATION 

A  point  of  practical  importance  is  the  securing  to  each  individual  of 
sufficient  fresh  air,  so  that  he  may  always  have  a  plentiful  supply  of  oxygen, 
and  may  be  relieved  of  his  waste  products.  It  is  found  that  a  dwelling-room 
becomes  unpleasant  and  stuffy  when  the  percentage  amount  of  COg  has 
reached  0-1  per  cent.  This  stuffiness  is  supposed  to  be  due  to  organic 
exhalations  from  the  skin,  lungs,  and  alimentary  canal,  some  of  which  have 
a  poisonous  effect,  giving  rise  to  headache  and  sleepinesss.  Since  these 
cannot  be  measured,  it  is  taken  as  a  cardinal  rule  in  ventilation  that  the 
amount  of  CO2  should  never  rise  above  0-1  per  cent. 

Since  in  questions  of  ventilation  we  have  generally  to  deal  with  trades  in 
which  the  metric  measure  is  not  used,  it  may  be  convenient  to  give  the  data 
as  to  carbon  dioxide  production  and  the  amount  of  air  required  in  cubic 
feet. 

An  adult  man  gives  off  about  0-6  cubic  foot  of  CO2  every  hour.  Hence 
in  that  time  he  raises  the  amount  of  CO2  in  1000  cubic  feet  of  air  from  -04 
per  cent,  (the  normal  amount  in  the  atmosphere)  to  0-1  per  cent.  He  must 
therefore  be  supphed  with  2000  cubic  feet  of  air  per  hour  in  order  to  keep 
the  amount  of  CO2  down  to  -07  per  cent. 

(Ordinary  air  contains  -04  per  cent.  CO2,  therefore  2000  cubic  feet  would 
contain  0-8  cubic  foot  CO 2,  which  with  the  0-6  cubic  foot  given  off  by  the  man 
would  be  1-4,  which  is  -07  per  cent.) 

In  order  that  the  air  may  be  easily  renewed  without  giving  rise  to  exces- 
sive draught,  a  certain  amount  of  cubic  space  must  be  allotted  to  each  man. 
Each  adult  should  have  in  a  room  1000  cubic  feet  of  space,  and  be  supplied 
every  hour  with  2000  to  3000  cubic  feet  of  air. 


SECTION  V 
THE   MECHANISMS   OF   OXIDATION   IN   THE   TISSUES 

The  blood  in  its  passage  through  the  capillaries  takes  up  carbon  dioxide 
from  the  tissues,  giving  oxygen  to  the  latter  in  exchange.  This  interchange 
is  determined  by  the  differences  in  tension  of  the  gases  on  the  two  sides  of 
the  capillary  wall.  Whereas  the  tension  of  oxygen  in  the  plasma  varies 
from  100  mm.  Hg  in  arterial  to  25  mm.  Hg  in  venous  blood,  the  tension  of 
oxygen  in  the  tissues  outside  the  vessels  in  most  cases  approaches  0,  as  is 
shown  by  Ehrhch's  methylene-blue  experiment  described  on  p.  1063.  On 
the  other  hand,  the  tension  of  carbon  dioxide  in  the  tissues,  as  judged  from 
the  examination  of  fluids  such  as  bile  and  urine,  varies  from  6  to  10  per  cent. 
of  an  atmosphere.  The  continuous  flow  of  oxygen  into,  and  of  carbon 
dioxide  away  from,  the  tissues  points  to  the  constant  occurrence  of  oxidative 
changes  in  the  tissue-cells.  By  the  blood  the  tissues  receive  not  only  oxygen 
but  also  food-stuffs,  namely,  proteins  or  amino-acids,  fats,  and  sugars, 
derived  from  the  alimentary  canal,  or,  in  starvation,  from  other  parts  of  the 
body.  The  activity  of  the  tissues,  whether  motor,  as  in  the  case  of  muscle, 
or  secretory,  as  in  the  case  of  glands,  is  derived  from  the  energy  set  free  in 
the  partial  or  complete  oxidation  of  these  food-stuffs,  which  occurs  -vv^thin 
the  active  cells  themselves.  A  study  of  the  mechanism  of  oxidation  in  the 
body  involves  therefore  a  consideration  of  the  processes  which  take  place 
within  the  confines  of  each  cell.  The  question  is  by  no  means  an  easy  one. 
Although  we  speak  of  the  '  burning  '  of  food-stuff's,  and  compare  the  processes 
in  the  body  to  those  which  take  place  in  combustion,  e.g.  in  a  candle-flame, 
the  analogy  is  after  all  a  very  rough  one.  In  the  first  place,  the  food-stuff's, 
even  after  absorption,  belong  to  a  class  of  substances  which  have  been 
designated  as  dysoxidisahle,  since  they  present  no  tendency  to  combine  with 
ordinary  atmospheric  oxygen.  Thus  sugars,  proteins,  or  fats,  if  kept  free 
from  microbial  infection,  may  be  kept  for  years  exposed  to  the  air  without 
undergoing  any  change.  It  is  true  that  in  certain  cases,  e.g.  in  alkaline 
solutions  of  sugar,  we  may  obtain  slow  absorption  of  oxygen  and  oxidation 
of  the  sugar.  The  changes  are,  however,  slight  and  limited  in  extent.  All 
these  food-stuff's  are  susceptible  of  combustion  if  raised  to  a  sufficiently  high 
temperature,  but  in  the  animal  body  the  processes  of  oxidation  have  to  go 
on  at  a  temperature  varying  between  5°  and  40°  C,  and  in  a  solution  which 
is  almost  neutral  in  reaction.  It  might  be  said  that  at  the  temperature  of 
an  ordinary  flame  the  combustion   of  the   food-stuff's  is  immediate  and 

11(1.5 


1106  PHYSIOLOGY 

complete,  whereas  in  tlie  body  the  oxidation  takes  place  by  stages.  Recent 
researcli  has  tended  to  remove  this  point  of  distinction  by  pointing  out  that 
even  in  an  explosion  of  a  mixture  of  methane  and  oxygen  there  is  a  series 
of  intermediary  products,  and  that  the  whole  process,  if  analysed,  is  made 
up  of  stages  in  which  hydrolysis  and  oxidation  go  on  simultaneously,  so 
that  on  this  account  it  is  difficult  to  cause  a  combination,  even  of  hydrogen 
and  oxygen,  in  the  complete  absence  of  any  watery  vapour.  The  oxidations 
in  the  body  are  strictly  limited  both  in  nature  and  extent.  The  mere  fact 
that  a  substance  is  readily  or  even  spontaneously  oxidisable  {autoxidisahle) 
affords  no  guarantee  that  it  will  undergo  oxidation  in  the  animal  body. 
Thus  phosphorus  or  pyrogallol  taken  by  the  mouth  can  be  recovered  in  an 
unoxidised  form  from  the  urine.  Carbon  monoxide  is  excreted  unchanged. 
There  must  apparently  be  some  definite  relationship  between  the  molecular 
structure  of  the  food-stuff  and  that  of  the  cells  of  the  body.  Thus  ordinary 
proteins  which  undergo  complete  oxidation  contain  large  quantities  of 
leucine.  This  substance  is  Isevorotatory  and  is  designated  i!-leucine.  If 
^leucine  be  administered  to  rabbits  it  is  completely  oxidised.  If  its  isomer 
(^-leucine,  resembhng  it  in  every  particular  so  far  as  we  can  see  except  in 
its  relation  to  polarised  light,  be  administered  to  a  rabbit,  the  greater  part 
of  the  substance  passes  through  the  body  unchanged.  In  the  same  way 
there  are  sixteen  sugars  of  the  formula  CgHjaOg.  Of  these  only  four,  namely, 
glucose,  fructose,  galactose,  and  mannose,  can  be  oxidised  in  the  animal 
body.  Other  sugars  differing  in  so  slight  a  degree  from  these  four  as, 
e.g.,  Z- glucose  or  Z-fructose,  cannot  be  utilised  by  the  body.  Not  only  must 
there  be  a  distinct  relation  between  the  structure  of  the  cell  and  the  molecular 
structure  of  the  food- stuff  supplied,  but  there  must  be  different  mechanisms 
for  the  food-stufis  and  their  derivatives.  Thus  in  certain  cases  of  disease 
or  of  abnormal  nutrition  the  body  may  lose  absolutely  the  power  of  utilising, 
i.e.  of  oxidising,  a  whole  class  of  food-stuffs.  In  severe  diabetes,  or  after 
destruction  of  the  pancreas,  glucose  behaves  in  the  body  as  if  it  were  one 
of  the  artificial  unassimilable  sugars.  The  normal  oxidation  of  fats  probably 
proceeds  by  stages  in  each  of  which  two  atoms  of  carbon  undergo  oxidation. 
The  penultimate  stage  in  the  oxidation  of  any  of  the  higher  fatty  acids  is 
thus  oxybutyric  acid.  In  complete  carbohydrate  starvation,  for  some 
reason  or  other,  the  body  loses  its  power  of  completing  this  last  stage,  so 
that  the  oxybutyric  acid  undergoes  no  further  oxidation,  and  either  accumu- 
lates in  the  body  or  is  excreted  combined  with  bases  in  the  urine.  In  the 
normal  individual  tyrosine,  whether  administered  separately  or  in  combina- 
tion in  protein,  is  completely  oxidised,  the  benzene  ring  being  broken  up. 
In  certain  rare  cases  of  disordered  metabolism  the  patient,  who  is  otherwise 
apparently  well,  is  unable  to  effect  the  total  oxidation  of  tyrosine,  which 
is  therefore  excreted  as  homogentisic  acid,  after  undergoing  only  the  first 
stage  of  its  normal  transformation  in  the  body.  These  various  mechanisms 
are  adjusted  in  each  case  to  the  functional  activity  of  the  cell  and  are  limited 
therefore,  not  by  the  supply  of  oxygen  or  of  food-stuff  to  be  oxidised,  but 
by  the  necessities  of  the  cell,  i.e.  the  adaptations  induced  in  it  by  its  environ- 


MECHANISMS  OF  OXIDATION  IN  TISSUES  1107 

mental  changes.  In  discussing  the  mechanism  of  intracellular  oxidation 
we  have  therefore  to  consider  in  the  first  place  how  the  dysoxidisable  food- 
stuffs are  made  to  combine  with  the  molecular  oxygen  diffusing  into  the 
cells  from  the  blood  in  the  capillaries,  and  in  the  second  place  the  means 
by  which  these  oxidative  changes  are  strictly  limited  in  accordance  with 
the  necessities  of  the  cell,  and  finally  the  nature  of  the  specific  oxidative 
mechanisms  for  each  kind  of  food-stuff  and  for  the  various  stages  in  the 
oxidation  of  each  food-stuff. 

We  are  very  far  as  yet  from  being  able  to  give  a  definite  answer  to  any 
one  of  these  questions.  Even  in  the  first  problem,  namely,  the  oxidation 
of  dysoxidisable  substances,  we  have  to  confine  ourselves  almost  exclusively 
to  speculation  on  possibilities.  Although  these  substances  will  not  unite 
with  the  oxygen  of  the  air,  in  which  the  combining  activities  of  the  oxygen 
are  satisfied  by  the  combination  of  two  atoms  to  form  one  molecule,  many 
of  them  readily  undergo  oxidation  if  subjected  to  the  action  of  '  atomic ' 
oxygen  or  '  active  '  oxygen,  and  it  has  been  suggested  that  the  problem  of 
the  oxidation  of  the  body  is  really  bound  up  with  the  question  as  to  the 
mode  of  activation  of  the  molecular  oxygen  derived  from  the  oxyhsemoglobin. 
Thus  Hoppe-Seyler  suggested  that  the  activation  of  oxygen  might  occur 
through  the  intermediation  of  reducing  substances.  He  supposed  that 
reducing  substances  might  be  formed  under  the  influence  of  ferments  by 
hydrolytic  splitting  of  the  food-stuffs.  A  reducing  substance  is  one  that 
has  sufficient  affinity  for  oxygen  at  the  ordinary  temperature  to  tear  asunder 
the  bonds  which  unite  two  atoms  of  oxygen  to  form  one  molecule,  and  to 
combine  with  one  or  both  of  the  atoms  so  set  free.  If  the  combination  is 
with  only  one  atom,  the  other  atom  of  the  oxygen  molecule  is  set  free  in  an 
active  form,  and  is  therefore  able  to  oxidise  dysoxidisable  substances  which 
may  be  present.  Thus,  when  a  mixture  of  ammonia  and  pyrogallol  is 
exposed  to  the  atmosphere,  the  oxygen  is  rapidly  absorbed,  forming  a  dark 
brown  solution,  pyrogallol  being  therefore  a  reducing  agent.  But  at  the 
same  time  a  certain  amount  of  the  ammonia  (a  dysoxidisable  substance) 
undergoes  oxidation  with  the  formation  of  nitrite.  In  the  slow  spontaneous 
oxidation  of  phosphorus  which  occurs  on  exposing  this  substance  to  the 
atmosphere,  ozone,  OgO,  is  always  formed.  As  a  type  of  the  formation  of 
reducing  substances  in  hydrolytic  fermentations  may  be  adduced  the  butp'ic 
acid  fermentation,  in  which  sugar  is  converted  into  butyric  acid,  carbonic 
acid,  and  hydrogen  :      ^^^^^^^  ^  ^^^^^^  ^  ^^^^  ^  .,^^ 

The  hydrogen  produced  in  this  process  would  act  as  a  reducing  agent. 
There  is  no  doubt  that  reducing  substances  are  formed  under  normal  circum- 
stances in  the  tissues,  as  is  shown  by  the  methylene-blue  experiment,  and 
it  is  possible  that  such  reducing  substances  may  aid  in  activating  oxygen 
and  in  the  induction  of  certain  oxidative  processes.  The  activation  of 
oxygen  would,  however,  not  explain  the  specific  character  of  the  various 
oxidations,  and  the  accurate  gradation  of  these  oxidations  to  the  necessities 
of  the  cell.     In   mnnv  cases  reducing  substances  may  themselves  act  as 


1108  PHYSIOLOGY 

carriers  of  oxygen,  and  their  action  be  more  or  less  specific.  If,  for  instance, 
glucose  be  boiled  with  an  ammoniacal  solution  of  cupric  hydrate,  it  undergoes 
oxidation,  the  cupric  being  reduced  to  cuprous  hydrate.  Cuprous  hydrate 
in  ammoniacal  solution  is  a  reducing  substance  ;  it  absorbs  oxygen  from 
the  air  and  is  reconverted  to  cupric  hydrate.  A  small  amount  of  cupric 
hydrate  therefore,  in  the  presence  of  air,  may  act  as  a  carrier  of  oxygen  from 
the  air  to  the  sugar  and  may  thus  oxidise  indefinitely  large  quantities  of 
sugar.  In  the  same  way,  if  indigo  in  alkahne  solution  be  boiled  with  sugar, 
it  undergoes  reduction  with  the  formation  of  a  colourless  compound.  On 
shaking  the  decolorised  solution  with  air  it  absorbs  oxygen  with  the  reproduc- 
tion of  indigo,  so  that  here  again  minute  quantities  of  indigo  blue  may  serve 
to  oxidise  large  quantities  of  glucose.  The  mode  of  action  of  these  oxygen 
carriers  resembles  closely  that  of  the  various  ferments  which  effect  the 
transference  of  water  from  the  menstruum  to  the  substrate  {e.g.  trypsin, 
invertase,.  &c.).  These  hydrolytic  ferments  differ  from  ordinary  hydrolytic 
agents,  such  as  dilute  acids,  in  the  specific  character  of  their  action.  Trypsin, 
for  instance,  will  hydrolyse  polypeptides  of  a  type  corresponding  to  those 
which  make  up  the  ordinary  food-products,  but  is  powerless  to  hydrolyse 
polypeptides  composed  of  artificial  amino-acids  which  are  the  optical  isomers 
of  those  occurring  in  the  body.  It  seems  possible  that  we  might  explain  the 
specific  oxidations  occurring  in  the  cell  by  assuming  the  presence  of  a  number 
of  ferments,  oxidases,  which  would  act  as  oxygen  carriers,  but  each  of  which 
would  only  be  able  to  act  on  a  certain  type  of  food-stufi  or  on  molecules 
of  a  given  configuration. 

Such  oxidative  ferments  have  been  described  as  existing  in  many  animal 
and  vegetable  extracts.  Many  species  of  fungus  contain  a  ferment  known 
as  tyrosinase,  from  the  fact  that,  when  it  is  added  to  solutions  of  tjncosine  in 
the  presence  of  air,  the  tyrosine  is  oxidised  with  the  formation  of  a  brown 
pigment.  The  same  ferment  is  able  to  effect  the  oxidation  of  other  aromatic 
substances.  The  browning  of  a  freshly  cut  potato  or  apple  on  exposure  to 
the  air  is  similarly  ascribed  to  the  oxidation  of  a  chromogen  by  the  oxygen 
of  the  air,  through  the  intermediation  of  an  oxidase  present  in  the  cells. 
If  benzyl  alcohol  or  sahcyl  aldehyde  be  added  to  a  suspension  of  liver-cells 
in  blood,  and  air  be  allowed  to  bubble  through  the  mixture  for  some  time, 
the  alcohol  or  aldehyde  is  oxidised  to  the  corresponding  acid.  In  the  same 
way  xanthine  (C5H4N4O2)  added  to  a  mixture  of  spleen  pulp  and  defibrinated 
blood  is  converted  into  uric  acid  (C5H4N4O3). 

Bach  and  Chodat  have  shown  that  in  many  cases  the  oxidase  is  not  a 
single  substance,  but  a  mixture  of  an  organic  peroxide  with  a  ferment, 
peroxidase,  which  has  the  property  of  sphtting  off  atomic,  i.e.  active,  oxygen 
from  the  peroxide.  These  peroxidases  have  the  same  effect  on  hydrogen 
peroxide.  They  must  be  distinguished  from  the  ferment  catalase,  which  is 
present  in  almost  all  animal  and  vegetable  tissues,  and  which  effects  a  rapid 
decomposition   of  hydrogen   peroxide   with  the   formation   of   molecular 

oxygen  : 

2H2O2  =  2H2O  +  O.,. 


MFX'HANISMS  OF  OXIDATION  IN  TISSUES  1109 

In  the  case  of  a  peroxidase  the  equation  would  be  represented  : 

H2O2  =  H2O  +  0'. 
Many  reactions  are  known  in  chemistry  in  which  the  part  of  a  peroxidase 
is  played  by  an  inorganic  catalyst.  Thus  hydrogen  peroxide  effects  a  slow 
oxidation  of  many  organic  substances,  but  the  oxidation  is  enormously 
hastened  if  to  the  mixture  be  added  a  trace  of  a  ferrous  salt  (Fenton's 
reaction).  The  same  part  may  be  played  by  salts  of  manganese,  and  it  is 
interesting  to  note  that  manganese  forms  an  essential  constituent  of  the 
peroxidase  laccase,  which  is  present  in  many  plants  and  is  responsible  for 
the  formation  of  the  Japanese  lacquer.  It  effects  a  specific  oxidation  of 
hydroquinone  and  pyrogallol.  The  oxidations  carried  out  by  the  use  of 
hydrogen  peroxide,  \\ath  or  without  a  catalyst  or  peroxidase,  present  a 
close  resemblance  to  the  oxidations  occurring  in  the  animal  body.  Thus 
Dakin  has  shown  that  saturated  fatty  acids,  even  the  higher  members  of 
the  series,  are  gradually  oxidised  if  warmed  gently  with  hydrogen  peroxide 
in  the  presence  of  ammonia,  and  the  course  of  the  reaction  resembles  in 
many  respects  that  which,  on  other  grounds,  we  have  assumed  to  take  place 
in  the  normal  metaboHsm  of  the  body. 

We  have  no  evidence  that  hydrogen  peroxide  is  formed  at  any  time  in 
the  body,  though  there  is  some  reason  to  assume  its  formation  in  the  process 
of  carbon  assimilation  in  the  green  leaf.  If  we  adopt  the  views  of  Bach  and 
Chodat  we  must  assume  that  every  animal  cell  contains  organic  peroxides 
as  well  as  peroxidases,  or  else  that  it  can  under  physiological  conditions 
form  these  substances.  Since  there  is  also  evidence  of  the  presence  of 
reducing  substances  in  the  cells,  we  may  conveniently  assume,  with  Ehrlich, 
that  distinct  side-chains  of  the  protoplasmic  molecule  have  specific  affinities 
for  oxygen.  When  all  these  affinities  are  saturated,  these  side-chains  will 
act  as  peroxides,  parting  with  their  oxygen  with  extreme  ease,  whereas 
when  the  greater  number  are  unsaturated,  the  resultant  effect  will  be  that 
of  a  reducing  agent.  The  same  protoplasmic  molecule  may  therefore, 
according  to  its  state  of  saturation  with  oxygen,  act  either  as  an  oxidising 
or  reducing  agent,  and  can  effect,  probably  through  the  intermediation  of 
specifically  adapted  oxidases,  the  oxidation  of  the  various  food-stuffs  stored 
up  as  the  paraplasm  of  the  cell.  Since  the  oxidative  processes  are  deter- 
mined, not  by  the  presence  of  oxygen,  but  by  the  functional  activities  of 
the  tissue,  we  must  assume  that  the  peroxidases  are  not  preformed  in  the 
cell,  but  exist  as  precursors,  zymogens,  from  which  they  can  be  set  free  in 
accordance  with  the  necessities  of  the  cell. 

It  is  probable  that  many  of  the  food-stuffs  or  other  proximate  con- 
stituents are  not  directly  accessible  to  oxidation,  and  that  the  first  step  in 
their  utiUsation  is  a  process  of  cleavage  or  hydrolysis,  which  itself  involves 
the  presence  of  specific  ferments.  Thus,  so  far  as  we  can  tell,  the  amino-acids 
undergo  deamination  before  oxidation.  They  can  thus  be  stored  up  in  the 
cell  either  free  or  in  the  form  of  protein  and  present  no  point  of  attack  to 
oxygen  until  the  process  of  hydrolysis  and  deamination  has  taken  place.  This 
course  of  events  is  certainly  true  for  some  of  the  members  of  the  purine  group. 


CHAPTER  XVII 
RENAL   EXCRETION 

SECTION  I 

THE  COMPOSITION  AND  CHARACTERS  OF  THE  URINE 

The  main  product  of  the  oxidation  of  carbon,  namely,  carbon  dioxide,  is 
discharged  by  the  lungs  and  to  a  slight  extent  by  the  skin.  Water,  taken 
as  such  with  the  food,  but  also  derived  to  a  shght  extent  from  the  oxidation 
of  hydrogen,  is  got  rid  of  by  the  lungs,  skin,  and  kidneys.  The  salts  of 
heavy  metals  when  administered  are  excreted  for  the  most  part  by  the 
alimentary  canal,  e.g.  iron,  bismuth,  mercury,  A  certain  proportion  of  the 
pigmentary  waste  products  of  the  body,  derived  from  the  breakdown  of  the 
blood-pigment,  is  also  got  rid  of  with  the  fseces.  With  these  exceptions 
practically  all  the  waste  products  resulting  from  metabolism  are  excreted 
in  the  urine  by  the  kidneys.  We  have  thus  to  seek  in  the  composition  of 
this  fluid  the  last  chapter  in  the  metabolic  history  of  a  large  number  of  the 
constituents  of  the  body.  Since,  moreover,  the  kidneys  may  excrete  almost 
any  substance  which  circulates  through  their  blood-vessels,  many  of  the 
intermediate  metabohtes  may  be  found  in  minute  quantities  in  the  urine 
and  may  be  isolated  by  working  up  large  quantities  of  this  fluid. 
Under  pathological  conditions  these  metabolites  may  appear  in 
the  urine  in  larger  amounts  and  serve  then  as  an  index  to  some  inter- 
ference with  the  later  stages  in  the  metabolism  of  fats,  carbohydrates,  or 
proteins. 

The  composition  of  the  urine  must  therefore  be  a  variable  one,  according 
to  the  activity  of  the  body,  the  quantity  and  nature  of  the  food  taken,  and 
the  relative  amount  of  water  escaping  by  the  kidneys,  lungs,  and  skin 
respectively.  But  just  as  we  can  describe  a  normal  diet  for  an  adult  man 
of  average  weight,  so  we  can  describe  an  average  composition  for  the  urine. 
The  history  of  the  urinary  constituents  has  been  given  for  the  most  part  in' 
the  chapter  dealing  with  the  metabolism  of  the  proximate  constituents  of 
the  food.  It  will  be  useful,  however,  to  enumerate  in  this  chapter  the  various 
constituents  of  the  urine  and  to  summarise  their  properties,  preparation, 
and  normal  significance. 

The  urine  of  man  is  a  clear  yellow  fluid  which  froths  when  shaken.     On 
standing,  a  cloud  of  mucus  is  deposited,  consisting  of  a  very  small  amount 

1110 


COMPOSITION  AND  CHARACTERS  OF  URINE  1111 

of  nucleoprotein  derived  from  the  epithelial  Hiiing  of  the  bladder  and 
urinary  passages.  In  concentrated  urine  a  deposit  occurs  on  coohng.  This 
deposit  dissolves  when  the  urine  is  warmed,  and  consists  of  urates.  Under 
certain  circumstances  urine  is  turbid  as  it  is  passed,  but  in  this  case  the 
turbidity  generally  consists  of  earthy  phosphates  and  is  not  cleared  up 
by  heating. 

The  colour  of  the  urine  varies  with  its  concentration.  After  severe 
sweating  the  amount  of  water  excreted  by  the  kidneys  is  small,  and  the 
urine  is  therefore  concentrated  and  of  high  colour.  After  copious  draughts 
of  Uquid  the  urine  may  be  very  pale  and  dilute. 

Ordinary  urine  has  an  aromatic  odour,  but  this  varies  largely  with  the 
character  of  the  food.  Many  food  substances  give  characteristic  odours, 
which  may  depend  on  alterations  undergone  by  them  in  their  passage 
through  the  body. 

The  specific  gravity  of  the  urine  is  proportional  to  its  concentration. 
Normally  it  is  1016  to  1020,  though  it  may  rise  as  high  as  10-10  or  sink  as 
low  as  1002. 

The  molecular  concentration  of  the  urine  is  almost  always  greater  than 
that  of  the  blood.  Its  osmotic  pressure  may  be  measured  by  determining 
the  depression  of  freezing-point.  The  a  of  urine  normally  varies  between 
0-87  and  2-71  (a  of  blood  =  0-56).  After  copious  draughts  of  water  the 
depression  of  freezing-point  in  the  urine  may  be  less  than  that  of  serum,  and 
may  be  as  small  as  0-25. 

The  reaction  of  urine  is  generally  described  as  acid.  It  is  acid  to  htmus 
and  to  phenolphthalein.  This  is  due  to  the  fact  that  neutral  constituents 
of  the  food  give  rise  to  acid  end-products  in  metaboHsm.  The  sulphur  of 
proteins  is  converted  into  sulphuric  acid  and  the  phosphorus  of  lecithin 
into  phosphoric  acid.  There  is  thus  a  predominance  of  acid  radicals  over 
bases  in  ordinary  urine.  This  statement,  however,  only  apphes  to  man  and 
to  carnivora.  In  the  food  of  herbivora  there  is  a  predominance  of  alkahne 
bases.  Vegetable  acids,  e.g.  tartaric,  mahc,  and  citric  acids,  undergo 
oxidation  to  carbonic  acid  in  the  body,  so  that  their  base?  leave  the  body  as 
alkaline  carbonates.  The  urine  of  such  animals  therefore  contains  an 
excess  of  alkaline  carbonates,  and  is  alkaline  in  reaction  and  froths  on  the 
addition  of  an  acid.  If  a  herbivorous  animal  be  starved,  so  that  it  has  to 
live  on  its  own  tissues,  it  becomes  for  the  time,  so  to  speak,  carnivoroub, 
and  its  urine  becomes  clear  and  acid.  The  urine  of  man  can  be  made 
alkahne  by  the  ingestion  of  large  quantities  of  vegetables  or  fruits.  Under 
such  circumstances  the  urine  as  passed  is  generally  tm'bid  from  the  presence 
of  precipitated  earthy  phosphates.  In  determining  the  reaction  of  urine  it 
is  usual  to  adhere  to  one  indicator,  e.g.  phenolphthalein,  and  to  give  the 
acidity  in  terms  of  decinormal  acid,  naming  the  indicator  used.  The 
acidity  {i.e.  the  concentration  of  H  ions)  can  also  be  determined  by  the 
electrical  method.  In  this  way  Hoeber  found  the  acidity  of  human  urine 
to  vary  between  •I-7  X  10"'  and  100  x  10"'.  On  the  average  it  was 
49  X  lO-'inthehtre. 


1112  PHYSIOLOGY 

THE  AVERAGE  COMPOSITION  OF  THE  URINE.  Several  analyses 
of  the  day's  urine  under  varying  conditions  of  food  have  already  been  given 
{v.  pp.  757,  780).  The  following  may  be  taken  as  a  fair  average  for  an  adult 
man  on  ordinary  mixed  diet : 

Total  amount  of  urine  =  1500  c.c. 

This  contains  about  60  grm.  of  sohds,  of  which  25  grm.  are  inorganic  and 
35  grm.  organic.     These  are  distributed  as  follows  : 


Inorganic  Constituents 

Organic  Constituents 

Sodium  chloride   . 

.     15-0  grm. 

Urea  .... 

.     30-0  grm 

Sulphui-ic  acid 

.       2-5    „ 

Uric  acid 

.      0-7    „ 

Phosphoric  acid    . 

.       2-5    „ 

Creatinine  . 

.       1-0    „ 

Potassium    . 

•       3-3    „ 

Hippuric  acid 

.      0-7    „ 

Ammonia     . 

.      0-7    „ 

Other  substances 

.       2-6    „ 

Magnesia 

.       0-5    „ 

Lime  . 

.      0-3    „ 

Other  substances  . 

•      0-2    „ 

The  quantity  of  urine  will  naturally  vary  with  the  water  leaving  the 
body  by  the  kidneys,  and  therefore  according  to  the  habit  of  the  individual 
with  regard  to  the  intake  of  fluids  and  with  his  occupation.  Thus  after 
copious  sweating  the  total  amount  may  fall  to  400  c.c.  in  the  course  of  the 
day.  If  large  draughts  of  hquid  be  taken  it  may  rise  to  3000  c.c.  or  more. 
There  are  also  diurnal  variations  in  the  amount  secreted,  depending  probably 
largely  on  the  circulation  through  the  kidneys.  The  secretion  is  at  a  mini- 
mum during  sleep,  and  especially  between  2  and  4  o'clock  in  the  morning. 
It  is  at  its  maximum  during  the  first  hours  after  rising,  and  increases  generally 
after  each  meal.  Muscular  exercise  may  also  give  an  initial  increase  owing 
to  the  greater  vigour  of  the  circulation  associated  with  exercise.  If  the 
exercise  is  severe  enough  to  cause  sweating  or  is  carried  to  fatigue,  there 
may  be  a  consequent  diminution  in  the  amount  of  urine  secreted. 


THE  INORGANIC  CONSTITUENTS  OF  THE  URINE 

(a)  ACID  RADICALS.  The  chlorides  of  the  urine  are  derived  almost 
entirely  from  the  chlorides  of  the  food.  Though  essential  constituents  of 
the  body  fluids,  it  does  not  seem  that  the  chlorides  enter  into  organic  com- 
bination with  the  constituents  of  the  cells.  The  output  of  chlorides,  which 
normally  varies  from  6  to  10  grm.  CI.  in  the  course  of  the  day,  will  therefore 
depend  on  the  amount  of  chlorides  taken  in  with  the  food.  If  these  be 
withdrawn  altogether,  the  chlorides  may  almost  disappear  from  the  urine, 
although  the  circulating  blood  contains  practically  the  same  amount  of 
chlorides  as  in  the  normal  individual,  showing  that  the  body  retains  the 
chlorides  necessary  for  the  proper  carrying  out  of  the  vital  processes  as 
long  as  possible.  Chlorides  may  also  disappear  from  the  urine  temporarily 
under  various  pathological  conditions.  This  is  especially  marked  in  cases 
of  acute  pneumonia. 


COMPOSITION  AND  CHARACTERS  OF  URINE  1113 

Sulphates.  The  salts  of  sulphuric  acid  do  not  form  an  important  con- 
stituent of  the  food.  The  sulphates  of  the  urine  are  derived  almost  entirely 
from  the  oxidation  of  the  sulpliur  of  the  protein  molecule.  The  output  of 
sulphates  is  therefore,  like  that  of  urea,  an  index  of  protein  metabolism. 
As  the  nitrogen  of  the  urine  goes  up,  so  the  sulphates  will  increase.  On  an 
average  diet  the  ratio  of  urinary  nitrogen  to  SO3  is  about  5:1;  though, 
owing  to  the  varying  content  of  different  proteins  in  the  sulphur,  this  ratio 
will  naturally  alter  with  the  nature  of  the  protein  taken  as  food.  The  daily 
output  of  sulphuric  acid  varies  between  1-5  and  3  grm.  SO3.  The  greater 
part  of  the  sulphate  is  present  as  sulphates  of  the  alkaline  metals.  A  certain 
proportion,  about  10  per  cent.,  is  present  in  the  form  of  conjugated  or 
ethereal  sulphates,  chiefly  indoxyl  sulphate.  A  small  proportion  of  the 
sulphur  excreted  in  the  urine  is  present  in  unoxidised  form  as  so-called 
neutral  sulphur.  The  neutral  sulphur  probably  includes  a  number  of 
different  bodies,  among  which  sulphocyanates  and  cystine  are  the  best 
known. 

Inorganic  sulphates  can  be  precipitated  from  the  urine  by  the  addition  of  hydro* 
chloric  acid  and  barium  chloride.  On  filtering  off  this  precipitate,  the  filtrate  contains 
the  ethereal  sulphates.  On  boiling,  the  hydiochloric  acid  decomjjoses  these  substances, 
setting  free  sulphuric  acid,  which  combines  with  the  excess  of  barium  i^resent  and  is 
precipitated  as  barium  suljihate.  This  second  precipitate  therefore,  when  weighed, 
gives  the  amount  of  ethereal  sulphates  present.  To  determine  the  neutral  sulphur  the 
fluid,  after  the  separation  of  both  kinds  of  sulphates,  is  treated  "with  sodium  carbonate 
to  precipitate  the  barium,  filtered,  and  the  filtrate  evaporated  to  dryness.  The  residue 
is  then  ignited  with  potassium  nitrate,  cooled  and  extracted  with  water.  By  this 
treatment  all  the  neutral  sulphur  is  converted  into  sulphates,  which  can  be  thrown  down 
from  the  solution  vnth  barium  chloride  and  weighed  in  the  usual  way. 

Phosphates.  The  phosphates  of  the  urine  are  derived  partly  from  the 
phosphates  of  the  food,  partly  from  the  oxidation  of  the  organic  phosphorus- 
containing  constituents  of  the  food  and  of  the  tissues,  e.g.  nuclein,  lecithin, 
&c.  If  the  food  contains  much  calcium  and  magnesium,  the  amount  of 
phosphates  excreted  by  the  urine  diminishes,  since  these  substances  are 
excreted  with  the  faeces  as  calcium  and  magnesium  phosphates.  According 
to  the  diet  therefore,  phosphoric  acid  may  be  excreted  either  by  the  intestine 
or  by  the  kidneys.  The  amount  of  phosphates,  reckoned  as  P2O5,  excreted 
in  the  course  of  the  day  may  vary  between  1  and  5  grm.  In  the  urine  the 
phosphates  exist  as  a  mixture  of  the  mono-  and  di-sodium  phosphates,  the 
relative  amounts  of  the  two  varying  with  the  acidity  of  the  urine.  If  the 
urine  is  neutral  or  alkahne  there  is  very  often  a  deposit  of  earthy  phosphates. 
Whether  this  deposit  is  present  or  not  depends  on  the  varying  solubility  of 
the  different  calcium  and  magnesium  phosphates.  Thus  the  mono-mag- 
nesium phosphate  MgH.,(P04)2  and  the  mono-calcium  phosphate  CaH.,(P04)2 
are  both  fairly  soluble  in  water,  and  their  solubility  is  increased  by  the 
presence  of  neutral  salts.  With  increased  acidity  of  the  urine  the  proportion 
of  the  two  bases  present  in  these  forms  is  diminished.  The  di-magnesium 
and  di-calcium  phosphates  are  only  slightly  soluble  in  water,  and  the  latter 
would,  if  present  in  the  urine,  be  deposited.     One  may  indeed,  in  slightly 


1114  PHYSIOLOGY 

acid  urine,  find  the  di-calcium  phosphate  occasionally  present  as  a  crystalhne 
deposit.  On  heating  the  urine  the  di-calcium  phosphate  breaks  up  into  a 
mono- calcium  phosphate  and  a  tri-calcium  phosphate,  while  the  acidity  of 
the  urine  is  increased  by  the  solution  of  the  mono-calcium  phosphate. 
Alkahne  urine  will  always  present  a  precipitate  of  tri-calcium  phosphate 
Ca3(P04)2.  When  normal  urine  is  allowed  to  stand,  the  urea  is  converted 
by  the  presence  of  micro-organisms  into  ammonium  carbonate,  and  the 
urine  becomes  alkahne.  Under  such  conditions  we  may  often  find  a  crystal- 
hne precipitate  of  ammonium  magnesium  phosphate,  NH4MgP04,  the  so- 
called  '  triple  phosphate.' 

(6)  THE  BASES  OF  THE  URINE.  The  bases  include  potash,  soda, 
ammonia,  magnesia,  and  hme. 

The  amount  of  potash  excreted  in  twenty-four  hours  varies  between  1-9 
and  3-2  grm.,  according  to  the  nature  of  the  food  taken.  With  a  large  meat 
diet,  which  contains  considerable  quantities  of  potassium,  the  output  of 
this  base  is  increased.  In  fasting  there  is  also  an  increase  in  the  output  of 
potash,  owing  to  the  utihsation  of  the  tissues  of  the  body  which  themselves 
are  rich  in  potassium. 

The  amount  of  sodium  excreted  in  the  twenty-four  hours  varies  on 
the  average  between  4  and  5  grm.,  but  depends  very  largely  on  the 
quantity  of  sodium  chloride  taken  with  the  diet.  The  alkaline  earths, 
lime  and  magnesia,  are  invariably  present  in  urine,  but  in  much  smaller 
quantities  than  the  alkahne  metals.  The  average  amount  of  these 
two  bases  in  the  twenty- four  hours  varies  in  each  case  between  0-1 
and  0-2  grm.  Their  output  by  the  urine  is  no  criterion  of  the  amount 
taken  in  with  the  food  or  absorbed  from  the  intestines,  since  both  these 
bases  may  be  re-excreted  into  the  gut  and  appear  as  insoluble  phosphates 
in  the  feeces. 

Normal  human  urine  always  contains  a  small  amount  of  ammonia] 
on  an  average  between  0-6  and  0-8  grm.  in  the  twenty-four  hours.  As  we 
have  already  seen,  in  dealing  with  the  origin  of  urea  in  the  body,  the  quantity 
of  ammonia  in  the  urine  is  an  index  to  the  excess  of  acids  over  bases  which 
have  to  be  excreted  by  this  fluid.  Thus  it  is  easily  possible  to  increase  the 
proportional  amount  of  ammonia  in  the  urine  by  the  administration  of 
mineral  acids.  An  increase  of  the  proportion  of  nitrogen  excreted  as 
ammonia,  apart  from  the  administration  of  acids  with  the  food,  is  an  im- 
portant indication  of  the  formation  of  abnormal  acid  substances  in  meta- 
bolism. Thus  in  diabetes,  when  the  last  stages  of  fat  oxidation  are  in 
default,  so  that  the  oxy-fatty  acids,  ^-oxybutyric  and  aceto-acetic  acids, 
accumulate  in  the  body,  there  is  always  a  considerable  rise  in  the  ammonia 
of  the  urine. 

It  is  usual  to  reckon  iron  among  the  bases  which  may  be  excretec!  by  the 
urine.  The  amount  of  this  substance  in  the  urine  is  extremely  small,  as  a 
rule  less  than  5  mg.  in  the  day.  It  affords  no  clue  to  the  iron  metabolism 
of  the  body,  since  the  main  channel  of  excretion  of  this  substance  is  the 
intestine. 


COMPOSITION  AND  CHARACTERS  OF  URINE 


1115 


ORGANIC  CONSTITUENTS  OF  THE   URINE 
Almost  all  these  constituents  contain  nitrogen,  which  in  man  is  dis- 
tributed among  the  various  urinary  constituents  as  follows  : 


Urea 
Ammonia 
Creatinine 
Uric  acid 


85-90  per  cent. 
2-4       „ 
3 
1-3       „ 


About  6  per  cent,  of  the  urinary  nitrogen  is  in  the  form  of  other  substances, 
such  as  hippuric  acid,  pigments,  &c. 

/NH 

OH  \«H^ 


UREA  or  CARBAMIDE,  COc^  Zu^  can  be   regarded   as   derived  from 


carbonic  acid,  CO<^qjj  by  the  replacement  of  each  OH  group  by  an  NHj 

group.     It  is  isomeric  with  ammonuim  cyanate,  NH4CNO.     If  a  solution 

of  potassium  cyanate  and  ammonium  chloride  be  warmed  together  and 

evaporated,  crystals  of  urea  may  be 

obtained    in    long    colourless    prisms 

(Fig.    516)    without    any    water    of 

crystallisation.     It  is  soluble  in  water 

and  alcohol,  and  insoluble  in  ether. 

Its  solutions  are  neutral  in  reaction, 

but   it  forms  crystalUne   salts    with 

strong    acids.       Thus    urea    nitrate, 

which  is  produced  by  treating  strong 

solutions  of  urea  with   concentrated 

nitric  acid,  forms  microscopic  rhombic 

plates  which  are  extremely  insoluble, 

so  that  their  formation  may  be  used 

as  a  test  for  urea    (Fig.  517).  With 

oxalic   acid  urea  solutions  yield    an 

insoluble    oxalate,     also    in    typical 

crystals.      Urea   when  heated   melts 

at  about  130°  C.     On  further  heating, 

it    undergoes    decomposition,    giving 

off  ammonia  and  forming  biuret,  as 

follows  : 

JNUo 


G 

Fig.  516.     Urea.     (Funke.) 


2  (C0<^^)  =  n;;>NH  +  NH3. 


CO 
C0<: 


NH, 


Fig.  517. 


Urea  nitrate.     Urea  oxalate. 


At  the  same  time  a  certain  amount  of  cyanic  acid  is  formed,  and  this 
polymerises  to  cyanuric  acid,  H3C3N3O3.  On  heating  with,  alkalies  or  with 
strong  acids  urea  undergoes  hydrolysis,  with  the  production  of  carbon 
dioxide  and  ammonia  : 

CONoH,  +  HoO  =  COo  +  2NH3. 

The  same  change  is  effected  in  urea  by  certain  micro-organisms,  c.y.  the 


1116  PHYSIOLOGY 

micrococcus  lU'ese,  which  is  responsible  for  the  ammoniacal  change  which 
occurs  in  urine  when  exposed  to  the  air. 

Urea,  being  the  chief  nitrogenous  constituent  of  the  urine,  is  the  most 
important  index  to  the  protein  metabohsm  of  the  body.  As  we  have  seen, 
urea  may  be  regarded  as  partly  exogenous,  partly  endogenous.  The  greater 
part  of  the  30  grm.  excreted  by  a  normal  indi\^dual  in  the  course  of  the  day  is 
derived  directly  from  the  proteins  of  the  foods,  as  a  result  of  the  deamination 
of  the  amino-acids,  which  occurs  shortly  after  their  absorption.  The 
ammonia  thus  formed  is  combined  with  carbonic  acid  and  carried  to  the 
Hver,  where  the  ammonium  carbonate  undergoes  dehydration  with  the  pro- 
duction of  urea.  Its  amount  will  therefore  be  directly  proportional  to  the 
amount  of  protein  taken  as  food.  A  smaller  proportion  is  derived  from 
the  breakdown  of  the  tissues  of  the  body.  This  endogenous  moiety  may 
undergo  considerable  increase  under  any  conditions  which  cause  a  rapid  dis- 
integration of  the  tissues.  Thus  there  is  a  large  rise  in  the  urea  output,  even 
in  a  starving  indi^ddral,  in  febrile  conditions. 

In  order  to  prepare  iirea  from  urine  advantage  may  be  taken  of  the  insolubility  of 
its  combination  with  nitric  acid.  Urine  is  concentrated  to  about  one-sixth  of  its  bulk. 
It  is  then  cooled  and  treated  with  twice  its  volume  of  pure  concentrated  nitric  acid, 
care  being  taken  to  keep  the  whole  mixture  cool.  Urea  nitrate  is  precipitated.  The 
precipitate  is  collected,  dried  roughly  by  pressing  between  filter  paper,  and  then  rubbed 
up  with  fresh  barium  carbonate.  Barium  nitrate  is  formed  and  urea  set  free.  The 
whole  mass  is  dried  and  treated  with  hot  absolute  alcohol,  in  which  the  barium  nitrate 
is  insoluble.  On  filtering  off  the  barium  nitrate  a  pure  solution  of  urea  is  obtained 
from  which  the  urea  will  crystalline  on  allowing  the  alcohol  to  evajjorate. 

CREATININE.  Creatinine  is  a  normal  constituent  of  urine,  in  which 
it  occurs  in  quantities  of  0-8  to  1-3  grm.  in  the  twenty-four  hours.  It  is 
easily  produced  from  creatine  by  boihng  the  latter  with  strong  hydrochloric 
acid,  when  a  process  of  dehydration  occurs.     Creatine  has  the  formula  : 

NHa 

NH  =  C— N(CH3)CH2-C00H. 

On  dehydration  it  is  converted  into  creatinine  : 

NH , 


KE  =  C— Kr(CH3)CH2CO 

Creatinine  may  be  obtained  from  urine  in  the  following  way.  The  urine  is  made 
alkaline  -nath  milk  of  lime  and  treated  with  calcium  chloride  and  filtered.  The  filtrate 
is  slightly  acidified  with  acetic  acid  and  evaporated  on  the  water  bath  to  a  syrupy  consis- 
tence. A  little  sodium  acetate  is  added  and  the  mixture  extracted  with  alcohol.  The 
filtered  alcoholic  extract  is  now  treated  wth  a  concentrated  neutral  alcoholic  solution  of 
zinc  chloride.  A  crystalline  precipitate  of  creatinine  zinc  chloride  is  produced.  After 
two  days  this  precipitate  is  collected  on  a  filter,  washed  with  alcohol,  dissolved  in  water, 
and  then  boiled  for  a  quarter  of  an  hour  with  lead  hydrate.'  The  mixture  is  then  filtered 
and  the  filtrate  evaporated  to  dryness.  The  dry  residue  is  now  extracted  with  cold 
alcohol  and  filtered.  On  allowing  the  alcohol  to  evaporate,  crystals  of  creatinine 
separate  out  (Fig.  518).     It  gives  the  following  tests  : 


COMPOSITION  AND  CHARACTERS  OF  URINE  1117 

(1)  WEYL'S  TEST.  On  treating  a  solution  of  creatinine  with  a  small  quantity  of 
very  dilute  sodium  nitroprusside  solution  and  then  with  weak  caustic  alkali,  a  rich 
ruby-red  colour  is  produced  which  gradually  changes  to  yellow.  On  now  adding  acetic 
acid  and  warming,  the  solution  becomes  green  and  then  blue,  and  finally  a  precipitate 
of  Prussian  blue  is  formed. 

(2)  JAFFE'S  TEST.  On  treating  a  solution  of  creatinine  with  a  few  drops  of  a 
watery  solution  of  picric  acid  and  dilute  caustic  potash,  an  inten.se  red  colour  is  produced. 
This  reaction  is  made  use  of  for  the  quantitative  estimation  of  creatinine  in  the  urine. 

Like  the  other  nitrogenous  constituents,  creatinine  can  be  regarded 
as  partly  exogenous,  partly  endogenous  in  origin.  The  exogenous  part  is 
derived  from  the  creatine  contained  in  meat.     When  meat  is  excluded  from 


Fig.  518.     Creatinine.     (Funke).  Fig,  519.     Uric  acid.     (Funke.) 

the  diet  the  output  of  creatinine  becomes  remarkably  constant  and  is  little 
affected  by  the  total  amount  of  proteins  taken,  the  amount  excreted  during 
starvation  being  practically  identical  with,  that  excreted  on  a  full  protein 
diet.  It  is  said  to  be  increased  during  febrile  conditions  and  as  a  result  of 
violent  muscular  exercise. 

URIC  ACID.     Uric  acid  is  2-6-8-trioxypurine. 

HN— CO  N=C(OH) 

II  II 

OC    C— NH,  or  (HO)C     C— NH 

I      II  >C0  II      II  >C(OH) 

HN— C— NH/  N— C  —  N/ 

Uric  acid  forms  small  rhombic  crystals.  The  crystalline  form  varies 
considerably  in  the  presence  of  impurities.  The  different  forms  of  uric 
acid  crystal  which  may  occur  in  the  urine  are  shown  in  the  accompanying 
figure  (Fig.  519).  It  is  extremely  insoluble  in  pure  water,  one  part  of  uric 
acid  requiring  39,000  parts  of  water  at  18°  C.  for  its  solution.  It  is  easily 
soluble  in  concentrated  sulphuric  acid  and  alkalies. 

It  may  be  prepared  from  human  urine  or  from  guano,  which  consists  almost  entirely 
of  urates.     In  order  to  prepare  it  from  guano,  this  is  dissolved  with  the  aid  of  heat  in 


1118  PHYSIOLOGY 

dilute  sodium  carbonate,  filtered,  and  the  filtrate  treated  with  a  few  drops  of  concen- 
trated hydrochloric  acid  and  boiled.  On  allowing  to  cool,  the  uric  acid  crystallises  out. 
From  urine  uric  acid  may  be  obtained  by  adding  one-fiftieth  of  its  volume  of  concen- 
trated hydrochloric  acid  and  allowing  to  stand  for  two  days.  The  uric  acid  is  thrown 
down  in  small  dark-red  or  brown  crystals.  They  can  be  collected  on  a  filter,  dissolved 
in  alkali,  decolorised  by  boiling  with  animal  charcoal,  and  the  pure  acid  thrown  down 
as  before  by  means  of  hydrochloric  acid. 

A  more  convenient  method  of  preparation  from  human  urine  is  based  on  the  fact 
that  ammonium  urate  is  insoluble  in  concentrated  solutions  of  ammonium  chloride 
(Hopkins).  The  urine  is  saturated  with  crystals  of  ammonium  chloride  and  a  few  drops 
of  strong  ammonia  added.  A  gelatinous  precipitate  of  ammonium  lu^ate  is  produced. 
This  is  collected  on  a  filter,  washed  oflf  with  a  minimum  amount  of  hot  water  into  a 
beaker,  and  a  few  drops  of  hydrochloric  acid  added.  The  mixture  is  boiled  and  then 
allowed  to  cool,  when  the  pure  acid  crystallises  out. 


TESTS  FOR  URIC  ACID 

(1)  MUREXIDE  TEST.  If  a  small  quantity  of  uric  acid  be  treated  with  a  little 
strong  nitric  acid  and  the  whole  evaporated  to  dryness  on  the  water-bath,  an  orange- 
red  residue  is  obtained,  which  on  treatment  with  ammonia  yields  a  fine  purple  colour. 
If  a  drop  of  sodium  hydrate  be  now  added  the  purple  changes  to  blue.  Instead  of  nitric 
acid,  bromine  water  may  be  employed. 

(2)  SCHIFF'S  TEST.  If  uric  acid  be  dissolved  in  a  little  soda  and  a  drop  be  placed 
on  filter  paper  previously  moistened  with  silver  nitrate,  a  yellow  or  brown  spot  is 
produced. 

(3)  On  boiling  uric  acid  with  Fehling's  solution  for  some  time,  a  yellowish  precipitate 
of  cuprous  hydrate  is  produced. 

(4)  An  alkaline  solution  of  uric  acid  on  treatment  with  a  few  drops  of  a  solution  of 
phosphomolyndic  acid  gives  a  dark  blue  precipitate  with  a  metallic  lustre,  consisting 
of  microscopic  prismatic  crystals. 

(5)  With  sodium  hypobromite  uric  acid  is  decomposed,  giving  off  about  half  of  its 
nitrogen  as  the  free  gas. 

URATES.  Of  the  four  hydrogen  atoms  in  uric  acid  two  can  be  replaced 
by  metalhc  radicals.  Uric  acid  thus  acts  as  a  weak  dibasic  acid.  It  forms 
three  orders  of  salts,  namely,  the  neutral  urates,  the  bi-urates,  and  the 
quadri-urates.  The  neutral  urates,  M\\J,  are  very  unstable,  and  only  exist 
in  the  presence  of  caustic  alkahes.  They  are  decomposed  even  by  the 
carbonic  acid  of  the  atmosphere.  The  bi-urates,  MHU,  are  the  most  stable 
of  the  urates.  They  may  be  prepared  by  dissolving  uric  acid  with  the  aid 
of  heat  in  weak  solutions  of  the  alkaline  carbonates,  from  which  they 
separate,  on  coohng,  in  stellar  crystals.  

The  qaudri-urates  have  the  formula  HgU,  MHU.  They  may  be  pre- 
pared by  boiling  uric  acid  with  dilute  solutions  of  potassium  acetate.  On 
cooling  the  mixture  the  quadri-urate  separates  as  an  amorphous  precipitate 
or  in  crystalhne  spheres.  The  quadri-urates  are  extremely  unstable,  and  in 
the  presence  of  water  are  broken  up  into  the  bi-urates  and  free  uric  acid. 
It  is  probable  that  under  normal  conditions  the  greater  part  of  the  uric  acid 
in  the  urine  is  present  in  the  form  of  a  quadri-urate  (Roberts),  and  the  so- 
called  lateritious  deposit,  the  brick-red  amorphous  precipitate  of  urates 
which  occurs  in  concentrated  urine  on  cooling,  consists  of  these  quadri- 
urates.     The  exact  condition  of  the  urate,  however,  will  depend  on  the 


COMPOSITION  AND  CHARACTERS  OF  URINE  1119 

reaction  of  the  urine.  A  bi-urate,  with  acid  sodium  phosphate,  is  decom- 
posed with  the  formation  of  uric  acid  in  the  following  way  : 

MHtJ  +  MH2PO4  =  H2U  +  M2HPO4. 

Thus  the  quadri-urates  present  in  the  urine  immediately  after  its  secre- 
tion will  tend  to  undergo  spontaneous  decomposition  into  uric  acid  and  the 
bi-urate,  and  the  latter  itself  may  be  decomposed  with  the  formation  of 
uric  acid  and  alkaUne  phosphate.  We  see  therefore  that  when  the  urine  is 
acid,  i.e.  there  is  a  predominance  of  acid  phosphates,  there  will  be  a  tendency 
to  the  precipitation  of  uric  acid  in  the  urinary  passages.  If,  however,  the  di- 
sodium  phosphate  be  in  excess  the  uric  acid  may  be  kept  in  solution  as  the 
quadri-urate  or  even  as  the  bi-urate. 

The  uric  acid  of  the  urine  is  derived  almost  entirely  from  the  purine 
metabohsm  of  the  body.  The  uric  acid  may  be  endogenous  or  exogenous, 
i.e.  may  be  derived  from  the  breaking  down  of  the  nucleins  of  the  cells  or 
by  a  direct  transformation  of  the  nucleins  contained  in  the  food.  The 
amount  passed  daily  varies  between  0-4  and  1  grm.,  according  to  the  nature 
of  the  diet.  It  is  not  absent  from  the  urine  even  during  complete  starvation. 
It  is  increased  when  foods  are  ingested  rich  in  nucleins,  such  as  Hver  or  sweet- 
breads, or  in  any  other  precursors  of  uric  acid,  e.g.  hypoxanthine,  such  as 
meat  or  meat  extract.  We  have  no  evidence  that  the  urinary  uric  acid 
in  the  mammal  is  formed  by  synthesis,  though  this  is  the  manner  in 
which  the  greater  part  of  the  uric  acid  excreted  by  birds  and  reptiles  is 
formed. 

Small  traces  of  purine  bases  also  occur  in  urine,  namely,  xanthine,  hypo- 
xanthine, and  adenine.  When  tea  and  coffee  are  taken  the  methyl-purines 
may  occur,  namely,  caffeine,  theobromine,  and  their  derivatives. 

HIPPURIC  ACID  is  a  frequent,  though  not  a  constant,  constituent  of 
human  urine.  It  is  derived  from  benzoic  acid  or  from  an  aromatic  sub- 
stance which  on  oxidation  can  give  rise  to  benzoic  acid.  In  the  Icidneys 
the  benzoic  acid  is  conjugated  with  glycine  to  form  hippuric  acid.  The 
amount  of  hippuric  acid  excreted  in  the  day  may  vary  between  0-1  and 
1  grm.  After  a  diet  rich  in  fruit  or  vegetables  its  amount  may  rise  to  2  arm. 
It  is  present  in  considerable  quantities  in  the  urine  of  herbivora  and  may  be 
most  easily  prepared  from  horses'  urine.     Hippuric  acid  has  the  formula  : 

CeHgCO 

I 
HNCH2COOH 

It  can  be  obtained  in  milk-white  crystals  (Fig.  520),  which  are  only  shghtly 
soluble  in  cold  water,  but  easily  soluble  in  alcohol,  ether,  and  acetic  acid. 
It  is  insoluble  in  petroleum,  ether,  and  benzol.  On  heating,  it  is  broken  up 
into  benzoic  acid  and  glycine.  On  heating  with  concentrated  nitric  acid 
it  forms  nitro-benzol,  which  can  be  recognised  by  its  characteristic  smell  of 
bitter  almonds. 

In  order  to  extract  it  from  tlie  urine,  the  urine  is  made  alkaline  with  sodium  carbo- 
nate, filtered,  and  the  filtrate  evaporated  to  a  syrupy  consistence.     This  is  then  treated 


1120 


PHYSIOLOGY 


with  alcohol,  the  alcohol  evaporated,  and  the  residue  repeatedly  extracted  with  acetic 
ether.  The  acetic  ether  is  collected,  evaporated  to  dryness,  and  the  residue  repeatedly 
extracted  with  petroleum  ether  to  remove  the  benzoic  acid  and  fat.  What  is  left  behind 
is  hippuric  acid,  which  can  be  purified  by  recrystallisation  from  alcohol  or  ether. 

AMINO- ACIDS.  According  to  Levene  and  van  Slyke  amino-acids  are 
always  present  in  the  urine,  and  contribute  about  1-5  per  cent,  of  the  total 
nitrogen. 

OTHER  AROMATIC  SUBSTANCES.  The  chief  of  these  is  the  so-called 
'  urinary  indican,'  or  potassium-indoxyl-sulphate.  This  is  derived  from  the 
indol  produced  in  the  intestines  from  the  tryptophane  contained  in  the 
proteins  of  the  food,  the  change  being  effected  by  the  influence  of  the  micro- 
organisms of  putrefaction.     The  amount  of  the  conjugated  sulphates  in 

the  urine  is  thus  an  index  of  the  extent 
of  putrefaction  in  the  intestines.  In 
dogs,  when  the  intestine  has  been 
disinfected  by  repeated  doses  of  calo- 
mel, the  conjugated  sulphates  entirely 
disappear  from  the  urine.  Urinary 
indican  has  the  formula  : 

H 
C 

/\ 


HC 


HC       C 


-COSOoOH 


CH 


Fig.  520.     Hippuric  acid.    (Ftjnke.) 


C 
H 


N 
H 


In  addition  to  the  tests  for  conjugated  sulphates  mentioned  earlier,  the  indoxyl- 
sulphate  can  be  detected  by  various  methods  dependent  on  the  formation  of  indigo  blue. 
The  urine  is  treated  with  an  equal  volume  of  concentrated  hydrochloric  acid  and 
several  cubic  centimetres  of  chloroform  added.  A  solution  of  chloride  of  lime  is 
now  added  drop  by  drop,  shaking  after  the  addition  of  each  drop.  A  blue  colour  is 
produced  which  is  extracted  by  the  chloroform.  It  is  important  not  to  add  too  much 
chloride  of  lime,  as  otherwise  the  blue  colour  first  produced  will  be  destroyed  by  further 
oxidation. 

THE  URINARY  PIGMENTS.  Normal  urine  gives  no  definite  absorption 
bands.  It  owes  its  colour  to  the  presence  of  a  yellow  pigment,  urochrome. 
In  order  to  separate  urochrome  from  urine,  the  urine  is  saturated  with 
crystals  of  ammonium  sulphate  and  filtered.  The  filtrate,  which  still 
contains  nearly  all  the  colour  of  the  urine,  is  shaken  up  with  alcohol,  which 
withdraws  the  greater  part  of  the  colouring-matter.  On  concentrating  the 
alcohohc  solution  and  pouring  it  into  an  equal  volume  of  ether,  an  amor- 
phous brown  precipitate  falls,  which  is  the  urochrome.  Urochrome,  on 
treatment  with  aldehyde,  yields  a  pigment  closely  similar  to  urobihn.  On 
the  other  hand,  urobilin,  treated  with  potassium  permanganate,  is  converted 
into  a  substance  practically  identical  with  urochrome.  Urochrome  must 
therefore  be  derived  from  the  same  source  as  urobihn. 


COMPOSITION  AND  CHARACTERS  OF  TRINE  1121 

Urobilin  is  rarely  present  in  normal  urine,  and  then  only  in  the  form  of 
a  chromogen,  from  which  it  must  be  set  free  by  acidification.  In  certain 
pathological  conditions,  especially  in  cirrhosis  of  the  liver,  urobilin  may 
occur  in  the  urine  in  considerable  quantities. 

In  order  to  extract  urobilin  from  such  urine,  the  urates  are  first  precipitated  by 
saturation  with  ammonium  chloride,  and  the  filtrate  is  then  saturated  \\-ith  ammonium 
sulphate  and  a  droj)  of  sulphuric  acid  added.  On  shaking  the  fluid  up  with  a  mixture 
of  two  parts  ether  and  one  part  chloroform,  the  urobilin  is  taken  up  by  the  latter. 
The  ether-chloroform  solution  is  separated  off  and  shaken  up  ^vith  caustic  soda,  when 
the  urobilin  passes  entirely  into  the  alkaline  solution. 

Urobilin  in  solution  gives  a  single  absorption  band  between  the  lines  b 
and  F,  i.e.  at  the  junction  of  the  green  and  blue  of  the  spectrum.  On 
treating  with  zinc  chloride  and  ammonia  its  solutions  show  a  well-marked 
green  fluorescence.  The  urobihn  of  urine  is  identical  vdih  stercobilin,  the 
colouring-matter  of  the  faeces.  It  is  formed  from  bile  when  the  latter 
decomposes,  and  is  probably  produced  in  the  intestines  by  the  action  of 
micro-organisms  on  bile  pigment. 

Other  pigments  which  may  occur  in  urine  are  uroerythrin  and  hsema- 
toporphyrin.  Uroerythrin  gives  the  pink  colour  to  urate  sediments.  Its 
chemical  nature  is  not  known.  It  is  distinguished  by  the  fact  that  on 
addition  of  caustic  soda  the  pink  colour  is  changed  to  green.  On  suspending 
the  red-coloured  precipitate  of  urates  in  hot  water  and  extracting  with  amyl 
alcohol,  a  pink  solution  is  obtained  which  shows  two  absorption  bands  in 
the  green  part  of  the  spectrum. 

HcBmotoporphjrin  is  only  present  in  very  small  amounts  in  normal  uiine, 
but  under  certain  conditions,  especially  after  poisoning  \vith  sulphonal,  it 
may  occur  in  such  large  quantities  as  to  give  the  urine  a  deep  purple  colour. 
Under  these  circumstances  it  is  found  in  the  form  of  alkaline  ha^natopor- 
phyrin  and  gives  the  characteristic  absorption  bands  of  the  latter. 

Urorosein  is  a  name  that  has  been  given  to  a  pigment  which  is  formed 
when  the  urine  is  treated  with  strong  mineral  acids.  It  is  probably  an 
indol  derivative.  It  gives  a  single  absorption  band  between  the  lines 
D  and  E. 

ABNORMAL  CONSTITUENTS  OF  THE  URINE 
A  very  large  number  of  substances  occur  in  the  urine  in  minute  traces  and  maj'  be 
detected  when  large  quantities  of  this  fluid  are  worked  up  at  one  time.  Most  of  the  so- 
called  pathological  constituents  may  be  detected  in  this  way  in  normal  urine.  It  is 
only  when  they  occur  in  casilj'  detectable  amoimts  that  their  presence  becomes  of  any 
significance. 

COAGULABLE  PROTEIN.  Under  normal  circumstances  urine  is  free  from  any 
coagulahlc  protein  exeopt  the  small  traces  of  nnicinous  material,  nucleoprotein,  vhich 
gives  the  cloudiness  to  the  urine.  If  the  kidncy-cclls  are  damaged  by  disease,  by  inter- 
ference with  their  blood-supply,  or  by  circulating  poisons,  the  glomerular  ei)ithelium 
permits  the  passage  of  a  certain  amount  of  the  proteins  of  the  plasma.  Under  these 
circumstances,  if  small  pieces  of  the  kidney  be  plunged  into  boiling  water,  the  coagulated 
protein  may  be  seen  in  Bowman's  capsule.  The  presence  of  eoagulable  protein  (gene- 
rally spoken  of  as  albumin)  in  the  urine  is  sigmficantof  the  pathological  conditions  of 
the  kidney  associated  with  Bright's  disease.     A  small  trace  •nnll  generally  be  found  in 

36 


1122 


PHYSIOLOGY 


the  urine  which  is  passed  shortly  after  taking  muscular  exercise.     Under  this  condition 
the  presence  of  albumin  in  the  urine  has  no  pathognomonic  significance. 

The  proteins  generally  found  are  identical  with  those  of  the  blood-plasma  and  con- 
sist of  serum  albumin  and  serum  globulin.     Their  presence  in  the  urine  may  be  detected 


Fig.  521.     Glucosazone. 

by  the  precipitate  produced  on  boiling.  In  carrying  out  this  test  a  few  cubic  centi- 
metres of  saturated  salt  solution  should  be  added  and  one  or  two  drops  of  dilute  acetic 
acid.     A  more  delicate  test  is  that  known  as  Heller's.     Some  strong  nitric  acid  is  placed 


Fig.  522.     Lactosazone. 


(Plimmer.) 


in  a  test-tube  and  the  urine  is  poured  carefully  down  the  side  of  the  tube  so  as  to  form  a 
layer  on  the  surface  of  the  nitric  acid.  If  albumin  be  present  a  white  ring  is  formed  at 
the  junction  of  the  two  liquids. 

SUGAR.     Normal  urine  contains  about  one  part  per  thousand  of  glucose.     In 
diabetes  the  power  of  assimilating  carbohydrates  is  diminished  or  destroyed.     The 


COMPOSITION  AND  CHARACTERS  OF  URINE  1123 

amount  of  sugar  in  the  blood  is  increased,  and  sugar  appears  in  large  quantities  in  the 
urine.  The  sugar  is  practically  always  glucose  or  dextrose.  Lactose  may  occur  in  the 
urine  of  nursing  women  even  in  conditions  of  health.  Since  both  these  sugars  will 
reduce  Fehling's  solution  it  becomes  important  to  be  able  to  distinguish  between  them. 
The  following  tests  are  used  for  the  detection  of  abnormal  amounts  of  sugar  in  the 
urine  : 

(1)  FEHLING'S  TEST.  The  urine  is  boiled  with  Fehling's  solution  (an  alkaline 
solution  of  copper  sul])hate  to  which  Rochelle  salt  has  been  added  to  keep  the  cupric 
hydrate  in  solution).  Under  the  action  of  glucose  or  lactose  the  cupric  hydrate  is 
reduced  to  an  insoluble  cuprous  hydrate,  which  forms  a  yellow  or  red  precipitate. 

(2)  The  phenylhydrazine  test  may  be  carried  out  as  follows  :  2  c.c.  of  .50  per  cent, 
acetic  acid,  saturated  with  sodium  acetate,  and  two  drops  of  i)henylhydrazine  are  added 
to  5  c.c.  of  urine.  The  mixture  is  evaporated  down  to  .3  c.c,  rapidly  cooled,  and  again 
warmed  in  a  water  bath.  It  is  then  allowed  to  cool  slowly.  Crystals  of  the  correspond- 
ing osazone  separate  out  in  the  hot  liquid  in  the  case  of  glucosazone,  on  cooling  in  the 
case  of  lactosazone  (Figs.  521,  522). 

(3)  The  most  convenient  way  of  distinguishing  between  lactose  and  glucose  is  by 
adding  a  little  yeast  to  the  urine  in  an  inverted  test-tube.  If  glucose  be  the  sugar 
present,  it  is  fermented  by  the  yeast  with  the  production  of  carbon  dioxide,  which  collects 
at  the  top  of  the  test-tube. 

In  rare  circumstances  fructose  or  Isevulose,  or  pentose  may  be  found  in  the  urine. 
The  former  would  be  detected  by  the  fact  that  it  rotates  polarised  light  to  the  left, 
instead  of  the  right,  as  is  the  case  with  glucose. 

GLYCURONIC  ACID.  Small  traces  of  this  are  present  in  normal  urine.  It  occurs 
as  a  conjugated  acid  after  the  administration  of  various  substances,  e.g.  camphor  and 
chloral.  If  phenol,  indol,  or  scatol  be  given  to  an  animal  which  is  receiving  very  little 
protein  in  its  diet,  these  substances  will  leave  the  body  conjugated,  not  with  sulphuric 
acid,  but  with  glycuronic  acid.  Glycuronic  acid  may  be  regarded  as  the  first  product 
of  oxidation  of  glucose,  having  the  formula  : 

COOH 

I        ■ 
(CH0H)4 

I 
CHO 

It  reduces  Fehling's  solution  and  rotates  the  plane  of  polarised  light  to  the  left. 

OXY-FATTY  ACIDS  AND  ACETONE.  These  substances  occur  often  as.sociatcd 
with  glucose  in  diabetes,  especially  towards  the  latter  stages.  They  represent  the  pen- 
ultimate stages  in  the  oxidation  of  the  fats.  Their  relation  to  one  another  is  seen  from 
their  formulae  : 

CH3  CH3  CH3 

CHOH  CO  CO 

I  I  I 

CH2  CHo  CH3 

I  I 

COOH  COOH 

Oxybutyria  aciil  Accto-acetic  acid  Acetono 

They  may  also  occur  in  any  condition  of  carbohydrate  starvation,  relative  or  abso- 
lute. Thus  they  are  found  in  the  urine  during  absolute  starvation  as  well  as  in 
individuals  on  a  pure  fat  and  protein  diet.  The  two  acids  are  generally  found  associated 
in  the  urine. 

The  presence  of  aceto-acetic  acid  may  be  detected  as  follows  : 

(1 )  To  some  urine  add  ferric  chloride  as  long  as  a  precipitate  of  ferric  phosphate  con- 
tinues to  form.  Filter  this  off  and  to  the  filtrate  add  a  few  more  di-o^js  of  ferric 
chloride.     If  the  acid  be  present  a  claret  colour  is  ]noduced. 


1124  PHYSIOLOGY 

(2)  On  heating  with  dilute  alkali,  aceto-acetic  acid  is  decomposed,  with  the  pro- 
duction of  acetone.  This  may  be  detected  by  its  odour  or  by  distilling  off  a  small 
proportion  of  the  fluid  and  testing  the  distillate  in  the  following  ways  : 

(a)  On  the  addition  of  sodium  hydrate  and  iodine  and  warming,  iodoform  is  formed. 

(&)  Legal's  test.  A  few  drops  of  freshly  prepared  sodium  nitroprusside  solution  is 
added  and  the  mixture  rendered  alkaline  with  sodium  hydrate.  A  deep  red  colour  is 
formed.     On  acidifying  with  acetic  acid  this  colour  is  changed  to  a  reddish  purple. 

CYSTINE.  This  substance,  which  is  a  normal  product  of  the  hydrolysis  of  proteins, 
is  found  as  a  constant  constituent  to  the  amount  of  half  a  gramme  a  day  in  the  urine  of 
certain  individuals.  The  condition  of  cystinuria  represents,  like  alcaptonuria,  an  inborn 
error  of  metabolism.  It  is  found  in  the  child  and  persists  throughout  life.  In  such 
cases  the  cystine  may  give  rise  to  urinary  deposits  or  even  to  a  urinary  calculus. 

HOMOGENTISIC  ACID.  This  is  an  aromatic  acid  having  the  composition  of 
dioxyphenyl  acetic  acid.     Its  formula  is  as  follows  : 

OH 

I 
CHo.COOH 


OH 

It  occurs  as  a  consitutent  of  the  urine  of  certain  individuals,  who  are  said  to  be 
affected  with  alcaptonuria.  The  urine  of  these  cases  is  remarkable  for  its  resistance  to 
putrefactive  changes.  It  slowly  darkens  on  exposure  to  the  air,  and  on  the  addition  of 
alkali  and  shaking  with  air  it  becomes  rapidly  brown  or  black.  It  reduces  Fehling's 
solution,  so  that  the  presence  of  sugar  may  be  suspected.  Such  urine  contains  homogen- 
tisic  acid  in  a  quantity  of  3  to  6  grm.  per  day.  The  amount  of  the  acid  excreted  varies 
with  the  protein  food  taken.  It  seems  that  in  these  cases  the  power  of  the  organism  to 
break  up  tyrosine  and  phenylalanine  is  entirely  absent.  If  either  of  these  substances  be 
administered  by  the  mouth  it  is  converted  almost  quantitatively  into  homogentisic  acid, 
which  appears  in  the  urine.  Individuals  with  alcaptonuria  continue  to  secrete  homo- 
gentisic acid  during  starvation,  so  that  the  tjTosine  and  phenylalanine  set  free  in  the 
course  of  tissue  disintegration  undergo  the  same  fate  as  when  they  are  derived  from  the 
food.  Alcaptoniu"ics  apparently  suffer  no  ill  effects  as  a  result  of  their  abnormal 
metabolism.     The  tyrosine  and  phenylalanine  can  be  absorbed  and  play  their  part 

in  building  up  the  proteins  of  the  tissues, 
but  the  process  or  ferment  is  wanting  which 
is  responsible  for  the  further  break-up 
of  the  first  product  of  their  oxidation, 
namely,  homogentisic  acid. 

URINARY   DEPOSITS 
In  addition  to    formed    elements, 
such  as  blood-corpuscles,  bacteria,  or 
pus-cells,  which  may  occur  in  abnor- 
mal urine,  the  following  deposits  may 
Fig.  523.     Various  forms  of  uric  acid  -i      e        j 

crystals.    (Frey.)  be  tound  : 

(a)  IN  ACID  URINE 
(1)  Amorphous  urates  occur  generally  as  a  brick-red  amorphous  deposit 
thrown  down  as  the  urine  cools.  It  is  redissolved  on  warming  the  urine,  and 
consists  generally  of  the  quadri-urates.  The  acid  urate  of  sodium  and  of 
ammonium  may  occasionally  occur  in  star-shaped  clusters  of  needles  or  as 
spherules  with  small  crystals  adhering  to  them. 


COMPOSITION  AND  CHARACTERS  OF  URINE 


1125 


(2)  Uric  acid.   Whetstone, dumb-bell, orsheaf-likeaggiegatioiisof  crystals, 
generally  deeply  pigmented  so  as  to  resemble  cayenne  pepper  (Fig.  523). 

(3)  Calcium  oxalate  (Fig.  524).     Colourless,  transparent,  highly  refrac- 


Fio.  524.      Urinary  deposit,  containing  uric 
acid,  sodium  urate,  and  calcium  oxalate. 


Fig.  525.     Deposit  of  '  triple  '  phosphate 
and  ammonium  urate.     (Funke.) 


tive  octahedral  crystals  (envelope-shaped), 
in  hydrochloric  acid. 

(4)  Ammonium  magnesium  phosphates 
crystals    have    been    compared    to 
knife-rests  or  coffin-hds  (Fig.  525). 
They  are  soluble  in  acetic  acid. 

(5)  Calcium  hydrogen  phosphate. 
CaHPO^.  These  are  rare.  They 
form  large  prismatic  crystals  often 
arranged  in  rosettes.  Easily  soluble 
in  dilute  acetic  acid.  On  adding  a 
solution  of  ammonium  carbonate  the 
crystals  are  eaten  away  and  form  an 
amorphous  deposit. 

(6)  Tyrosine,  fine  needles  in  star- 
shaped  bundles,  and  cystine,  in 
regular  hexagonal  plates,  may  occur 
under  very  rare  circumstances. 


Insoluble  in  acetic  acid,  soluble 
(in  faintly  acid  urine).     The 


Fig.  520. 


Aninionivnn  urate. 


(h)  IN  ALKALINE   URINE 

(1)  The  commonest  precipitate  consists  of  earthy  phosphates,  amor- 
phous, easily  soluble  in  dilute  acetic  acid. 

(2)  Ammonium  magnesium  phosphate  or  triple  jihosphate  is  common 
in  urine  which  has  undergone  ammoniacal  fermentation. 

(3)  Acid  ammonium  urate  (Fig.  52(5)  may  also  occui-  in  alkaline  urine. 
On  treatment  with  HCl  it  is  dissolved  and  uric  acid  in  crystals  slowly 
separates  out. 


1126  PHYSIOLOGY 

QUANTITATIVE  ESTIMATION  OF  THE  CHIEF   URINARY 
CONSTITUENTS 

It  may  be  useful  here  to  summarise  the  most  trustworthy  methods  which  are 
employed  for  the  estimation  of  the  chief  urinary  constituents.* 

The  TOTAL  '  ACIDITY  '  of  the  urine  is  measured  by  titrating  it  against  decinormal 
alkali  in  the  presence  of  an  indicator,  such  as  phenolphthalein.  The  indistinctness  of 
the  end-point  is  due  to  the  presence  of  calcium  salts  and  ammonium  salts.  Folin  there- 
foi'e  recommends  that  the  titration  be  carried  out  in  the  presence  of  potassium  oxalate, 
which  diminishes  the  error. 

Method.  To  25  c.c.  urine  add  15  to  20  grm.  potassium  oxalate  and  1  to  2  drops  of 
phenolphthalein.     Shake  thoroughly  for  one  or  two  minutes,  and  whilst  the  solution 

is  still  cold  from  the  effect  of  the  oxalate,  titrate  with  —  NaOH  until  a  permanent  pink 
remains.  ^ 

TOTAL  NITROGEN.  In  all  metabolic  experiments,  the  determination  of  the  total 
nitrogen  of  the  food,  the  urine,  and  the  fseces  is  indispensable.  In  each  case  Kjeldahl's 
method  is  employed.  This  method  depends  on  the  fact  that  all  the  nitrogenous  sub- 
stances met  with  in  the  body,  when  heated  for  a  considerable  time  with  concentrated 
sulphuric  acid,  undergo  oxidation,  the  nitrogen  being  finally  converted  into  ammonia. 
On  adding  alkali  to  the  mixture  the  ammonia  is  set  free  from  its  combination  with  the 
sulphuric  acid  and  can  be  distilled  off  and  received  into  a  vessel  containing  a  known 
amount  of  decinormal  acid.  By  titrating  this  acid  after  the  operation  we  can  determine 
the  quantity  of  ammonia  which  has  been  produced.  To  carry  out  this  method  5  c.c. 
of  m-ine  are  heated  with  20  c.c.  sulphuric  acid  and  a  small  quantity  of  copper  sulphate 
and  potassium  sulphate.  The  copper  sulphate  is  to  aid  the  oxidation  of  the  organic 
substances,  the  potassium  sulphate  is  to  raise  the  boiling-point  of  the  mixture.  The 
boiling  is  continued  for  half  an  hour.  The  flask  is  then  cooled  and  half  filled  with  dis- 
tilled water.  •  A  special  form  of  distillation  tube  (Fig.  527)  is  now  attached  by  a  rubber 
cork  which  fits  tightly,  but  just  before  this  is  done  an  excess  of  strong  caustic  soda 
sufficient  to  neutralise  the  concentrated  sulphuric  acid  is  run  in  under  the  acid.  The 
other  end  of  the  distillation  tube  is  at  once  arranged  to  dip  under  the  surface   of  a 

measured  quantity  of  standard  acid  {e.g.  10  c.c H2SO4),  diluted  with  water,  and  con- 
tained in  a  600  c.c.  Erlenmeyer  flask.  The  flask  is  then  shaken  and  heated.  In  about 
a  quarter  of  an  hoiu-  the  ammonia  is  completely  distilled  off,  and  its  amount  can  be 

determined  by  titrating  the  acid  in  the  flask  with  —  NaOH,  methyl  orange  being  used 
as  indicator. 

UREA.  The  method  usually  adopted  for  estimating  the  urea  is  that  devised  by 
Hiifner.  It  depends  on  the  fact  that  urea  is  decomposed  by  an  alkaline  hypobromite 
with  the  production  of  CO2  and  nitrogen.  In  the  presence  of  an  excess  of  alkali  the  CO2 
is  absorbed  and  the  nitrogen  may  be  collected  and  measured,  and  serves  as  an  index 
of  the  amount  of  urea  present.     The  reaction  which  occurs  is  as  follows  : 

C0(NH2)2  +  SNaBrO  +  2NaOH  =  3NaBr  +  N2  -f  Na2C03  +  SHgO 

60  grm.  22-4  litres  =  28  grm. 

1  grm.  372  c.c. 

Actually,  however,  only  354'33  c.c.  nitrogen  are  evolved  by  1  grm.  urea. 

The  disadvantage  of  this  method  is  that  other  substances,  such  as  ammonia,  creati- 
nine, and  uric  acid,  give  off  a  certain  amount  of  their  nitrogen  with  sodium  hypobromite, 
so  that  the  method  is  not  strictly  accurate,  though  enough  so  for  most  clinical  purposes. 
In  actually  carrying  out  the  method  5  c.c.  of  urine  are  treated  with  25  c.c.  of  freshly 

*Fuller  details  will  be  found  in  Plimmer's  "  Practical  Physiological  Chemistry," 
from  which  most  of  the  methods  here  given  are  taken. 


COMPOSITION  AND  CHARACTERS  OF  URINE 


1127 


prepared  solution  of  sodiuiu  hypobroniite,  and  the  nitrogen  evolved  is  collected  in  a 
graduated  tube  over  water. 

Folin'fi  Method.  In  Kjeid-thrs  method  all  the  nitrogenous  constituents  of  the  urine 
are  converted  into  ammonia  by  boiling  with  strong  sulphuric  acid.  This  conversion 
occurs  with  extreme  readiness  in  the  case  of  urea,  so  that  by  using  a  weaker  acid  and 
carefully  regulating  the  temperature  the  hydrolysis  may  be  confined  practically  to  the 
urea  itself.     This  is  the  principle  of  Folin's  method  of  estimating  urea. 

Five  cubic  centimetres  of  urine  are  measured  into  a  200  c.c.  Erlemneyer  flask.  Five 
cubic  centimetres  of  concentrated  hydrochloric  acid,  20  grm.  crystallised  magnesium 
chloride,  a  piece  of  paraffin  the  size  of  a  small  hazel  nut,  and  finally  2  or  3  drops  of  a 
1  per  cent,  solution  of  alizarin  red  in  water  are  added.  A  special  safety  tube  is  then 
inserted  into  the  neck  of  the  flask  and  the 
mixture  boiled  until  each  returning  ch'op  from 
the  safety  tube  produces  a  very  perceptible 
bump.  The  heat  is  then  reduced  somewhat, 
and  the  heating  is  continued  for  a  full  hour.  The 
alizarin  red  is  used  in  order  to  ensure  that  the 
contents  of  the  flask  do  not  become  alkaline.  At 
the  end  of  an  hour  the  contents  of  the  Hask  are 
put  into  a  litre  flask  with  about  700  c.c.  water 
and  20  c.c.  of  a  10  per  cent,  sodium  hydrate, 
and  the  ammonia  is  then  distilled  off  into  a 
measured  quantity  of  acid.  The  results  obtained 
in  this  way  will  give  us  the  total  amount  of 
urea  together  with  any  ammonia  which  was 
preformed  in  the  urine.  It  is  therefore  neces- 
sary also  to  determine  the  amount  of  this  pre- 
formed ammonia. 

ESTIMATION  OF  AMMONIA.  In  Folin's 
method  for  the  estimation  of  ammonia,  this  is 
set  free  by  the  addition  of  weak  alkali  (sodium 
carbonate)  and  is  then  removed  from  the  urine 
at  ordinary  room  temperature  by  passing  a  strong 
current  of  air  thi'ough  the  liquid.  The  issuing 
current   of    air    carrymg    the    ammonia   passes 

through  a  measured  quantity  of  decinormal  acid.  If  the  air  current  be  sufficiently 
strong,  one  and  a  half  hours  is  sufficient  to  remove  the  whole  of  the  ammonia  from  25  c.c. 
of  urine.  The  decinormal  acid  is  then  titrated  and  the  amount  of  the  ammonia  reckoned. 
In  carrying  out  the  method  25  c.c.  of  urine  is  measured  into  a  cylinder  30  to  40  cm. 
high  and  about  a  gramme  of  sodium  carbonate  and  some  petroleum  (to  prevent  foaming) 
are  added.  The  upper  end  of  the  cylinder  is  then  closed  by  a  doubly  perforated  rubber 
stopper  through  which  pass  two  glass  tubes,  only  one  of  which  is  long  enough  to  reach 
below  the  surface  of  the  liquid.  The  shorter  tube,  about  10  cm.  in  length,  is  con- 
nected with  a  calcium  chloride  tube  tilled  with  cotton,  and  this  in  turn  is  connected 
with  a  glass  tube  extending  to  the  bottom  of  a  wide-mouthed  bottle,  capacity  about 
500  c.c,  which  contains  20  c.c.  decinormal  acid  in  200  c.c.  of  water. 

A  more  convenient  method  for  the  estimation  of  ammonia  is  that  originally  pro- 
posed by  Schitf  and  recently  worked  out  by  Malfatti.  It  depends  on  the  fact  that  when 
a  neutral  solution  of  an  ammonium  salt  is  treated  with  formaldehyde,  combination 
occurs  with  the  formation  of  hexamethylene  tetramine  (urotropine)  and  the  liberation 
of  a  corresponding  amount  of  acid,  which  can  be  estimated  by  titrating  with  decinormal 
alkali.     The  reaction  which  occurs  is  as  follows  : 

6CH2O  +  2(XH4)2S04  =  6H2O  +  N4(CH2)r,  -f  2H2SO4. 
Formaldehyde  Hexamethylene  tetramine 

In  carrying  out  this  method  25  c.c.  of  urine  are  measured  by  means  of  a  piiiette  into  a 
flask  or  beaker  and  diluted  with  five  times  its  volume  of  water.     Four  or  live  drojjs  of 


Fig.  527. 


1128  PHYSIOLOGY 

phenolphthalein  are  then  added  and  decinormal  sodium  hydrate  is  run  in  until  there  is 
a  slight  permanent  pink  colour.  The  amount  of  alkaline  solution  necessary  to  produce 
this  colour  is  a  measure  of  the  acidity  of  the  urine.  Ten  cubic  centimetres  of  formalin, 
diluted  v/ith  three  volumes  of  water  and  previously  neutralised  to  phenolphthalein 
with  decinormal  alkali,  are  then  added.  The  colour  disappears  owing  to  the  setting 
free  of  the  acid  radicals  previously  combined  with  ammonia.  Decinormal  alkali  is  then 
run  into  the  mixture  until  a  permanent  pink  colour  is  again  obtained.  The  number  of 
cubic  centimetres  of  the  decinormal  alkali  required  in  this  second  case  corresponds  to 
the  amount  of  decinormal  ammonia  previously  present  in  the  25  c.c.  of  urine. 

This  method  gives  somewhat  higher  figures  than  the  method  of  Tolin  just  described, 
owing  to  the  fact  that  the  small  traces  of  amino-acids,  which  may  be  present  in  the  urine, 
react  to  formalin  in  a  very  similar  way.  The  difference  does  not  exceed  10  per  cent., 
so  that  the  method  is  amply  delicate  for  clinical  purposes. 

CREATININE.  In  Folin's  method  for  the  determination  of  creatinine,  which  is 
now  universally  employed,  advantage  is  taken  of  the  colour  reaction  given  by  creatinine 
(and  by  no  other  normal  urinary  constituent)  with  picric  acid  in  alkaline  solution 
(Jafire's  reaction),  the  colour  being  compared  with  that  of  a  standard  potassium 
bichromate  solution.  The  reagents  employed  are  decinormal  potassium  bichromate 
containing  24-55  grm.  per  litre,  saturated  picric  acid  solution  containing  about  12  grm. 
per  litre,  and  a  10  per  cent,  solution  of  sodium  hydrate.  For  the  comparison  of  the 
colours  a  Duboscq  colorimeter  is  employed. 

Ten  cubic  centimetres  of  urine  are  measured  into  a  500  c.c.  flask  ;  15  c.c.  of  picric 
acid  and  5  c.c.  of  sodium  hydrate  are  then  added  and  the  mixture  allowed  to  stand  for 
five  minutes.  Some  of  the  potassium  bichromate  solution  is  placed  into  one  of  the 
cylinders  of  the  colorimeter  and  its  depth  accurately  adjusted  to  the  8  mm.  mark. 
At  the  end  of  five  minutes  the  contents  of  the  500  c.c.  flask  are  diluted  up  to  500  c.c. 
with  water  and  some  of  the  mixture  placed  into  the  other  cylinder  of  the  colorimeter, 
and  the  two  colours  are  then  compared.  The  calculation  of  the  results  is  very  simple. 
If,  for  example,  it  is  found  that  it  takes  9-5  mm.  of  the  unknown  urine  picrate  solution 
to  equal  the  8  mm.  of  the  bichromate,  then  the  10  c.c.  of  urine  contains 

8*0 
10  X  —   =8-4  mg.  creatinine. 
9-5  ^ 

ESTIMATION  OF  URIC  ACID.     The  best  method  for  this  purpose  is  a  slight  modi- 
fication by  Folin  of  the  method  devised  by  Hopkins. 
For  this  method  the  following  reagents  are  required  : 

(1)  A  solution  of  ammonium  sulphate,  uranium  acetate,  and  acetic  acid,  made  up  as 

follows  :  500  grm.  ammonium  sulphate,  5  grm.  uranium  acetate,  and  60  c.c.  10  per 
cent,  acetic  acid  are  dissolved  in  650  c.c.  water.  The  volume  of  this  solution  is 
almost  exactly  1000  c.c. 

(2)  Ten  per  cent,  ammonium  sulphate  solution. 

(3)  —  potassium  permanganate  solution  made  by  dissolving  1-581  grm.  pure  potassium 
permanganate  in  one  litre  of  water  ;  1  c.c.  =  -00375  grm.  uric  acid. 

Measure  200  c.c.  urine  with  a  pipette  into  a  500  c.c.  flask  and  add  50  c.c  of  the 
ammonium  sulphate  and  uranium  acetate  reagent.  Mix  the  solutions  and  allow  to 
stand  for  about  half  an  hour  so  as  to  allow  the  precipitate  to  settle.  This  precipitate 
contains  a  mucoid  substance  (and  phosphates)  which,  if  not  thus  removed,  renders  the 
subsequent  filtration  and  washing  of  the  ammonium  urate  precipitate  very  slow.  Filter 
off  the  supernatant  liquid  through  a  dry  filter  into  a  dry  vessel,  and  measure  out  125  c.c. 
( =  100  c.c.  urine)  of  this  with  j)ipettes  into  a  beaker.  Add  5  c.c.  concentrated  ammonia, 
mix  well,  and  allow  to  stand  covered  with  paper  for  twelve  to  twenty-four  hours. 

Carefully  decant  the  suijernatant  liquid  upon  a  filter,  wash  the  precipitate  of  ammo- 
nium urate  on  to  the  filter  with  10  per  cent,  ammomum  sulphate,  and  wash  this  once 
or  twice  with  the  same  reagent  to  remove  the  chlorides  as  completely  as  possible. 

Remove  the  filter  from  the  funnel,  open  it,  and  with  a  fine  stream  of  water  wash 


COMPOSITION  AND  CHARACTERS  OF  URINE  1129 

the  ammonium  urate  precipitate  into  a  beaker.  To  the  ammonium  urate  precipitate, 
suspended  in  about  100  c.c.  water,  add  15  c.c.  strong  sulphuric  acid  and  titrate  at  once, 
without  cooling,  with  the  potassium  permanganate  solution.  At  first  every  small 
addition  of  the  permanganate  is  decolorised  before  it  diffuses  through  the  liquid,  but 
towards  the  end  the  decolorisation  is  slower  and  the  permanganate  should  be  added 
two  drops  at  a  time  until  a  faint  pink  colour  is  seen  throughout  the  whole  solution. 
The  amount  of  uric  acid  can  then  be  calculated,  1  c.c  of  the  permanganate  solution  being 
equivalent  to  -00375  grm.  uric  acid. 

CHLORIDES.  The  chlorides  of  urine  are  estimated  by  Volhard's  method.  The 
principle  of  this  method  consists  in  precipitating  the  chlorides  by  excess  of  a  standard 
solution  of  silver  nitrate  in  the  presence  of  nitric  acid.  The  excess  of  silver  is  then 
estimated  in  an  aliquot  part  of  the  filtrate  with  a  solution  of  potassium  or  ammonium 
sulphocyanate  which  has  been  previously  standardised  against  the  silver  solution,  a 
ferric  salt  being  used  as  indicator. 

The  following  solutions  are  required  : 

(1)  Standard  silver  nitrate  solution  either  —  or  so  that  1  c.c.  corresponds  to  -01  grm. 

NaCl.  10 

(2)  Potassium  sulphocyanate  solution  (8  grm.  per  litre). 

(3)  Pure  HNO3  free  from  chlorides. 

(4)  A  saturated  solution  of  iron  alum. 

The  potassium  sulphocyanate  solution  must  be  standardised  against  the  silver  nitrate 
solution.  This  is  carried  out  as  follows  :  Place  10  c.c.  AgNOg  solution  with  a  pipette 
in  a  beaker,  add  5  c.c.  pure  HNO3,  5  c.c.  iron  alum  solution,  and  80  c.c.  water.  Now 
run  in  the  sulphocyanate  solution  from  a  burette  until  a  permanent  red  tinge  is  obtained. 
Note  the  amount  required  for  the  10  c.c.  AgNOg  solution. 

The  method  of  analysis  is  carried  out  as  follows  :  Place  10  c.c.  urine  in  a  100  c.c. 
measuring  flask  with  a  pipette.  Then  add  about  4  c.c.  pure  nitric  acid  and  10  or  20  c.c. 
with  a  pipette  of  the  standard  silver  nitrate  solution.  Now  fill  up  to  the  mark  with 
distilled  water,  mix  thoroughly,  and  filter  into  a  dry  vessel  through  a  dry  paper.  Take 
exactly  50  c.c.  of  the  filtrate  with  a  pipette  and  titrate  with  the  sulphocyanate  solution 
until  a  permanent  red  colour  is  obtained,  iron  alum  having  been  added  before  the  titra- 
tion is  commenced.     Calculation  of  results  : 

50  c.c.  filtrate  =  S  c.c.  KCNS 

.-.100  c.c.        „      =2Sc.c.   „ 

Now  X  c.c.  KCNS  =  10  c.c.  AgNOg 

oe                          10  X  25  .    __ 
.-.  2yS'c.c.        „      =  AgNOa 

This  is  the  excess  not  utilised  to  precipitate  the  chlorides 

10  X  2S\ 
.-.  (20  —  =  amount  of  AgNOg  solution  used. 

X         I 
Hence  NaCl  in  grammes  per  10  c.c.  in  the  volume  passed  in  twenty-four  hours. 

ESTIMATION  OF  PHOSPHATES.  The  method  depends  upon  the  precipitation 
of  all  the  phosphates  by  a  standard  solution  of  uranium  acetate  or  uranium  nitrate  in 
the  presence  of  sodium  acetate  and  acetic  acid  as  (Ur02)HP04.  The  determination  of 
the  end-point,  when  soluble  uranium  salt  is  in  solution,  is  shown  by  means  of  potassium 
ferrocyanide,  or  by  cochineal  tincture,  which  becomes  green. 

The  following  reagents  are  required  : 

(1)  Acid  sodium  acetate  solution  (100  grm.  NaAc,  30  grm.  HAc,  1000  c.c.  HgO). 

(2)  Cochineal  tincture  (5  grm.  cochineal  extracted  for  several  days  with  150  c.c.  alcohol 

and  100  c.c.  water  and  then  filtered). 

(3)  Standarel  uranium  solution  (I  c.c.  =  -005  grm.  P2O5  or  5  mg.). 

This  must  be  prepared  by  standardising  against  a  standard  phosphate  solution. 
Generally  sodium  phosphate  is  employed  ;  about  12  grm.  are  weighed  out  and  dissolved 
in  1000  c.c.  water  ;  50  c.c.  of  this  solution  are  evaporated  to  dryness,  incinerated,  and 

36* 


1130  PHYSIOLOGY 

weighed  as  pyroiDhosphate.  From  the  weight  of  this  the  amount  of  P2O5  in  50  c.c.  can 
be  calculated  and  the  remainder  of  the  solution  can  be  diluted,  so  that  50  c.c.  contain 
0-1  grm.  P2O5.  It  is  simpler  to  use  acid  potassium  phosphate,  KHgPO^,  which  can  be 
weighed  directly  and  dissolved  in  water,  so  that  50  c.c.  contain  0-1  grm.  P2O5.  Fifty 
cubic  centimetres  of  this  solution  are  titrated  with  the  uranium  solution  (36  grm.  in 
one  litre)  in  the  manner  described  below,  and  the  uranium  solution  is  then  diluted  so 
that  1  c.c.  =  5  mg.  P0O5. 

The  method  of  analysis  is  carried  out  as  follows  :  Place  50  c.c.  urine  with  a  pipette 
in  a  100  c.c.  beaker,  add  5  c.c.  acid  sodium  acetate  solution  and  a  few  drops  of  cochi- 
neal tincture.  Heat  the  urine  to  boiling  and  run  in  slowly  the  standard  uranium 
acetate  solution  from  a  burette  as  long  as  a  precipitate  is  formed.  Again  heat  to 
boiling  and  add  the  uranium  solution  drop  by  drop,  until  the  red  colour  is  changed  to 
green.  This  end-point  can  also  be  tested  by  taking  out  a  drop  and  placing  it  in  contact 
with  a  drop  of  potassium  ferro-cyanide  solution  or  a  little  heap  of  finely  powdered  sub- 
stance on  a  white  piece  of  porcelain.  A  brown  colour  or  precipitate  is  formed  when 
excess  of  soluble  uranium  salt  is  present  in  the  solution.  (A  few  more  drops  may  be 
required  to  reach  this  point  than  to  turn  the  cochineal  green.) 

The  principle  of  the  estimation  of  sulphates  has  already  been  described.  It  is  not 
advisable  to  attempt  this  volumetrically. 


SECTION   II 
THE  SECRETION   OF   URINE 


cl^-M 


With  the  single  exception  of  hippiiric  acid  all  the  constituents  of  the  urine 
are  formed  in  parts  of  the  body  other  than  the  kidneys.  Extirpation  of 
both  kidneys  leads  to  an  accumulation  of  these  specific  urinary  con- 
stituents in  the  blood  and  tissues.  The  work  of  the  kidney  is  therefore 
confined  to  an  excretion  of  preformed  constituents.  Considered  from  a 
broad  standpoint,  the  function  of  this  organ  is  the  preservation  of  the  normal 
composition  of  the  circulating  blood. 
Whenever  the  latter  contains  an  abnor- 
mal constituent  or  any  of  its  normal 
constituents  are  present  in  abnormal 
quantities,  the  kidney  excretes  the  sub- 
stance in  question  until  the  composition 
of  the  blood  is  restored.  We  have  to 
determine  the  conditions  which  influence 
the  quantity  and  quality  of  the  urine 
secreted  by  the  kidneys,  and  to  ascribe 
to  each  element  in  these  organs  its  proper 
share  in  the  total  work  of  the  kidney. 


In  no  other  organ  of  the  body  are  our  views 
as  to  function  so  intimately  dejicndent  on  our 
knowledge  of  structure  as  in  the  kidney.  This 
organ  is  a  branched  tubular  gland  consisting 
in  man  of  ten  to  fifteen  nearly  equal  divisions, 
known  as  the  Malpighian  ])yramids.  In  certain 
animals,  such  as  the  rabbit  and  rat,  only  one 
pyramid  is  present.  It  is  divided  into  an  outer 
portion  or  cortex,  an  inner  portion,  the  medulla, 
and  between  these  the  '  boundary  layer,'  con- 
taining the  larger  branches  of  the  renal  blood- 
vessels (Fig.  528).  From  the  outer  boundary 
of  the  Malpighian  i)yramids   of   the  medulla  a 

number  of  processes,  the  medullary  rays,  pass  out  into  the  cortex  towards  the  surface 
of  the  kidney.  All  parts  of  the  kiilney  are  made  up  of  branched  tulules  embedded  in 
scanty  connective  tissue  and  richly  supplied  with  blood-vessels.  Each  tubule  begins 
by  a  blind  dilated  extremity  in  the  cortex,  known  as  Bowman's  capsule,  which  surrounds 
a  bunch  of  cai)illary  blood-vessels,  the  gloniciulus,  the  two  together  forming  the  Mal- 
pighian body.  From  Bownum's  capsule  a  short  neck  leads  into  a  proximal  convol- 
uted tubule,  and  this  into  a  U-shaped  portion  which  jmsses  down  in  a  medullary  ray 

II 31 


Fig.  528.     Section  of  human  kidney. 

(t'ADI.\T.) 

a,  cortex ;  h^  medulla  or  Malpighian 
pyramids  ;  c,  papilla  ;  rf,  ureter  ; 
<',  e,  boundary  zone. 


1132 


PHYSIOLOGY 


into  the  underlying  portion  of  the  medulla,  and  consists  of  straight  descending  and 
ascending  limbs  and  the  loop  of  Henle.  The  ascending  limb  passes  into  a  distal  convo- 
luted tubule,  and  this  by  a  '  junctional  tiibule  '  joins  with  a  number  of  others  to  form  a 
straight  '  collecting  tubule.'  Several  of  these  unite  to  form  the  papillary  ducts,  which 
open  on  the  surface  of  the  i^apilla  in  the  expanded  ]3art  of  the  renal  duct  or  ureter 
(Fig.  529).  The  whole  tubule  consists  of  epithelium  lying  on  a  basement  membrane  ; 
the  epithelium  varies  in  structure  in  different  parts  of  the  tubule.  The  bunch  of 
glomerular  caj)illaries  is  covered  with  a  very  thin  layer  of  endothelial  cells,  and  a  similar 
layer  forms  the  lining  of  Bowman's  capsule.  The  convoluted  tubules  contain  cells 
which  are  roughly  cubical  or  cylindrical  in  cross-section,  but  do  not  present  very 
definite  cell  outlines.     These  cells,  which  are  similar  in  the  two  sets  of  convoluted 


Cortex 


Boundary  zone 


Fig.  529.     Diagram  showing  course  of  urinary  tubules,  and  the  distribution 
of  blood-vessels.     (From  Yeo.) 


tubules,  have  long  been  distinguished  as  '  redded  epithelium  '  (Fig.  530)  on  account  of 
the  ease  with  which  a  radial  disposition  of  rods  or  granules  is  demonstrated  in  their 
protoplasm.  As  ordinarily  prepared,  the  free  margin  of  these  cells,  where  they  abut 
on  the  lumen,  is  irregular.  This  appearance  is  due  to  the  readiness  with  which  the 
cells  undergo  alteration  under  the  influence  of  different  fixing  reagents,  especially  of 
such  as  contain  water.  When  properly  fixed  it  is  seen  that  the  rodded  structure  as 
described  by  Heidenhain  is  due  to  rows  of  granules  arranged  vertically  to  the  basement 
membrane.  Moreover  the  free  margin  of  the  cells,  instead  of  being  irregular,  consist  of 
a  well-marked  striated  border,  formed  of  a  number  of  very  fine  hairs  closely  set  together 
and  springing  from  a  row  of  granules  in  the  peripheral  part  of  the  cell  (Fig.  531).  The 
hairs,  which  make  up  the  striated  border  (sometimes  called  the  '  brush  border  '),  have 
not  been  observed  to  present  ciliary  movement,  and  are  probably  comparable  with  the 
similar  structures  found  clothing  the  free  border  of  the  epithelium  of  the  intestinal 
villus.  Such  cells  are  characteristic  features  of  the  epithelium  lining  the  urinary  organs 
in  all  types  of  animals,  and  are  well  marked  in  the  nephridia  of  worms.  Besides  these 
rows  of  granules  other  granules  are  found,  especially  towards  the  free  margin  of  the  cell 
and  round  about  the  nucleus.  Some  of  the  granules  appear  to  be  of  a  fatty,  others  of 
a  protein  character. 

The  descending  limb  of  Henle's  loop  is  narrow,  and  possesses  flattened  epithelial 
cells,  while  the  ascending  limb  presents  an  epithelium  similar  to  that  of  the  convoluted 


THE  SECRETION  OF  URINE 


1133 


tubules,  but  with  less  marked  striation.  The  junctional  and  collecting  tubules  are 
lined  with  cubical  or  columnar  cells  with  a  clear  protoplasm.  The  marked  differences 
between  the  structure  of  these  various  parts  point  to  a  differentiation  of  function  and 
division  of  labour  among  them  in  the  preparation  of  the  fully  formed  urine.  This  con- 
clusion is  borne  out  by  a  study  of  the  blood-supply  of  the  kidney.     The  large  renal 


'1 


Fig.  530. 


A  portion  of  convoluted  tubulo  with    rocltled  '  epithelium. 

(HEIDENnAIN.) 


artery  divides  in  the  pelvis  into  four  or  five  branches,  which  pass  uji  to  the  boundary 
zone  and  there  give  off  arteries  in  different  directions  ;  those  which  run  towards  the 
surface  are  the  interlobular  arteries.  Each  of  these,  which  is  an  end-artery  presenting 
no  anastomoses  wath  its  fellows,  gives  off  on  all  sides  short  wide  branches,  which  pass 
to  the  glomeruli  and  constitute  the  vasa  afferentia  of  these  bodies.  Each  vas  afterens 
has  a  thick  muscular  wall.     The  glomerulus  itself  consists  of  a  number  of  anastomosing 


.-».*,.  « 


^ 


Fig.  531.     Cross-sections  of  convoluted  tubules  from  kidney  ol  nit.     (Sauer.) 
A,  during  slight  secretion  ;   b,  during  maximal  secretion. 


wide  capillaries  invested  by  an  extremely  thin  wall,  which  is  sometimes  said  to  consist 
simply  of  a  protoplasmic  film  devoid  of  nuclei.  The  glomerular  capillaries  are  collected 
together  to  form  an  efferent  vessel,  the  ra.s  cffrrcns,  which  is  narrower  than  the  vas 
artVrcns,  but,  like  the  latter,  presents  a  well-marked  nuiscular  coat.  The  vas  efferens 
breaks  up  again  into  a  second  set  of  capillaries,  which  ramify  around  the  tubules  of  the 
cortex  and  communicate  with  a  similar  network  round  the  tubules  of  the  medulla.  The 
medullary  pyramids  are  also  provided  with  blood  by  a  plexus  of  capillaries  talcing  their 


1134  PHYSIOLOGY 

origin  from  little  bunches  of  vessels,  the  vasa  recta  {v.  Fig.  529),  which  leave  the  concave 
side  of  the  arterial  arches  of  the  boundary  zone  to  run  towards  the  papilla,  and  receive 
also  a  few  vessels  which  spring  from  the  vasa  afferentia  of  the  cortical  vessels.  From  the 
capillaries  of  the  tubules  the  blood  is  collected  again  into  veins,  which  leave  the  kidney 
partly  by  the  cortex  and  capsular  vessels,  partly  by  large  venous  trunks  which  join  to 
form  the  renal  vein  at  the  hilum  of  the  kidney.  The  kidney  is  richly  supplied  with 
nerves,  which  are  chiefly  distributed  to  the  muscular  walls  of  its  blood-vessels.  Some 
authors  have  described  a  fine  nerve-plexus  suiTounding  the  tubules  and  sending  branches 
between  and  into  the  cells  of  the  convoluted  tubules  themselves. 

The  main  points  in  the  above  description  of  the  structure  of  the  kidney 
were  made  out  by  Bowman  in  1840,  and  suggested  the  theories  of  urinary 
secretion  both  of  Bowman  and  of  Ludwig  (1844),  theories  which  have 
furnished  the  basis  of  all  our  subsequent  investigation  of  the  subject.  Both 
observers  appreciated  the  great  difference  between  the  membrane  covering 
the  glomerular  loop  and  the  lining  membrane  of  the  tubule,  and  both  drew 
attention  to  the  difference  in  the  circulation  in  these  two  portions  of  the 
kidney.  The  glomerular  capillaries,  supplied  with  blood  through  a  short 
wide  artery  and  drained  by  an  efferent  vessel  smaller  than  the  afferent, 
would  represent  a  region  of  very  high  capillary  blood-pressure,  whereas  the 
pressure  in  the  capillaries  surrounding  the  tubules  must  be  low  and  similar 
to  that  in  other  capillary  regions.  Bowman  therefore  suggested  that  the 
urine  consisted  of  two  parts,  namely,  one  part  containing  the  water  and 
salts  produced  by  a  process  of  filtration  through  the  walls  of  the  glomerular 
capillaries,  and  another  part,  containing  the  specific  urinary  constituents 
urea,  uric  acid,  &c.,  secreted  by  the  cells  probably  of  the  convoluted  tubules. 
To  Ludwig,  on  the  other  hand,  it  seemed  possible  at  first  to  account  for  the 
whole  process  of  formation  of  urine  without  the  assumption  of  any  active 
intervention  on  the  part  of  the  cells  of  the  tubules.  He  imagined  that  the 
whole  of  the  urinary  constituents  passed  from  the  blood  to  the  urinary 
tubule  in  the  glomerulus  by  a  process  of  filtration.  The  glomerular  transu- 
date would  represent  therefore  a  very  dilute  urine  containing  the  crystalloids 
of  the  blood  in  the  same  concentration  as  in  the  blood  and  with  no  more 
urea  than  the  blood  itself  contained.  The  great  difference  in  urea  content 
between  the  blood  and  the  fully  formed  urine  he  ascribed  to  a  process  of 
concentration  taking  place  in  the  fluid  in  its  passage  through  the  tubules,  in 
which  water  and  certain  of  the  salts  were  reabsorbed,  a  process  of  reabsorp- 
tion  conditioned  by  the  difference  in  protein  content  between  the  urine  within 
the  tubules  and  the  lymph  under  low  pressure  on  the  outside  of  the  tubules. 
We  know  now  that  in  its  original  form  the  theory  of  Ludwig  is  untenable. 
If  a  process  of  concentration  takes  place  within  the  tubules  it  must  involve 
the  performance  of  work  by  the  cells  lining  these  tubules,  and  could  not  take 
place  as  a  result  of  mere  differences  of  colloid  content  between  the  two  fluids. 
It  was  shown  long  ago  by  Hoppe-Seyler  that,  if  urine  be  dialysed  against 
serum,  a  passage  of  water  takes  place,  not  from  urine  to  serum,  but  from 
serum  to  urine,  i.e.  the  latter  is  much  more  concentrated  than  the  former. 
The  movement  of  water  from  one  fluid  to  another  through  a  colloid  mem- 
brane depends  on  the  relative  osmotic  pressures  of  the  two  fluids,  and  this 


THE  SECRETION  OF  URINE  1135 

in  turn  is  determined  by  the  molecular  concentration  of  the  two  fluids.  It 
is  easy  to  estimate  the  molecular  concentration  of  any  sample  of  serum  or 
urine.  The  method  which  is  most  convenient  is  to  determine  the  depression 
of  freezing-point  in  the  two  fluids.  Whereas  serum  ordinarily  freezes  at 
—  0-56°  C.  to  —  0'59°  C,  the  freezing-point  of  urine  is  generally  lower  and 
may  vary  from  this  figure  to  as  much  as  -  4-5°  C.  For  the  production 
therefore  of  urine  from  blood-plasma,  a  certain  amount  of  work  has  to  be 
done,  and  the  seat  of  this  work  we  can  locate  only  in  the  cells  of  the  kidney. 
We  may  determine  the  minimum  work  necessary  to  form  a  certain  amount  of 
urine  of  a  given  concentration  by  measuring  the  amount  of  heat  that  must 
be  imparted  to  the  blood-plasma  in  order  to  reduce  it  to  the  same  concentra- 
tion and  volume,  or  we  can  calculate  it  if  we  know  the  freezing-points  of  the 
two  fluids.  A  depression  of  freezing-point  A  =  -  1°  C.  corresponds  to  an 
osmotic  pressure  of  122-7  metres  of  water.  To  concentrate  100  c.c.  of  a 
saline  fluid  such  as  urine  so  as  to  halve  its  bulk  and  double  its  depression  of 
freezing-point,  e.g.  from  -  1°  C.  to  —  2°  C,  would  therefore  require  the 
expenditure  of  work  equivalent  to  that  which  would  be  required  to  compress 
100  c.c.  of  a  gas  at  a  pressure  of  122-7  metres  of  water  to  half  its  bulk. 

The  abandonment  of  Ludwig's  view  as  to  the  mechanism  of  the  concentra- 
tion does  not,  however,  place  his  theory  out  of  court.  The  question  will 
still  have  to  be  discussed  whether  the  chief  object  of  the  tubules  is  the  con- 
centration of  the  fluid  produced  in  the  glomeruli,  or  whether  they  add  to  this 
fluid  by  a  further  secretory  process,  or  whether  they  may  not  possibly 
possess  both  functions  and  in  their  various  parts  alter  the  fluid  flowing 
through  them  either  by  addition  or  by  withdrawal  of  water  or  dissolved 
constituents.  The  common  point  in  the  two  theories  is  the  sharp  distinc- 
tion which  is  drawn  between  the  nature  of  the  glomerular  activity  and  the 
nature  of  the  activity  of  the  tubules.  The  questions  which  we  have  to 
decide  by  experiment  are  : 

(1)  The  nature  of  the  glomerular  activity  and  the  conditions  which 
determine  the  amount  of  fluid  formed  by  the  glomeruli,  and  especially 
whether  the  energy  required  for  the  formation  of  the  glomerular  fluid  is 
furnished  by  the  heart  through  the  blood -pressure  ^^^thin  the  capillaries  or 
by  the  endothelium  covering  these  capillaries. 

(2)  The  function  of  the  tubules,  whether  they  secrete  or  absorb,  and 
what  part  is  played  in  these  processes  by  the  various  segments  of  the  tubules 
which  difEer  so  widely  in  their  histological  characters. 


THE  SECRETION  OF  WATER  AND  SALTS.     FUNCTIONS 
OF  THE  GLOMERULI 

It  is  generally  assumed,  as  the  best  explanation  of  knowi\  facts  with 
regard  to  the  secretion  of  urine,  that  a  watery  exudation  free  from  protein  is 
formed  in  the  glomeruli,  and  that  this  becomes  concentrated  on  its  way 
through  the  tubules  either  by  the  absorption  of  water  and  certain  salts  or  by 
the  secretion  and  addition  of  urea,  uric  acid.    &c.,  as  well  as  such  salts  as 


1136  PHYSIOLOGY 

acid  phosphates.  As  to  the  nature  of  the  glomerular  functions  two  opinions 
have  been  held.  According  to  the  Ludwig  school  the  process  is  one  simply 
of  filtration,  in  which,  under  the  pressure  of  the  blood  in  the  glomerular 
capillaries,  the  water  and  crystalloid  constituents  of  the  plasma  are  filtered 
through  the  glomerular  epithehum,  leaving  behind  the  protein  constituents. 
According  to  Heidenhain  the  process  cannot  be  regarded  as  one  simply  of 
filtration,  but  involves  the  secretory  activity  of  the  glomerular  epithehum. 
If  the  glomerular  urine  is  a  filtrate  it  must  resemble  blood-plasma  in  practic- 
ally all  particulars  except  its  protein  content,  since  the  blood  pressure,  which 
is  the  only  force  causing  filtration,  is  too  small  to  effect  any  appreciable 
separation  of  salts.  On  the  other  hand,  a  certain  minimum  difference  of 
pressure  between  the  two  sides  of  the  membrane  must  be  present  in  order  to 
separate  the  colloids  from  the  other  constituents  of  the  plasma.  We  have 
seen  in  chapter  iv  (p.  143)  that  in  order  to  produce  a  filtrate  containing  only 
water  and  salts  from  serum  a  minimum  difference  of  pressure  of  30  mm.  Hg. 
is  necessary,  corresponding  to  the  osmotic  pressure  of  the  colloidal  con- 
stituents of  the  blood-plasma  or  serum.  Thus  in  order  to  produce  a  filtrate, 
free  from  protein,  from  the  blood-plasma  circulating  through  the  glomerular 
capillaries,  the  pressure  of  the  urine  in  the  tubules  and  ureter  must  always 
be  at  least  30  mm.  lower  than  the  pressure  of  the  blood  in  the  glomeruh.  A 
direct  determination  of  the  latter  figure  is  not  possible.  The  anatomical 
arrangements  are  such  as  to  bring  this  pressure  up  to  a  high  point.  Not  only 
are  the  vasa  afferentia  very  short,  but  the  vasa  efferentia  are  only  two- 
thirds  of  the  diameter  of  the  vasa  afferentia.  Moreover  the  sudden  increase 
of  bed  which  ensues  as  the  blood  passes  from  the  vas  afferens  to  the  bundle 
of  capillaries  must  itself  cause  a  rise  of  pressure  in  the  latter,  due  to  the 
transformation  of  the  kinetic  energy  of  the  moving  fluid  into  the  statical 
energy  represented  by  pressure  on  the  walls  of  the  vessels. 

This  point  can  be  rendered  clearer  by  the  following  considerations.     If  fluid  is  flowing 
in  a  tube  of  continuous  bore  ah  (Fig.  532)  there  will  be  a  continuous  fall  of  pressure 


pressure  ""•---,_ 


'                      1 

~'^  pressure      ''""•—, 

"'"-'-^  c 

b 


Fig.  532. 


from  a  to  h.  If,  however,  in  the  tube  ahc  the  segment  h  be  of  much  greater  diameter 
than  the  segments  a  and  c,  although  while  the  fluid  is  at  rest  the  pressures  will  be  equal 
at  all  points  of  the  system,  as  soon  as  the  fluid  moves  from  a  to  c,  although  there  is  a  fall 
of  pressure  between  a  and  c,  a  manometer  attached  to  h  may  show  an  actual  greater 
pressure  than  a  manometer  inserted  at  a.  Fluid  is  flowing  from  a  place  of  lower  to  a 
place  of  higher  pressure.  The  apparent  paradox  is  due  to  the  fact  that  the  energy 
causing  the  fluid  to  move  from  a  to  &  is  of  two  kinds.  It  equals  \mv^  +  P,  i.e.  represented 
by  the  kinetic  energy  of  the  moving  mass  of  fluid  as  well  as  the  difference  of  pressure 


THE  SECRETION  OF  URINE  1137 

between  any  two  points  of  the  tube.  The  total  energy  will  diminish  continuously  from 
a  to  c,  and  is  used  in  overcoming  the  resistance  of  the  system.  We  may  say  then  that  the 
sum  of  these  two,  namely,  |m«"  +  P,  is  greater  at  a  than  b,  and  is  greater  at  b  than  c  ; 
but  as  the  fluid  passes  from  the  narrow  tube  a  into  the  wide  tube  b  there  is  a  sudden 
fall  of  its  velocity  and  a  consequent  diminution  of  the  factor  l^v^.  In  order  to  provide 
for  a  continuous  fall  in  the  total  energy  of  the  fluid,  namely,  hmv^  +  P,  the  diminution 
in  the  factor  Imv^  must  cause  a  corresponding  increase  in  the  factor  P,  i.e.  in  the  lateral 
pressure  exercised  by  the  fluid  on  the  vessel  wall.  As  the  total  diameter  of  the  bed  of 
the  stream  in  the  capillaries  may  be  twenty  times  that  of  the  bed  in  the  vas  afferens 
the  velocity  of  the  blood  in  these  capillaries  will  be  only  one-twentieth  of  that  in  the 
artery  and  the  kinetic  energy  of  the  blood  only  one  four-hundredth.  It  is  possible 
therefore  that  the  pressure  exercised  by  the  blood  on  the  walls  of  the  capillaries  may  be 
even  greater  than  that  in  the  interlobular  arteries,  and  this  effect  will  be  still  further 
aided  by  the  narrow  diameter  of  the  vas  efferens.  Although  therefore  the  pressure  in 
the  ordinary  capillaries  of  the  body  is  probably  not  greater  than  20  to  30  mm.  Hg.,  the 
glomerular  capillaries  might  present  a  pressure  little  inferior  to  that  in  the  main  arteries 
of  the  body. 

The  pressure  in  the  ureter  is  under  normal  circumstances  approximately 
nil,  whereas  that  in  the  glomerular  capillaries  is  probably  not  more  than 
20  mm.  Hg.  below  that  in  the  main  arteries  of  the  body,  so  that  there  is  a 
difference  of  pressure  on  the  two  sides  of  the  membrane  more  than  sufficient 
to  cause  a  constant  filtration  of  a  protein-free  fluid  from  the  blood-plasma 
coursing  through  these  capillaries.  On  raising  the  pressure  on  the  tubule 
side  the  filtration  ought  to  come  to  an  end  when  the  pressure  approaches 
a  figure  which  is  30  to  40  mm.  below  that  in  the  glomerular  capillaries.  A 
number  of  observers  have  found  that  urinary  secretion  ceases  when  the 
blood  pressure  falls  to  between  40  and  50  mm.  Hg.  The  urinary  secretion 
can  be  stopped  by  raising  the  pressure  in  the  tubules  by  means  of  ligature 
of  the  ureter.  On  applying  the  ligature  the  secretion  continues  for  a  time 
until  the  pressure  in  the  ureter  rises  up  to  a  certain  point,  when  the  secretion 
comes  to  an  end.  In  one  experiment  the  following  pressures  were  obtained 
in  a  dog  which  was  secreting  urine  copiously  under  the  action  of  diuretin. 
Manometers  were  connected  both  with  the  carotid  artery  and  with  the  ureters 
so  that  no  outflow  of  urine  was  possible  : 

Arterial  pressure  Ureter  pressure 

140 72 

138 92 

133 88 

In  this  experiment  therefore  secretion  came  to  an  end  with  a  difference 
of  pressure  between  ureter  and  arteries  of  between  40  and  50  mm.  Hg. 

The  absolute  pressure  attained  within  the  ureter  in  any  given  experiment  after  liga- 
ture of  these  tubes  will  vary  with  several  factors.  In  the  first  place,  if  the  minimum 
secreting  pressure  is  really  conditioned  by  the  colloid  content  of  the  blood-plasma,  it 
will  be  less  the  smaller  the  projwrtion  of  colloids  in  the  plasma.  In  some  exiieriments 
(Magnus)  a  flow  of  urine  was  observed  with  a  blood -pressure  as  low  as  18  mm.  Hg.,  but 
in  this  case  the  blood  was  extremely  dilute  as  the  result  of  the  continuous  injection  into 
the  blood-vessels  of  normal  salt  solution.  Barcroft  and  Knowlton  have  sliown  that  the 
diuresis  brought  about  by  injection  of  saline  (Ringer's)  solution  is  inhibited  by  mixing 


1138  PHYSIOLOGY 

with  the  saline  fluid  colloids,  such  as  gelatin  and  gum,  which  possess  an  osmotic  pressure. 
Colloids  such  as  starch,  with  no  measurable  osmotic  pressure,  have  no  such  effect. 

On  the  other  hand,  the  ureters,  or  at  any  rate  the  urinary  tubules,  cannot  be  regarded 
as  absolutely  water-tight.  Not  only  are  the  cells  of  these  tubules  capable  of  taking  up 
fluid,  but  it  is  probable  that  at  high  pressures  a  certain  amount  of  actual  filtration  takes 
place  between  these  cells.  This  process  of  reabsorption  will  tend  to  diminish  the  actual 
pressure  of  the  fluid  in  the  ureters,  so  that  the  secretion  of  urine  may  apparently  come 
to  a  standstill  when  there  is  still  a  difference  of  pressure  between  blood  and  urine  con- 
siderably over  50  mm.  Hg.  Under  such  circumstances  the  ureter  pressure  will  be  higher, 
and  the  difference  of  pressiire  between  urine  and  blood  less,  the  more  rapid  the  formation 
of  urine  by  the  glomeruli.  In  a  number  of  experiments  by  V.  E.  Henderson,  it  was 
found  that  the  figure  B.P.  -  U.P.  tended  to  approximate  40  mm.  Hg.  the  more  rapid 
the  secretion  of  urine  was.  With  a  slow  secretion  the  flow  of  urine  apparently  ceased 
when  there  was  as  much  as  80  mm.  Hg.  difference  of  pressure  on  the  two  sides  of  the 
glomerular  membrane. 

We  may  conclude  that,  for  the  production  of  any  urine  by  the  kidney, 
a  certain  minimum  difference  of  pressure  is  necessary  between  the  blood  in 
the  glomeruli  and  the  urine  in  the  tubule,  and  that  this  difference  becomes 
less  the  smaller  the  protein  content  of  the  blood.  Since  the  only  work 
required  in  the  formation  of  a  protein-free  filtrate  from  the  blood  is  that  due 
to  the  osmotic  pressure  of  the  proteins  themselves,  and  the  observed  difference 
of  pressure  during  secretion  is  greater  than  this  osmotic  pressure,  we  are 
justified  in  concluding,  provisionally  at  any  rate,  that  the  mechanical  factors 
present  at  the  upper  end  of  the  urinary  tubule  are  sufficient  to  account  for  the 
production  of  a  glomerular  transudate  free  from  protein,  but  containing  the 
same  proportion  of  water  and  salts  as  the  blood-plasma  circulating  through 
the  capillaries. 

If  the  process  occurring  in  the  glomeruli  is  simply  one  of  filtration,  three 
conditions  must  be  realised  : 

(1)  The  amount  of  filtrate,  so  long  as  the  ureter  pressure  is  constant, 
must  depend  on  the  pressure  and  rate  of  flow  of  the  blood  in  the  glomerular 
capillaries,  and  must  fall  or  rise  with  the  latter. 

(2)  The  constitution  of  the  fully  formed  urine  as  it  appears  in  the  ureters, 
after  modification  by  addition  or  subtraction  on  the  part  of  the  tubular  cells, 
must  approximate  more  closely  to  the  supposed  glomerular  transudate, 
containing  the  same  proportion  of  salts  as  the  blood-plasma,  the  more  rapidly 
the  formation  of  the  glomerular  transudate  takes  place  :  i.e.  the  quicker  the 
flow  of  urine  the  more  nearly  must  its  composition,  reaction,  and  osmotic 
pressure  resemble  those  of  the  blood-serum. 

(3)  The  total  quantity  of  solids  excreted  in  any  given  time  must  be 
increased  with  any  increase  in  the  urinary  flow.  For,  whatever  the  activity 
of  the  tubules,  the  glomeruli  must  blindly  turn  out  a  certain  proportion  of 
solids  with  every  cubic  centimetre  of  fluid  that  they  form. 

We  may  deal  first  with  the  influence  of  alterations  in  the  renal  blood- 
supply  on  the  flow  of  urine.  Ligature  of  the  renal  vein  diminishes  and  soon 
stops  the  flow  altogether.  Since  this  procedure  must  cause  a  large  rise  of 
pressure  in  the  capillaries  of  the  kidney,  this  result  was  regarded  by  Heiden- 
hain  as  disproving  any  possibility  of  the  glomerular  process  being  of  the 


THE  SECRETION  OF  URINE 


1139 


nature  of  a  filtration.  At  any  given  time,  however,  the  glomeruh  contain  but 
Httle  blood.  With  total  cessation  of  the  renewal  of  this  blood,  their  contents 
will  rapidly  become  so  concentrated  that  they  will  be  little  more  than  a  mass 
of  red  corpuscles.  No  filtration  of  water  and  salts  can  take  place  unless  there 
is  a  continual  renewal  of  the  fluid  on  the  blood  side  of  the  filter. 

On  the  other  hand,  alterations  in  the  blood-supply  to  the  kidney, 
determined  by  changes  on  the  arterial  side,  have  pronounced  effects  on  the 
amount  of  urine  formed.  The  pressure  in  the  glomerular  capillaries  and  the 
rate  of  flow  through  these  capillaries  can  be  increased  in  either  of  two  ways  : 

(a)  By  increase  of  the  driving  force,  i.e.,  the  general  blood-pressure  ; 

(b)  By  a  diminution  of  the  resistance  to  the  flow  of  blood  through  the 
kidneys,  as  by  dilatation  of  the  vessels  of  this  organ. 

The  blood-flow  through  the  kidney  can  be  investigated  either  by  record- 
ing the  total  volume  of  this  organ  or  by  determining  the  amount  of  blood 
which  leaves  it  through  the  renal  vein,  according  to  the  methods  described 
in  chapter  xiii. 

It  is  necessary  at  the  same  time  to  take  a  record  of  the  arterial  blood- 
pressure  by  means  of  a  mercurial  manometer.  It  is  evident  that  an  expan- 
sion of  the  kidney  may  be  caused  by  a  rise  of  general  arterial  pressure,  or, 
the  latter  remaining  constant,  by  a  dilatation  of  the  kidney- vessels ;  and, 
conversely,  a  fall  of  kidney  volume  may  be  due  either  to  a  fall  of  general 
blood -pressure  or  to  a  constriction  of  the  renal  blood-vessels.  By  taking 
these  two  records  it  is  possible  to  tell  whether  a  given  increase  of  blood-flow 
through  the  organ  is  of  local  or  of  general  causation,  i.e.  is  active  or  passive. 
Thus  the  volume  of  the  kidney  gives  us  an  indirect  clue  to  the  pressure  in 
and  the  flow  through  the  kidney-vessels.  The  flow  through  the  vessels 
can  be  determined  directly  either  by  a  cannula  in  the  inferior  vena  cava,  all 
veins  other  than  the  renal  being  clamped,  or  by  Brodie's  method  already 
described  (p.  994). 

The  results  of  the  experiments  carried  out  by  these  methods  can  be 
represented  in  the  following  tabular  form  : 


I'rocodiiri' 

Gnnrral  blooil- 
pri'ssurc 

l\ona\  vessels 

Kidney  volume 

Urinary  flow 

Division  of  spinal  cord  in 

Falls  to 

Relaxed 

Shrinks 

Ceases 

neck 

40  mm. 

Stimulation  of  cord  . 

Rises 

Constricted 

Shrinks 

Diminished 

Stimulation  of  cord  after 

Rises 

Passively 

Swells 

Increased 

section  of  renal  nerves   . 

dilated" 

vStimulation  of  renal  nerves 

Unaffected 

Constricted 

Shrinks 

Diminished 

Stinuilation   of  splanchnic 

Rises 

Constricted 

Shrinks 

Diminished 

nerve 

Division  of  one  splanchnic 

nerve  : 

{a)  In  dog 

Unaffected 

Dilated 

Swells  (?) 

Increased 

(l>)  In  rabbit      . 

Falls 

Relaxed 

Shrinks  (?) 

Diminished 

Plethora 

Rises 

Dilated 

Swells 

Increased 

Hiemorrhage    . 

Falls 

Constricted 

Shrinks 

Diminislied 

1140  PHYSIOLOGY 

It  will  be  seen  that  in  every  case  where  an  increased  blood-flow  attended 
with  a  rise  of  blood-pressure  in  the  glomerular  capillaries,  is  brought  about, 
the  urinary  flow  is  at  the  same  time  increased. 

Another  factor,  altering  the  ease  with  which  filtration  of  watery  fluid 
and  salts  would  take  place  through  the  glomerular  capillaries,  would  be  the 
composition  of  the  blood-plasma.  Any  dilution  of  this  plasma  must  render 
filtration  more  easy,  while  a  concentration  would  make  it  more  difficult. 
As  a  matter  of  fact  hydraemia,  and  especially  hydraemic  plethora  caused  by 
injection  of  normal  sahne  into  the  circulation,  evoke  an  increased  flow  of 
urine.  A  smaller  effect  is  produced  by  injection  of  defibrinated  blood,  and 
if  the  blood  has  been  previously  concentrated  by  depriving  the  animals  of 
water,  there  may  be  little  or  no  increase  in  flow,  in  consequence  of  the  high 
osmotic  pressure  of  the  proteins  of  the  plasma  injected. 

Experiments  on  the  action  of  diuretics  have  a  close  bearing  on  the  nature 
of  the  process  occurring  in  the  glomeruh.  A  large  increase  in  the  urinary 
flow  can  be  brought  about  by  the  intravenous  injection  of  saline  diuretics 
such  as  sodium  sulphate  or  potassium  nitrate,  or  of  neutral  crystalloids  such 
as  urea  or  sugar.  The  question  arises  whether  the  mechanical  changes 
thereby  induced  in  the  renal  circulation  are  sufficient  to  account  for  the 
diuresis.  Three  factors  might  be  concerned  in  promoting  an  increased 
glomerular  transudation.     These  are  : 

(1)  A  rise  of  pressure  in  the  glomerular  capillaries. 

(2)  Acceleration  of  the  blood-flow  from  the  capillaries. 

(3)  Diminution  of  the  amount  of  proteins  in  the  blood-plasma. 

When  a  concentrated  solution  of  salt  is  injected  into  the  circulation  the 
osmotic  pressure  of  the  plasma  is  raised  and  water  passes  from  the  tissue- 
cells  into  the  blood-stream,  in  consequence  of  the  osmotic  diflerences 
between  the  blood  and  cells  so  induced.  As  a  result  the  total  volume  of  the 
circulating  fluid  is  increased  by  the  addition  to  it  of  water  derived  from  the 
tissues,  i.e.  a  condition  of  hydrsemic  plethora  is  set  up,  just  as  if  a  large  bulk 
of  normal  saline  fluid  had  been  injected  into  the  circulation.  So  long  as 
this  hydraemic  plethora  continues,  so  long  is  there  a  rise  both  in  arterial  and 
venous  pressures  and  an  increase  in  the  velocity  of  the  circulating  blood. 
The  kidney  placed  in  an  oncometer  shows  a  great  increase  in  volume.  While 
the  plethora  lasts  there  are  mechanical  conditions  at  work  in  the  kidneys, 
i.e.  increased  pressure,  increased  rate  of  flow,  and  diminished  concentration 
of  plasma — all  of  which  would  concur  in  producing  an  increased  glomerular 
transudation.  With  certain  salts,  such  as  sodium  chloride,  the  diuresis  is 
coterminous  with  the  hydraemic  plethora,  but  with  other  members  of  this 
class,  such  as  grape  sugar,  the  diuresis  outlasts  the  plethora,  so  that  the  con- 
tinued increased  secretion  of  urine  leads  to  an  actual  concentration  and 
diminution  of  the  volume  of  the  circulating  blood,  as  is  shown  in  Fig.  533. 
If  the  kidney  be  placed  in  an  oncometer,  it  is  found  that  the  dilatation  of  the 
kidney  outlasts  the  plethora,  and  comes  to  an  end  only  with  the  cessation 
of  the  increased  urinary  flow.  There  must  be  local  influences  at  work 
(perhaps  the  direct  effect  of  the  sugar  on  the  blood-vessels)  which  lead  to  an 


THE  SECRETION  OF  URINE  1141 

active  dilatation  of  the  renal  vessels,  and  a  consequent  rise  of  pressure  and 
velocity  of  the  blood  in  the  glomeruli.  That  the  vascular  change  is  really 
responsible  for  the  increased  urinary  flow  is  shown  by  the  fact,  determined  by 
Cushny,  that  if  the  swelling  of  the  kidney  be  prevented  by  means  of  an 


170 

leo 

150 

I+O 
130 
1-20 

no 

100 
90 

so 

70 
en 
50 
40 

30 
20 
10 


( 

A 

^^ 

\, 

1 

\ 

\ 

■  -h 

s 

.^ 

^ 

Art.   VtV.   mm 

Wr 

I           1 
Haemoglobin 

^^-.  - 

.-- 

Percent,. 
1 

T 

N 

\ 

I        / 

'K 

\ 

i 

a 

• 

\ 

\ 

r" 

n 

V 

/ 

p 

N 

\ 

iX) 

o 

\ 

^^ 

Kidn-v   V,',]unip 

^ 

~~~~~~~ 

\- 



. 

/ 

^ 

-^__ 

frme 

1                     1 

10   '.lo   .-^O    4'J 


?y      ao      'M      luu     110     i-jij    loo     uo     i5& 


Fig.  533.  A  conaparison  of  the  effects  of  intravenous  injection  of  30  grni.  glucose 
in  concentrated  solution  on  the  arterial  blood-pressure,  the  concentration  of  the 
blood,  the  kidney  volume,  and  the  urinary  flow.     Abscissa  =  time  in  minutes. 

adjustable  clamp  on  the  renal  artery,  no  diuresis  is  produced  ;  so  long  as 
the  kidney  is  kept  at  its  normal  size  the  flow  of  urine  remains  at  the  same 
rate  as  before. 

With  regard  to  the  specific  diuretics,  such  as  caffeine,  the  question  is 
not  quite  so  clear.  In  most  cases  injection  of  caffeine  in  the  rabbit  brings 
about  a  dilatation  of  the  kidney  and  a  proportional  increase  in  the  secretion 
of  urine.  But  cases  have  been  recorded  in  which  expansion  of  the  kidney 
occurred  without  any  increase  in  urinary  flow,  and,  on  the  other  hand, 
augmented  urinary  flow  without  any  increase  in  the  kidney-volume,  or 
even  in  the  rate  of  blood-flow  through  the  kidney  (at-  determined  by  Brodie's 
method).     The  general  rule,  however,  is  that  a  greater  rate  of  blood-flow  is 


1142 


PHYSIOLOGY 


obtained  fciri  passu  -wdth  the  increased  urinary  flow  ;  and  a  consideration 
of  certain  peculiarities  in  the  renal  circulation  must  prevent  us  from  laying 
too  much  stress  on  apparent  exceptions  to  the  rule.  To  the  blood  entering 
the  kidneys  by  the  renal  arteries  two  ways  are  open.  The  blood  may  pass 
through  the  vasa  afierentia,  through  the  glomeruli  and  tubular  capillaries, 
back  to  the  renal  vein.  On  the  other  hand,  it  may  escape  the  glomeruli 
altogether,  and  pass  through  the  vasa  recta  directly  into  the  intertubular 
capillaries  and  so  into  the  renal  veins.  It  is  a  common  experience,  in 
injecting  the  blood-vessels  of  the  kidneys  fost-mortem,  to  find  the  renal 
arteries,  intertubular  capillaries,  and  veins  filled  to  distension  with  the 
injected  mass,  but  hardly  any  in  the  glomeruli.  One  must  assume  in  such 
a  case  that  there  has  been  spasmodic  contraction  of  the  muscular  coats  of 
the  vasa  afferentia  (cp.  Fig.  534).      The  normal  amount  of  blood  might 


Bowman's 
Capsule 

Fig.  534.  Diagram  (after  Morat)  to  illustrate  the  effect  of  active  changes  in  the 
vasa  afferentia  and  efferentia  on  the  pressure  in  the  glomerular  capillaries. 
If  the  vas  afferens  constricts,  the  pressure  will  be  represented  by  the  lower 
dotted  line.  On  the  other  hand,  constriction  of  the  vas  efferens  would  raise  the 
pressure  in  the  glomerulus  till  it  almost  equalled  that  in  the  renal  artery,  as  is 
shown  by  the  upper  dotted  line. 
A,  arteries  ;  G,  glomerular  capillaries  ;   c,  tubular  capillaries  ;  v,  vein. 

therefore  circulate  through  the  kidney  without  any  flowing  through  the 
filtering  apparatus,  i.e.  the  glomeruli.  On  the  other  hand,  a  dilatation  of 
the  afferent  vessels  and  a  shght  constriction  of  the  efferent  vessels  would 
cause  a  considerable  rise  of  pressure  in  the  glomerular  capillaries,  and  a 
consequent  increased  transudation,  without  necessarily  altering  to  any 
marked  extent  the  total  circulation  of  blood  through  the  whole  organ.  The 
changes  in  the  afferent  and  efferent  vessels  and  the  glomeruli  are,  however, 
beyond  our  control  or  powers  of  observation,  so  that  it  is  impossible  to 
devise  at  the  present  time  any  crucial  experiment  which  might  decide  the 
nature  of  the  process  occurring  in  the  glomeruli. 

THE  COMPOSITION  OF  THE  URINE.  If  the  glomerular  function  is 
that  of  mere  filtration,  we  should  expect  that  the  more  rapidly  the  process 
occurs,  the  more  nearly  would  the  urine  which  is  turned  out  into  the  ureters 
resemble  the  blood-plasma  in  composition,  reaction,  and  osmotic  pressure, 
since  the  glomerular  filtrate  hurried  through  the  tubules  would  have  very 
little  time  to  undergo  any  changes  resulting  in  its  concentration.  If,  on  the 
other  hand,  the  diuresis,  produced  by  salt  or  sugar  solutions,  is  to  be  ascribed 


THE  SECRETION  OF  URINE 


1143 


to  a  stinmlatiou  of  the  renal  epithelium,  the  differences  between  blood- 
plasma  and  urine  should  be  greatest  at  the  height  of  the  diuresis,  when  the 
concentration  of  the  specific  stimulant  is  also  at  its  highest.  The  following 
experiment  shows  that  the  more  rapid  the  secretion  of  urine,  the  more  closely 
does  its  concentration,  as  indicated  by  its  osmotic  pressure  and  depression 
of  freezing-point  (A),  approximate  that  of  the  blood-plasma. 

A  dog  received  -40  grm.  of  dextrose  dissolved  in  -40  ccm.  of  water.  The 
following  Table  represents  the  relative  concentrations  of  urine  and  blood- 
serum  at  different  stages  in  the  diuresis  thereby  produced  : 


Time 

Urine 

Rate  of  flow 

A  of  urine 

A  of  blood-serum 

11.30-12 

10  c.c. 

3-3 

2-360 

0-625  (at  12.0) 

From  12.0 

to  12.7  injecte 

d  40  grm.  dextrose  into  jugular  vein                     j 

12.7  -12.15 

35  c.c. 

45 

1-210 

— ■ 

12.16-12.20 

20  c.c. 

50 

0-975 

0-700  (at  12.16) 

12.20-12.30 

52  c.c. 

52 

0-835 

— 

12.30-12.40 

45  c.c. 

45 

0-825 

0-700  (at  12.30) 

12.40-12.50 

22  c.c. 

22 

0-830      j 

0-675  (at  12.40) 
0-675  (at  12.50) 

A  still  closer  approximation  of  the  concentration  of  the  urine  to  that  of  the 
plasma  was  obtained  by  Galeotti  in  some  experiments  in  which  the  modifying 
influence  of  the  tubular  epithelium  on  the  glomerular  transudate  had  been 
prevented  by  poisoning  the  animal  with  corrosive  sublimate,  which  causes 
destruction  of  the  epithelium,  but  is  said  to  leave  the  glomeruli  intact. 

Since  the  glomerular  transudate  must  have  a  concentration  approxi- 
mately identical  with  that  of  the  blood-plasma,  it  would  be  impossible  for 
a  urine  formed  by  mere  filtration  to  have  a  concentration  less  than  that  of 
the  blood-plasma.  It  is,  however,  of  frequent  occurrence  that,  after 
copious  potations  of  tea  or  light  beer,  urine  is  passed  with  an  osmotic  pressure 
and  a  molecular  concentration  considerably  below  that  of  the  blood.  In 
one  case  Dreser  obtained  a  urine  with  a  freezing-point  of  A  =  0-16°  C,  and 
the  same  result  has  been  obtained  on  one  or  two  occasions  when  the  diuresis 
has  been  produced  by  the  administration  of  caffeine.  If  we  assume  that  this 
hypotonic  fluid  is  formed  by  the  glomeruli,  we  must  at  once  give  up  any  idea 
of  the  process  in  these  structures  being  essentially  one  of  filtration.  But  it 
is  possible  that  the  epithelium  of  the  tubules  can  secrete  water  as  well  as 
solid  constituents.  The  fine  adaptation  of  the  kidney  to  slight  changes 
in  the  composition  of  the  blood  is  apparently  an  endowment  of  the  tubular 
epithelium,  and  in  those  cases  where  large  quantities  of  hypotonic  urine  are 
passed  there  is  not  at  any  time  any  appreciable  change  either  in  the  composi- 
tion of  the  blood  or  in  its  total  volume.  Water  is  absorbed  from  the  ali- 
mentary canal  and  is  almost  immediately  excreted  by  the  kidneys.  When 
we  attempt  to  produce  the  same  effect  by  infusion  of  large  quantities  of 
water  or  hypotonic  solutions  into  the  blood-stream,  we  get  a  flow  of  urine 
apparently  determined  entirely  by  the  circulation  through  the  kidney  and 


1144  PHYSIOLOGY 

having  a  concentration  not  inferior  to  that  of  the  blood.  The  passage  of 
hypotonic  urine  can  be  ascribed  to  a  modification  of  the  glomerular  transu- 
date as  it  passes  through  the  tubules,  a  modification  due  partly  to  the  ab- 
sorption of  salts  from  the  fluid,  partly,  perhaps  chiefly,  to  a  secretion  of 
water  or  extremely  dilute  salt  solution  by  the  cells  of  the  tubules  themselves. 

Certain  other  observations  accord  with  our  hypothesis  that  in  Bowman's  capsule  a 
fluid  is  transuded  having  the  same  molecular  concentration  as  blood-plasma,  and  there- 
fore considerably  less  concentrated  than  normal  urine.  Ribbert  succeeded  in  extir- 
pating the  whole  of  the  medullary  portion  of  the  kidney  in  the  rabbit,  leaving  the  cortex 
intact,  and  found  in  this  case  that  during  the  survival  of  the  animal  the  urine  passed  was 
much  more  dilute  than  normal.  In  cases  where  there  is  destruction  of  the  tubular 
epithelium,  while  the  glomeruli  remain  intact,  either  in  consequence  of  disease  or,  as 
in  Galeotti's  experiments,  as  a  result  of  poisons,  we  are  accustomed  to  obtain  a  dilute 
copious  urine  ;  and  the  continual  passage  of  such  urine  is  in  man  regarded  as  a  sign  of 
one  form  of  renal  disease. 

The  experimental  facts  which  we  have  passed  in  review  do  not  therefore 
negative  the  view  that  the  glomerular  epithehum  plays  the  part  of  a  passive 
filter  in  the  formation  of  urine,  and  that  the  energy  of  the  process  by  which 
'  urine  '  is  produced  in  Bowman's  capsule  is  entirely  furnished  by  the  heart 
in  driving  the  blood  at  a  high  pressure  through  the  glomerular  capillaries. 

FUNCTIONS  OF  THE  RENAL  TUBULES 
Whatever  the  nature  of  the  glomerular  activity,  it  is  evident  that  the 
multiform  epithehum  of  the  tubules  may  alter  the  glomerular  transudate, 
either  by  the  absorption  or  by  the  secretion  of  water  or  solid  constituents. 
We  may  deal  with  the  evidence  for  the  occurrence  of  these  two  processes 
separately. 

SECRETION  BY  THE  URINARY  TUBULES.  Although  it  is  impossible 
to  collect  the  secretion  of  the  glomeruH  apart  from  that  of  the  tubules,  the 
arrangement  of  the  blood-vessels  in  certain  animals  enables  us  to  influence 
separately  the  circulation  to  these  two  parts  of  the  kidney.  The  amphibian 
kidney  receives  a  blood-supply  from  two  sources.  A  number  of  renal 
arteries  leaving  the  aorta  enter  the  kidney  and  supply  the  whole  of  the 
glomeruli,  the  vasa  efferentia  from  which  pass,  as  in  the  mammaUan  kidney, 
into  the  intertubular  capillaries.  These  are  also  supphed  with  blood  of 
venous  character  by  the  renal  portal  vein.  If  all  the  renal  arteries  be  divided 
or  ligatured,  the  glomeruli,  as  was  shown  by  Nussbaum,  are  entirely  cut  out 
of  the  circulation,  though  the  tubules  continue  to  receive  venous  blood 
through  the  renal  portal  vein.  Nussbaum  stated  that  ligature  of  all  the 
renal  arteries  caused  cessation  of  the  urinary  secretion,  which  could  be 
reinduced  by  injection  of  urea.  He  concluded  that  urea  with  water  was 
secreted  by  the  tubules,  whereas  peptone,  sugar,  and  haemoglobin  were 
turned  out  by  the  glomeruli.  Beddard  showed  that  these  results  of  Nuss- 
baum must  have  been  due  to  the  fact  that  he  had  not  obstructed  the  whole 
of  the  renal  arteries.  One  or  two  of  these  small  vessels  will  suffice  to  supply 
blood  to  a  considerable  number  of  the  glomeruli.      After  complete  obstruc- 


THE  SECRETION  OF  URINE  1U5 

tion  of  the  arteries,  no  iirinaiy  flow  could  be  induced  even  with  subcutaneous 
injection  of  urea.  But  the  cutting  oft'  of  the  arterial  blood-supply  from  the 
tubules  caused  a  rapid  destruction  of  the  tubular  epithelium,  so  that  the 
result  of  the  experiment  could  not  be  taken  as  negativing  the  possibiHty  of 
this  epithelium  having,  when  in  a  normal  state  of  nutrition,  some  secretory 
power.  He  therefore  carried  out,  with  Bainbridge,  another  series  of  ex- 
periments of  the  same  description,  in  which  the  frogs,  after  ligature  of  the 
renal  arteries,  were  kept  in  an  atmosphere  of  pure  oxygen.  Under  these 
circumstances  sufficient  oxygen  diftused  into  the  blood  of  the  renal  portal 


^a^  boc 
1 

'\i'A 

f^ma  — Vena  cava 

T•3s^ls /  J/J;  . 

"fe^^.     /Renal  aKt-eries 

Kidney Vy 

lo^' 

Renal  poi'l-al— # 

J^ 

Anr.abciom.v.-»\    1> 

^ 

^- — Femoral  v. 
Fig.  535.     The  vascular  sui^ply  to  the  kidney  in  the  frog. 

vein  to  maintain  an  adequate  supply  of  this  gas  to  the  tubules.  No  desquam- 
ation of  the  epithelium  resulted,  and  injection  of  urea  produced  a  small 
flow  of  urine  even  when,  by  subsequent  injection  of  the  blood-vessels,  it  was 
proved  that  every  glomerulus  had  been  cut  out  of  the  circulation. 

The  view  that  a  portion  of  the  tubules  is  secretory  in  function  is  further  supported 
by  histological  examination  of  these  structures  under  various  conditions  of  activity. 
In  the  cells  of  the  convoluted  tubules  various  kinds  of  granules  and  of  vacuoles  may  be 
distinguished.     Gurwitsch  divides  these  vacuoles  into  three  classes  : 

(1 )  Large  granules  staining  densely  with  osmic  acid,  and  probably  rich  in  lecithin. 

(2)  Smaller  very  numerous  granules  consisting  of  some  form  of  protein  material. 

(3)  Large  vacuoles  lying  close  to  the  free  margins  of  the  cells,  whose  contents  do 
not  undergo  coagulation  with  the  ordinary  fixing  reagents,  and  therefore  are  free  from 
protein,  fat,  or  mucin.  Tliese  vacuoles  arc  esi)ecially  marked  in  kidneys  which  are 
secreting  at  a  great  rate,  in  consequence  of  the  injection  of  saline  diuretics  or  of  large 
quantities  of  normal  salt  solution.  They  may  be  regarded  as  excretory  vacuoles,  and 
consist  of  water  or  saline  Ihiids  which  have  been  collected  by  the  cells  and  are  being  passed 
on  by  them  to  the  lumen  of  the  tubules. 

As  a  rule  it  is  impossible  to  trace  any  definite  constituent  of  the  urine 
on  its  way  through  the  cells  of  the  tubules.  But  if  a  solution  of  uric  acid  in 
piperazin  be  injected  intravenously  into  a  rabbit,  the  kidneys,  taken  twenty 
to  sixty  minutes  after  the  injection,  present  tubules  full  of  uric  acid  con- 
cretions. In  the  medullary  portion  of  the  kidney  this  uric  acid  precipitate  is 
confined  to  the  lumen  of  the  tubules,  but  in  the  convoluted  tubules  granules 


1146  PHYSIOLOGY 

of  uric  acid  are  to  be  found  in  the  epithelial  cells,  especially  towards  their 
inner  border.  Since  these  cells  are  able  to  excrete  uric  acid  when  present 
in  abnormal  quantities  in  the  blood,  it  is  a  reasonable  assumption  that  they 
also  undertake  the  secretion  of  this  substance  under  normal  conditions. 
Certain  observers  have  in  fact  described  the  presence  of  urate  granules  in  the 
cells  of  the  convoluted  tubules  of  the  bird's  kidney. 

Although  the  larger  number  of  the  urinary  constituents  must  escape 
detection  on  their  way  through  the  cells,  we  can  throw  some  light  on  the 
excretory  functions  of  the  kidney  by  studying  the  mechanism  by  means 
of  which  it  excretes  certain  dyestuifs,  such  as  sulphindigotate  of  soda 
('  indigo  carmine  ').  If  the  indigo  be  injected  into  the  veins,  it  is  excreted 
in  a  concentrated  form,  both  by  the  liver  and  by  the  kidney,  so  that  the 
urine  assumes  a  dark  blue  colour.  If  the  animal  be  killed  when  the  excretion 
of  the  pigment  is  at  its  height,  and  the  kidneys  be  rapidly  fixed  with  absolute 
alcohol  (which  precipitates  the  dyestuff),  all  parts  of  the  kidney  present  a 
blue  colour,  which  is  especially  marked  in  the  medulla.  Under  these  cir- 
cumstances the  urine,  which  is  being  excreted  by  the  glomeruh,  rapidly 
carries  down  the  dyestuff ,  wherever  it  may  be  turned  out,  into  the  tubules 
of  the  pyramids.  In  order  to  discover  the  exact  locality  of  the  cells  in- 
volved in  its  excretion,  we  must  stop  the  glomerular  transudate  by  some 
means  or  other.  This  stoppage  of  the  urinary  flow  can  be  effected  in  two 
ways,  viz.  by  section  of  the  spinal  cord  in  the  neck,  so  as  to  reduce  the 
blood-pressure  to  about  40  mm.  Hg.,  i.e.  below  the  minimum  necessary  for 
the  production  of  urine,  or  by  cauterising  portions  of  the  surface  of  the 
kidney  by  means  of  silver  nitrate.  If  the  indigo  be  injected  into  the  veins, 
after  section  of  the  cord,  and  the  animal  be  killed  half  an  hour  later,  and  the 
kidneys  fixed  with  absolute  alcohol,  they  are  found  to  be  of  a  bright  blue 
colour,  although  no  urine  has  been  secreted.  On  cutting  into  the  kidneys 
the  colour  is  seen  to  be  confined  to  the  cortex,  and  on  making  microscopic 
sections  granules  of  the  pigment  are  found  within  the  lumen  and  in  the 
epithelial  cells  of  the  convoluted  tubules.  If  the  kidneys  have  been 
cauterised,  the  stain  is  confined  to  the  convoluted  tubules  of  the  cortex  only 
under  those  areas  which  have  been  cauterised,  and  where  the  glomerular 
functions  have  been  abolished.  It  has  been  suggested  that  the  appearances 
after  the  injection  of  indigo  are  due,  not  to  the  secretion,  but  to  the  absorp- 
tion of  water  in  the  convoluted  tubules.  A  certain  amount  of  the  dyestuff 
is  thus  rendered  visible  by  becoming  more  concentrated,  and  is  precipitated 
in  a  granular  form,  as  soon  as  the  salt  concentration  of  the  fluid  reaches  a 
certain  height.  The  fact  that  these  appearances  are  wanting  after  the 
injection  of  ordinary  carmine,  which  stains  the  glomeruli  as  well  as  the 
tubules,  combined  with  the  histological  facts  mentioned  in  the  last  paragraph, 
render  this  a  somewhat  forced  explanation  ;  and  we  must  take  the  results 
of  the  injection  of  indigo-carmine  as  telling  rather  in  favour  of  a  secretory 
than  of  an  absorptive  function  on  the  part  of  the  convoluted  tubules. 

The  question  as  to  the  secretory  activity  of  the  kidney  can  be  attacked 
from  another  side.     The  glomerular  filtrate  can  contain  only  those  crystal- 


THE  SECRETION  OF  URINE  1U7 

loids  of  the  blood  which  are  diffusible  and  are  not  closely  combined  with 
its  colloidal  constituents.    Loewi  has  shown  that  in  this  connection  a  contrast 
is  to  be  drawn  between  the  behaviour  of  substances,  such  as  urea  or  sodium 
chloride,  and  certain  other  constituents  of  the  blood  such  as  phosphates  or 
sugar.     Any  increase  in  the  rate  at  which  the  glomerular  secretion  takes 
place  must  cause  a  corresponding  increase  in, the  total  amount  of  the  solid 
diffusible  constituents  of  the  blood-plasma  which  are  turned  out  within  a 
given  time.     Thus  every  diuresis  increases  the  total  output  of  chlorides  and  of 
urea.     On  the  other  hand,  a  diuresis  caused,  for  example,  by  drinking  large 
quantities  of  water  does  not  increase  the  total  output  of  phosphates  in  a 
given  time,  nor  does  it  increase  the  very  small  amount  of  sugar  which  is 
normally  excreted  by  the  kidneys.     If,  however,  sodium  phosphate  be 
previously  injected  into  the  blood,  then  any  diuresis  increases  the  output 
of  this  salt.     The  same  thing  holds  for  sugar.     If  an  excess  of  free  uncom- 
bined  sugar  be  present  in  the  blood,  either  in  consequence  of  intravenous 
injection  of  this  substance  or  as  a  result  of  previous  extirpation  of  the  pan- 
creas, any  form  of  diuresis  will  increase  the  rate  at  which  it  is  turned  out 
by  the  kidneys.     Loewi  concludes  that  phosphates,  which  must  be  present 
in  minimal  quantities  in  the  glomerular  transudate,  are  for  the  most  part 
secreted  by  the  activity  of  the  cells  of  the  convoluted  tubules.  Under  abnormal 
conditions,  e.g.  as  after  administration  of  phloridzin,  the  cells  of  the  kidneys 
can  be  excited  to  a  similar  activity  with  regard  to  sugar.     After  phloridzin 
injection  the  urine  contains  considerable  quantities  of  sugar,  but  the  rate  at 
which  the  sugar  is  secreted  is  not  affected  in  any  way  by  raising  the  rate  of 
urinary  secretion,  e.g.  by  the  injection  of  such  substances  as  sodium  sulphate, 
which  increases  the  rapidity  of  the  glomerular  process  of  transudation. 

ABSORPTION  BY  THE  RENAL  TUBULES.  The  experiments  of  Ribbert, 
mentioned  above,  in  which  removal  of  the  medullary  portion  of  the  kidney 
led  to  the  formation  of  an  increased  quantity  of  a  more  watery  urine,  points 
to  the  possession  by  the  tubules  of  a  power  of  absorbing  water.  We  have 
other  evidence  that  this  power  of  resorption  is  not  confined  to  water,  but 
may  affect  also  the  dissolved  constituents  of  the  glomerular  transudate.  It 
was  pointed  out  by  Meyer  that,  if  two  salts,  such  as  sodium  sulphate  and 
sodium  chloride,  were  present  at  the  same  time  in  the  glomerular  transudate, 
any  process  of  resorption  should  affect  chiefly  the  more  diffusible  salt,  namely, 
sodium  chloride.  Such  a  differential  resorption  would  account  for  the  much 
greater  diuretic  power  of  sodium  sulphate  as  compared  with  sodium  chloride. 
In  certain  experiments  Cushny  produced  a  diuresis  by  the  injection  of 
equal  parts  of  equivalent  NaCl  and  Na.^SOj  solutions  into  the  veins  of  a 
rabbit.  An  increased  flow  of  urine  was  produced  which  lasted  two  hours 
and  a  half.  The  chlorides  of  the  urine  rose  with  the  diuresis  and  reached 
their  maximum  at  the  height  of  the  urinary  flow.  They  then  sank,  and  in 
some  experiments  had  practically  disappeared  from  the  urine  towards  the 
end  of  the  observation.  The  concentration  of  the  sulphates,  however,  con- 
tinued to  rise  in  the  urine  to  the  end  of  the  experiment.  Thus  in  the  first  of 
two  identical  experiments,  when  the  rabbit  was  killed  at  the  height  of  the 


1148 


PHYSIOLOGY 


diuresis,  the  serum  contained  0-547  per  cent,  chlorine  and  0-259  per  cent, 
sulphate,  while  the  urine  contained  0-372  per  cent,  chlorine  and  0-546  per 
cent,  sulphate.  In  the  second,  in  which  the  rabbit  was  killed  when  the  rate 
of  the  urinary  flow  had  considerably  diminished,  the  serum  contained  0-493 
per  cent,  chlorine  and  0-191  per  cent,  sulphate,  while  the  urine  contained 
•094  per  cent,  chlorine  and  2-0  per  cent,  sulphate.  These  results  are  illus- 
trated in  Fig.  536. 


1 

1 

1 

n 

\ 

If 

V 

\ 

\ 

\ 

\ 

( 



\ 

\, 

; 

( 

1 

\ 

\N 

* 

\S 

\, 

1 

1 

\N 

v^ 

s 

jl 

1 

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if 

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V 

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N 

■^ 

m 

m 

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*-. 

.- 



^.. 

="" 

=—' 

/5  30  4-5  60  75  ^0  105  120  135 

Fig.  536.     Curves  showing  excretion  of  urine  (thick  line),  of  sulphate  molecules 

(SO                                                          /  CI 
-— ^,  thinline),  and  of  CI  molecules  ( ,  dottedline),  after  injection  of  50  c. c. 
96                                                          \35-5 
of  a  solution  containing  1  -775  grm.  Cl  and  4-8  grm.  SOj  per  100  c.c.    The  black 
line  along  the  base  marks  the  duration  of  the  injection.     (Cushny.) 

The  difference  between  the  two  salts  can  be  made  still  more  striking  if 
the  process  of  resorption  be  augmented  by  increasing  the  pressure  within 
the  tubules  by  partial  obstruction  of  one  ureter.  Thus  in  one  experiment, 
where  diuresis  was  produced  by  the  injection  of  30  c.c.  of  a  solution  con- 
taining 5-85  per  cent.  NaCl  +  14-2  per  cent.  Na2S04,  the  right  ureter  was 
partially  clamped  so  as  to  make  the  right  kidney  secrete  against  a  pressure 
of  31  mm.  Hg.     The  following  results  were  obtained  : 


Urine  c.c. 

01.  g. 

S04g. 

4.37  till  4.47 

)  Left  kidney         .... 
\  Right  kidney      .... 
Difference  (absorption) 

24 

8 

16 

0-0809 
0-0142 
0-0677 

0-1080 
0-0667 
0-0413 

We  must  conclude  that  the  tubular  epitheUum  possesses  the  power  of 
modifying  the  glomerular  transudate  not  only  by  the  absorption  of  water 


THE  SECRETION  OF  URINE  1U9 

but  also  by  the  absorption  of  dissolved  constituents,  and  that  the  relative 
permeability  of  the  cells  to  the  constituents  is  at  any  rate  one  factor  in  deter- 
mining the  substances  absorbed.  It  is  not,  however,  the  only  factor.  The 
function  of  the  kidney  is  to  preserve  the  normal  constitution  of  the  body 
fluids  by  turning  out  those  substances  which  are  abnormal  or  present  in  too 
great  an  amount.  The  behaviour  of  the  tubule  cells  with  regard  to  any  given 
substance  will  therefore  depend  to  a  certain  extent  on  the  previous  nutritive 
history  of  the  body. 

If,  for  instance,  in  consequence  of  the  administration  of  sodium  chloride 
in  large  quantities  to  the  animal  during  the  few  days  preceding  the  experi- 
ment, the  body  is  overloaded  with  this  salt,  it  becomes  an  abnormal  con- 
stituent and  the  kidney  secretes  a  urine  far  richer  in  sodium  chloride  than  is 
the  blood-plasma.  Moreover,  when  diuresis  is  produced  in  such  an  animal 
by  the  injection  of  equivalent  quantities  of  sodium  chloride  and  sodium 
sulphate,  there  is  no  diminution  of  the  NaCl  in  the  urine  towards  the  end  of 
the  diuresis,  but  its  percentage  rises  steadily  as  the  rate  of  urinary  flow 
diminishes.  On  the  other  hand,  a  total  deprivation  of  sodium  chloride 
extending  over  several  days,  although  not  altering  to  any  large  extent  the 
percentage  amount  of  this  salt  in  the  blood-plasma,  leads  to  a  total  dis- 
appearance of  the  salt  from  the  urine,  the  whole  of  the  sodium  chloride 
present  in  the  glomerular  transudate  being  absorbed  on  its  way  through  the 
urinary  tubules. 

It  has  been  suggested  that  the  effects  of  certain  diuretics  on  the  kidney, 
such  as  caffeine,  diuretine,  or  theocine,  may  be  largely  conditioned  not  so 
much  by  their  influence  on  the  glomerular  circulation  as  by  a  paralytic  eft'ect 
on  the  absorptive  functions  of  the  tubules.  According  to  Loewi,  on  injec- 
tion of  caffeine  or  diuretine,  the  increase  of  total  amount  of  urine  is  not 
accompanied  by  any  diminution  in  the  percentage  amount  of  NaCl.  Perhaps, 
however,  the  strongest  evidence  in  this  direction  is  afforded  by  an  experi- 
ment of  Pototzky.  A  rabbit  had  been  fed  on  a  diet  almost  totally  devoid 
of  chlorides,  and  was  therefore  excreting  a  urine  containing  only  -08  per 
cent.  NaCl.  Under  the  influence  of  diuretine  the  urine  was  increased  and 
the  concentration  of  the  NaCl  rose  to  0-64  per  cent.  The  same  increase  in 
the  percentage  amount  of  sodium  chloride  in  the  urine  has  also  been  observed 
after  the  injection  of  theocine,  which  has  therefore  been  specially  recom- 
mended as  a  diuretic  in  cases  of  dropsy,  where  a  diminution  of  the  salt 
content  of  the  body  is  a  valuable  means  for  the  diminution  of  the  dropsical 
fluid  present  in  the  tissue  spaces. 

THE  RENAL  MECHANISM 
What  conclusions  can  we  draw  from  this  mass  of  experimental  data 
as  to  the  functions  of  the  kidney  as  a  whole,  and  as  to  the  part  played  by 
its  various  constituent  elements  in  the  secretion  of  urine  ?  The  amazing 
adaptability  of  its  functions  to  the  needs  of  the  organism  has  been  abund- 
antly illustrated  in  the  facts  with  which  we  have  dealt.  Its  ordinary  activity 
is  determined  by  the  production,  as  a  result  of  the  normal  processes  of  meta- 


1150  PHYSIOLOGY 

bolism,  of  soluble  iion- volatile  substances  in  every  cell  of  the  body.  These 
substances,  together  with  the  excess  of  water  taken  in  with  the  food  above 
that  lost  by  respiration  and  cutaneous  transpiration,  are  turned  out  by  the 
kidney  as  urine.  The  activity  of  this  organ  must  therefore  be  determined  in 
the  first  place  by  cbemical  stimuli.  It  must  react  to  the  slightest  deviation 
from  normal  of  the  blood  composition  by  excreting  water  or  dissolved 
substances.     This  dehcate  sensibihty  is  displayed  in  two  directions  : 

(1)  Under  the  influence  of  certain  substances,  such  as  urea,  uric  acid, 
or  water,  the  cells  of  the  convoluted  tubules  take  up  the  substance,  which 
is  in  excess,  from  the  surrounding  lymph  and  accumulate  it  in  vacuoles, 
which  are  discharged  on  the  inner  surface  of  the  cells  into  the  lumen  of  the 
tubules. 

(2)  Besides  this  specific  secretory  activity  of  the  cells  of  the  convoluted 
tubules,  the  tubules  as  a  whole  are  endowed  with  the  power  of  absorbing 
both  water  and  dissolved  substances  from  the  fluid  in  their  lumen.  Whether 
this  absorptive  power  is  Hmited  to  the  cells  of  Henle's  loop,  as  was  first 
suggested  by  Ludwig,  or  occurs  coincidently  with  secretion  in  the  cells  of  the 
convoluted  tubules,  as  might  be  imagined  from  the  close  analogy  between 
the  structure  of  these  cells  and  that  of  the  intestinal  epithehum,  we  have 
not  sufiicient  evidence  to  decide.  We  do  know,  however,  that  the  quality 
of  the  absorption  is  strictly  regulated  according  to  the  needs  of  the  organism, 
so  that  the  constituents  which  are  precious  are  reabsorbed  for  service  in  the 
body,  while  those  which  are  in  excess  or  are  of  no  value  to  the  organism 
are  allowed  to  pass  out  into  the  ureters.  The  process  of  resorption  is 
indeed,  as  is  shown  by  Cushny's  experiments,  largely  dependent  on  the 
physical  qualities  of  the  substances  undergoing  absorption,  and  especially 
on  the  permeabihty  of  the  renal  cells  to  these  substances.  The  physical 
conditions  are,  however,  subordinated  to  the  physiological,  so  that  a  salt  so 
diffusible  as  potassium  iodide  is  left  in  the  fluid,  while  sodium  chloride  may 
be  reabsorbed  in  large  quantities. 

The  necessity  for  the  endowment  of  the  tubular  epithelium  with  a  resorp- 
tive  as  well  as  a  secretory  function  is  determined  by  the  presence  at  the 
beginning  of  the  tubule  of  a  mechanism — the  glomerulus,  devoid  of  the 
fine  selective  power  or  chemical  sensibihty  possessed  by  the  cells  of  the 
convoluted  tubules.  The  production  of  urine  by  the  glomerulus  is  ap- 
parently regulated  entirely  by  the  pressure  and  velocity  of  the  blood  through 
its  capillaries  and  by  the  colloid  content  of  the  blood-plasma.  We  may 
assume  that  in  Bowman's  capsule  there  is  under  normal  conditions  a  constant 
production  of  a  fluid  free  from  protein,  but  having  the  same  crystalloid 
concentration  as  the  blood-plasma.  With  any  rise  of  general  blood -pressure 
the  amount  of  this  transudate  is  increased  ;  with  any  fall  it  is  diminished. 
The  small  qualitative  changes  which  are  constantly  occurring  in  the  blood 
as  the  result  of  the  taking  of  food  or  the  activity  of  different  organs,  probably 
produce  but  little  effect  on  the  amount  of  glomerular  fluid.  Only  indirectly, 
as  the  result  of  these  events  on  the  general  blood-pressure,  or  possibly  in  con- 
sequence of  the  production  of  substances  having  a  vaso-dilator  effect  on 


THE  SECRETION  OF  URINE  1151 

the  renal  vessels,  will  the  amount  of  the  urine  turned  out  b}^  the  glomeruli 
be  affected.  These  structures  therefore  have  the  twofold  function  of 
regulating  the  total  amount  of  circulating  fluid  and  of  providing  an  in- 
different fluid,  which  will,  so  to  speak,  flush  the  kidney  tubules  and  carry- 
down  any  constituents  excreted  in  a  concentrated  form  by  the  cells  of  these 
tubules.  The  constant  production  of  a  glomerular  transudate  might  result, 
especially  in  terrestrial  animals,  in  the  loss  to  the  organism  of  water,  or, 
under  certain  nutritive  conditions,  of  substances  indispensable  as  normal 
constituents  of  the  serum,  such  as  sodium  chloride,  which  could  not  be  made 
good  at  the  expense  of  the  food.  It  is  for  this  reason  that  an  absorptive 
mechanism  sensitive  to  and  reflecting  the  nutritive  condition  of  the  whole 
body,  especially  as  concerns  water  and  salts,  should  be  present  in  the  tubules. 
As  the  result  of  the  complementary  processes  of  absorption  and  secretion  in 
the  tubules,  the  unchanging  glomerular  filtrate  undergoes  great  modifica- 
tions in  its  passage  towards  the  ureter.  It  receives  urea,  uric  acid,  phos- 
phates, and  under  certain  conditions  water,  from  the  cells  of  the  convoluted 
tubules.  It  gives  up  salts,  especially  sodium  chloride,  and  generally  water 
to  the  same  or  other  cells  of  the  tubules.  So  that  finally,  instead  of  a  fluid 
isotonic  with  the  blood  and  containing  only  about  0-1  per  cent,  urea,  we 
have  a  fluid  of  deep  yellow  colour,  with  a  molecular  concentration  four  or  six 
times  greater  than  that  of  the  blood,  and  containing  between  2  and  3  per 
cent.  urea.  We  have  at  the  present  time  no  means  of  judging  the  relative 
amounts  of  fluid  furnished  respectively  by  the  glomeruli  and  the  tubules  to 
the  fully  formed  urine.  It  is  probable  that,  under  ordinary  circumstances, 
the  processes  of  secretion  and  absorption  of  fluid  go  on  pari  passu  in  the 
urinary  tubules  just  as  they  do  in  the  mucous  membrane  of  the  small  in- 
testine. The  demonstration  of  secretory  powers  in  the  cells  of  the  con- 
voluted tubules  relieves  us  from  the  necessity  of  the  assumption  made 
by  Ludwig  as  to  the  quantity  of  fluid  normally  turned  out  through  the 
glomeruli.  On  the  hypothesis  that  the  sole  function  of  the  tubules  was  one 
of  absorption,  and  that  all  the  urinary  constituents  were  derived  from  the 
glomerular  transudate,  thirty  litres  of  fluid  would  have  to  be  filtered  through 
the  glomeruli  in  order  to  excrete  the  30  grm.  urea  which  is  the  daily  output 
of  a  man.  Of  these  thirty  litres,  twenty-eight  litres  would  have  to  be 
reabsorbed  in  tho  tul)ules.  Since  the  amount  of  blood  flowing  through  the 
two  kidneys  in  a  man  probably  vaiies  between  1()00  and  1800  litres  in  the 
twenty-four  hours,  there  would  be  no  difficulty  in  the  production  of  such  an 
amount  as  thiity  litres,  which  would  only  represent  a  concentration  in  the 
blood  in  its  passage  through  the  glomeruli  of  under  2  per  cent.  The  secre- 
tion and  reabsorption  of  such  large  (|uantities  of  fluid  seem,  however,  a 
clumsy  way  of  arriving  at  a  urine,  whose  composition  should  be  adopted 
to  the  needs  of  the  animal  ;  and  as  we  have  seen,  the  occurrence  of  an  actual 
secretion  of  urea  by  the  cells  of  the  tubules  removes  the  necessity  for  assum- 
ing any  such  wasteful  proceeding.  It  is  probabh^  that  the  actual  amount  of 
the  glomerular  filtrate  in  the  twenty-four  hours  may  not  exceed  to  anv  large 
extent  the  actual  amount  of  urine  formed  by  the  whole  kidney  in  this  time. 


SECTION  III 

THE  PHYSIOLOGY   OF   MICTURITION 

The  urine  as  it  is  formed  passes  through  the  ureters  to  the  bladder,  where 
it  gradually  accumulates,  and  is  voided  at  intervals. 

The  ureters  are  muscular  tubes  hned  by  transitional  epithehum.  The 
muscular  coat  is  composed  of  three  layers  of  unstriated  fibres,  a  middle 
circular  coat  lying  between  external  and  internal  longitudinal  coats.  If 
the  ureter  be  exposed  in  the  living  animal,  contraction  waves  are  seen  to 
pass  along  its  muscular  coat  from  the  pelvis  of  the  kidney  to  the  bladder, 
driving  the  contained  fluid  in  front  of  them.  The  frequency  of  the  con- 
tractions is  increased  by  warming  the  ureter,  and  to  a  certain  extent  by 
distension,  so  that  the  waves  are  more  frequent  when  the  secretion  of  urine 
is  profuse.  The  ureters  enter  the  bladder  at  or  near  its  base,  at  the  two 
posterior  angles  of  the  region  known  as  the  trigonum.  Their  entrance  is 
oblique,  so  that  a  valvular  orifice  is  formed,  which  effectively  prevents 
reflux  of  urine  from  bladder  to  ureter.  Rhythmic  waves  of  contraction  are 
observed  also  in  the  excised  ureters,  when  these  are  kept  warm  in  normal 
saline  solution.  By  Engelmann  they  were  regarded  as  myogenic,  since  they 
were  present  in  the  middle  third  of  the  ureter,  which  he  imagined  to  be 
entirely  free  from  ganghon-cells.  As  a  matter  of  fact  ganghon-cells  are 
found  throughout  the  ureter,  though  in  larger  numbers  at  its  two  ends.  The 
ureters  are  supplied  with  nerve  fibres  from  the  splanchnic  nerves  by  way 
of  the  renal  plexus,  and  at  their  lower  ends  from  the  hypogastric  nerves. 
Stimulation  of  the  latter  as  a  rule  increases  the  rhythm  of  the  contraction 
presented  by  the  lower  end  of  the  ureter.  The  splanchnic  nerves  have  been 
stated  to  produce  either  acceleration  or  inhibition  of  the  contractions  at  the 
upper  end  ;  their  action  is,  however,  uncertain.  It  is  by  the  rhythmic 
advancing  waves  of  contraction  of  the  ureter  that  the  urine  is  continuously 
passed  on  to  the  bladder,  so  that  the  pelvis  of  the  kidney  is  kept  empty  of 
fluid  whatever  the  position  of  the  animal. 

The  bladder  is  lined  by  transitional  epithelium,  closely  adherent  to  the 
underlying  muscular  coat.  It  is  usual  to  describe  in  the  latter  three  layers 
of  muscular  fibres  : 

(1)  An  outer  layer  composed  of  bundles  running  longitudinally  from 
the  neck  of  the  bladder  to  the  fundus,  sometimes  distinguished  by  the 
name  of  the  detrusor  urince.  At  the  neck  of  the  bladder  these  bundles  send 
some  fibres  to  be  attached  to  the  pubes  as  the  pubo- vesical  muscles.     On 

1152 


THE  PHYSIOLOGY  OF  MICTUKITION  1153 

the  dorsal  surface  some  bundles  in  the  male  pass  on  to  the  prostate  and  the 
urethra,  while  in  the  female  they  end  in  the  tough  connective  tissue  in  the 
urethro- vaginal  septum. 

(2)  The  middle  layer,  which  is  the  thickest  of  the  three,  is  composed 
of  fibres  arranged  circularly  and  forming  a  continuous  layer. 

(3)  The  inner  layer  is  thin  and  incomplete,  and  is  composed  of  anasto- 
mosing bundles  of  fibres  with  meshes  in  between  them  which  are  covered 
by  the  folds  of  the  mucous  membrane.  The  bundles  of  fibres  run  freely 
from  one  layer  to  the  other,  and  there  is  no  doubt  that  the  name  of  detrusor 
ought  physiologically  to  be  applied  to 

the  whole  of  the  three  coats,  which  act 
as  one  in  diminishing  the  capacity  of 
the  bladder.  At  the  base  of  the  blad- 
der the  structure  of  the  wall  is  modified 
over  the  triangular  region  lying  between 
the  orifices  of  the  ureters  and  of  the 
urethra  (the  trigonum)  by  the  differen-  Ureter-- - 
tiation  here  of  fibres  which  serve  as  a 

sphincter   and   prevent  the  escape   of  _ 

•  rx         ^1,    4-  •  +1  Prosrate- 

urine.     Over  the  trigonum  the  mucous 

membrane  of  the   bladder   is    smooth  Memb.- 

and  closely  adherent  to  the  subjacent  Bulb 

muscular  fibres,  which  themselves  are  Fig.  537, 

much  more  closely  packed  than  the  rest 

of  the  bladder  wall.  From  these  muscular  fibres  the  most  important  sphincter, 
the  sphincter  trigoni,  is  formed.  Bundles  of  muscle  fibres  pass  from  the 
trigonal  muscle  obhquely  forwards  and  downwards  (the  individual  being  con- 
sidered in  the  erect  posture),  and  form  a  loop  around  the  orifice  of  the  bladder, 
lying  on  the  ventral  side  of  the  bladder  below  and  quite  distinct  from  the 
thick  coat  of  circular  fibres  belonging  to  the  bladder  itself  (ss.  Fig.  537). 

This  sphincter  is  the  most  important  mechanism  for  the  retention  of 
urine.  If  a  catheter  be  passed  into  the  urethra  no  urine  escapes  until  its 
orifice  has  actually  entered  the  bladder.  The  wall  of  the  urethra  is  sur- 
rounded by  circular  muscular  fibres,  which,  by  their  tonic  contraction,  will 
also  tend  to  prevent  the  escape  of  urine  along  the  canal.  This  urethral 
muscle  is  strengthened  by  two  sphincter  muscles  which  are  voluntary  and 
composed  of  striated  fibres.  The  chief  one,  which  has  been  named  by 
Kalischer  the  sphincter  urogenitalis,  but  is  better  known  as  the  compressor 
urethrce,  forms  a  flat  ring  around  the  second  part  of  the  urethra,  extending 
in  the  male  from  the  prostate  to  the  bulb,  where  its  function  is  taken  up 
by  the  bulbo-cavernosus. 

The  bladder  is  therefore  supplied  with  a  powerful  muscular  wall,  the 
contraction  of  which  will  cause  its  evacuation,  and  with  sphincters  of  two 
kinds,  one  involuntary,  the  sphincter  trigoni,  at  the  upper  neck  of  the 
bladder,  and  two  voluntary,  the  sphincter  urogenitalis  and  bulbo-cav.^rnosus 
muscles,  which  can  emptv  the  lower  parts  of  the  urethra. 

37 


1154 


PHYSIOLOGY 


The  nerve-supply  of  the  bladder  (Fig.  539)  is  derived  from  two  main 
sources,  namely,  from  the  upper  four  lumbar  nerves  through  the  sympa- 
thetic system,  and  from  the  second  and  third  sacral  nerves  by  means  of 


Ant.  long  m. 
Circular  muse. 

Pubo-vesical  m. 
Symphysis 


Ant.  circular  m 

Ant.  long.  m. 

Os  pubis 
Sphincter  urogenitalis 


Circular 
longitudinal 


Os  pubis 


Circular  coat 
Longitudinal  coat 

Sphincter  trigoni 
Prostate 


Circular  coat 
Longitudinal  coat 


Sphincter  trigoni 


Circular  coat 
Longitudinal  coat 

Sphincter  trigoni 
Longitudinal  muscle 

Fibres  running  to  urethro- 
vaginal st'ijtum 


Fig.  538.     Sagittal  sections  through  neck  of  bladder. 
(Metzner  after  Kalischee.) 
A,  in  middle  line  (male)  ;  b,  slightly  to  left  of  middle  line  (male)  ; 
c,  ditto  (female). 

the  pelvic  visceral  nerves  or  nervi  erigentes.  The  upper  lumbar  nerves 
send  white  rami  communicantes  to  the  lateral  chain  of  the  sympathetic, 
and  thence  to  the  collateral  ganglia,  which  are  grouped  round  the  inferior 
mesenteric  artery  to  form  the  inferior  mesenteric  ganghon.  Most  of  the 
fibres  end  in  this  collection  of  ganglion-cells,  and  a  new  relay  of  axons  passes 
by  two  main  trunks,  the  hypogastric  nerves,  into  the  pelvis  on  each  side  of 


THE  PHYSIOLOGY  OF  MICTURITION 


1155 


the  rectum  and  ends  in  a  plexus,  the  hypogastric  plexus,  at  the  base  of  the 
bladder.  From  this  plexus  fibres  pass  to  the  bladder  wall.  The  pelvic 
visceral  nerves  are  derived  from  the  second  and  third  sacral  nerves.  They 
make  no  connection  with  the  sympathetic  system,  but  pass  directly  to  the 

J 

lO'l 3rd  lumb.  vert. 

'11       I  I  ^r-  ~- 

■  1        1     '         't 

Sup.  lufs.  ganglion. 


Sup.  ines.  uf rVL's 

Median  mcs.  nerves 

Inf.  mcs.  nerve 


Inf.  mes.  ganglion (^ 


ilyiJDgastric  nerve 


llecf  lun 


.Sacral  nerves 


Ym.  539.     Nerve  supply  to  blatklcr  of  cat.     (Nawrocki  and  Skabitschewsky.) 

hypogastric  plexus  and  are  carried  with  branches  of  this  plexus  to  the  neck 

of  the  bladder.  The  fibres  do  not  run  directly  from  the  spinal  cord  to  their 
ending  in  the  bladder  wall,  but  make  connection  with  cells  situated  peri- 
pherally, partly  in  the  hypogastric  plexus,  but  chiefly  in  the  walls  of  the 
bladder  itself.  Both  sets  of  fibres  supply  also  the  rectum  and  the  colon, 
and  carry  efi'erent  impulses  to  the  bladder.  Aft"erent  impulses  from  the 
bladder  travel  chiefly  in  the  pelvic  visceral  nerves. 

THE   FILLING  OF  THE   BLADDER 
Under  normal  circumstances  the  sphincters  at  the  neck  of  the  bladder  are 
in  a  state  of  tonic  contraction,  presenting  a  resistance  to  the  empt\nng  of 


1156  PHYSIOLOGY 

this  organ  which  will  vary  according  to  their  degree  of  contraction.  Thus  it 
requires  a  considerably  greater  pressure  in  the  bladder  to  overcome  the 
resistance  of  the  sphincters  during  Hfe  than  after  death  of  the  animal.  In 
some  cases  after  death  they  may  permit  the  passage  of  urine  when  the 
pressure  of  the  bladder  is  only  about  20  mm.  water,  whereas  in  the  normal 
animal  the  pressure  has  as  a  rule  to  be  at  least  160  mm.  of  water  before  any 
escape  takes  place.  The  urine  therefore  as  it  is  secreted  must  accumulate 
and  distend  the  bladder.  The  bladder  wall  reacts  to  a  distending  force  in 
the  manner  which  is  characteristic  of  all  muscular  tissue,  especially  un- 
striated.  An  extending  force  apphed  to  an  unstriated  muscle  fibre  has  a 
double  effect.  In  the  first  place,  if  the  stretching  force  is  apphed  very 
slowly,  a  considerable  increase  in  length  of  the  muscle  may  occur  with  the 
application  of  a  very  small  amount  of  force.  If,  however,  the  force  be 
applied  more  rapidly,  the  sudden  increase  of  tension  acts  as  a  direct  excitant 


U.B. 


_20-'  ^ 

^/'\AA.VX^AUAAAAA/X\AAAA^^^A^AAVMAV^vAA^/^^AMW 

Fig.  540.     Tracings  of  rhythmic  contractions  of  urinary  bladder. 
(Sherrington.) 

to  the  muscle,  causing  it  to  enter  into  contraction,  which  may  be  tonic  or 
rhythmic.  The  effect  of  the  entry  of  urine  into  the  empty  bladder  on  the 
tension  in  this  organ  will  depend  therefore  on  the  rapidity  with  which  the 
kidneys  are  secreting.  Under  normal  circumstances  micturition  occurs 
in  man  when  the  intravesical  pressure  has  risen  to  about  150  mm.  water. 
Under  these  conditions  the  bladder  will  contain  between  230  and  250  c.c. 
of  urine.  If,  however,  the  secretion  of  urine  has  occurred  very  rapidly,  the 
same  pressure  may  be  attained  with  a  much  smaller  bladder  content,  and  if 
the  bladder  be  artificially  distended  by  the  injection  of  fluid  through  a 
catheter,  50  c.c.  of  fluid  may  suffice  to  raise  the  pressure  to  this  level.  As  the 
urine  is  slowly  secreted,  the  bladder  wall  at  first  gives  to  the  incoming  fluid, 
so  that  a  considerable  amount  can  be  stored  without  any  marked  rise  of  pres- 
sure. Later  on  the  pressure  begins  to  rise  more  rapidly,  and  finally  attains 
a  pressure  of  between  120  and  150  mm.  water.  At  this  point  the  second 
effect  of  the  stretching  of  the  muscular  wall  makes  its  appearance.  A  mano- 
meter connected  with  the  bladder  shows  a  series  of  rhythmic  contractions 
of  the  muscular  wall  (Fig.  540),  each  lasting  about  a  minute,  at  first  slight 
in  extent,  but  becoming  more  marked  as  the  distension  of  the  bladder 
augments.  In  a  bladder  entirely  cut  off'  from  its  connection  with  the 
central  nervous  system  these  automatic  rhythmic  contractions  gradually 


THE  PHYSIOLOGY  OF  MICTURITION  1157 

increase  in  force  until  one  of  them  suffices  to  overcome  the  resistance  pre- 
sented by  the  tonically  contracted  sphincter.  A  partial  emptying  of  the 
bladder  therefore  takes  place,  but  the  pressure  falls  below  that  necessary  to 
overcome  the  resistance  of  the  sphincter  before  the  bladder  has  been  quite 
emptied,  so  that  there  is  always  under  these  circumstances  a  certain  amount 
of  residual  urine  left  in  the  bladder.  This  is  the  condition  found  in  animals 
where  the  lower  part  of  the  spinal  cord  has  been  extirpated,  or  in  man  where 
the  same  part  of  the  central  nervous  system  has  been  destroyed  as  the  result 
of  accident  or  disease. 


THE  MECHANISM  OF  EVACUATION  OF  THE   BLADDER 

In  the  denervated  bladder  the  factor  finally  causing  partial  evacuation 
is  the  gradual  increase  in  the  intravesical  tension  from  the  accumulation  of 
fluid  in  this  viscus.  The  same  factor  is  prepotent  in  determining  the  onset 
of  normal  micturition  in  an  animal  with  the  nervous  connections  of  its 
bladder  intact.  Apart  from  the  control  of  the  higher  centres,  micturition 
will  take  place  each  time  that  the  tension  in  the  bladder  has  reached  a 
certain  height,  i.e.  about  15  cm.  water,  the  amount  of  fluid  in  the  bladder 
at  the  time  depending  on  the  one  hand  on  the  rate  at  which  the  fluid  has 
entered  this  organ  from  the  ureters,  on  the  other  hand  on  the  irritability 
of  the  bladder  wall  itself  and  of  the  nervous  centres  concerned  with  its  motor 
innervation.  The  efi'ect  of  the  gradual  accumulation  of  fluid  and  rise  of 
tension  is  twofold.  In  the  first  place,  it  acts  on  the  bladder  wall,  causing 
rhythmic  contractions  of  ever-increasing  intensity  ;  in  the  second  place,  the 
mere  stretching  of  the  bladder  originates  impulses  in  the  sensory  nerve- 
endings  in  its  wall,  which  are  reinforced  at  every  rise  of  tension  caused 
by  the  rhythmic  contractions.  These  impulses  travel  up  to  the  spinal 
centres,  and  are  summated  until  they  result  in  a  sudden  discharge  of  efterent 
impulses  of  two  kinds,  namely  : 

(1)  Motor  impulses  to  the  whole  musculature  of  the  fundus  of  the 
bladder  (the  detrusor  in  its  widest  sense) ; 

(2)  An  inhibition  of  the  tonic  contraction  of  the  sphincter.  This  in- 
hibition may  be  determined  by  inhibitory  impulses  travelling  to  the  sphincter 
and  causing  its  relaxation,  or  by  the  central  inhibition  of  the  impulses 
nornially  going  to  the  sphincter  and  maintaining  its  tonic  contraction.  The 
resultant  of  these  two  processes,  the  contraction  of  the  detrusor  and  the 
relaxation  of  the  sphincter,  is  a  complete  emptying  of  the  bladder,  and  the 
act  is  completed  by  the  contraction  of  the  involuntary  and  voluntary 
nniscles  surrounding  the  urethra  and  causing  complete  expulsion  of  the 
contents  of  this  tube. 


THE  INNERVATION  OF  THE   BLADDER 

ACTION  OF  THE  PELVIC  VISCERAL  NERVES.     In  all  animals  excita- 
tion of  the  peripheral  end   of  one   pelvic  visceral  nervo  causes  a   strong 


1158 


PHYSIOLOGY 


contraction  of  the  same  side  of  the  bladder,  involving  all  its  coats  and  some- 
times extending  to  a  slight  extent  to  the  contralateral  half  of  the  bladder. 
When  both  pelvic  nerves  are  stimulated  simultaneously  contraction  of  both 
sides  of  the  bladder  causes  a  considerable  rise  of  pressure  in  its  interior 
(Fig.  541)  which  is  always  sufficient  to  overcome  the  resistance  of  the 
sphincter  and  to  cause  a  complete  emptying  of  the  bladder.  There  is  no 
doubt,  therefore,  that  these  nerves  are  the  most  important  for  the  act  of 
micturition.  As  to  the  action  of  these  nerves,  however,  on  the  sphincter  the 
results  of  difierent  experimenters  are  somewhat  at  variance.  In  the  cat 
there  seems  to  be  no  doubt  that  inhibition  of  the  sphincter  may  result  from 
stimulation  of  the  pelvic  visceral  nerves.  On  the  other  hand,  Fagge, 
working  on  the  dog,  found  that  although  micturition  was  excited  by  the 
stimulation  of  these  nerves,  the  expulsion  of  urine  did  not  occur  until  the 


Fig.  541.     Curve  showing  rise  of  pressure  in  the  bladder  caused  by  stimulation 
of  s,  sacral  nerves  ;  h,  hypogastric  nerves.     (Fagge.) 
The  scale  indicates  centimetres  of  water. 

intravesical  tension  had  reached  the  point  at  which  the  resistance  of  the 
sphincter  could  be  overcome  without  any  alteration  of  its  state  of  con- 
traction, i.e.  the  point  at  which  fluid  injected  into  the  bladder  through 
the  ureter  began  to  escape  from  the  urethra  without  stimulation  of  any 
nerves  whatever. 

Observations  on  man  would  support  the  view  that  an  active  relaxation  of 
the  sphincter  trigoni  is  a  necessary  part  of  the  act  of  micturition.  Thus  in 
experiments  by  Reyfisch  a  rigid  catheter  was  introduced  into  the  bladder, 
which  was  fully  distended  with  fluid.  On  withdrawing  the  catheter  until  its 
opening  lay  just  outside  the  bladder  in  the  posterior  urethra,  the  flow  of 
urine  stopped.  The  man,  however,  was  able  to  micturats  directly  he  was 
told  to,  and  to  stop  again  at  will.  It  was  impossible  in  this  case  for 
any  of  the  urethral  muscles  to  be  concerned,  since  the  rigid  catheter 
impeded  their  action.  The  relaxation  of  the  sphincter  must  therefore 
be  brought  about  by  impulses  descending  the  pelvic  visceral  nerves, 
which  we  may  regard  as  motor  to  the  '  detrusor  '  and  inhibitory  to  the 
sphincter  of  the  bladder. 


THE  PHYSIOLOGY  OF  MICTURITION  Jill) 

tSection  of  the  nerve  on  one  side  causes  no  abnormality  in  micturition. 
After  three  weeks,  stimulation  of  the  intact  nerve  causes  contraction  of  the 
whole  bladder,  owing  to  the  outgrowth  of  preganglionic  fibres  from  the  sound 
trunk  to  the  decentralised  ganglia  of  the  opposite  side  (Elliott).  Section  of 
both  nerves  paralyses  micturition,  but  power  of  partial  evacuation  of  the 
bladder  may  return  in  a  few  weeks.  If  now  the  hypogastrics  be  cut,  or 
even  the  sacral  corcl  extirpated,  the  bladder  is  not  completely  paralysed,  but 
its  evacuation  becomes  unconscious  and  incomplete. 

ACTION  OF  THE  HYPOGASTRIC  NERVES.  These  nerves,  which 
are  derived  from  the  sympathetic  system,  show  marked  differences  in  their 
action,  according  to  the  animal  which  is  the  subject  of  investigation.  In 
the  dog  the  hypogastric  nerves  cause  a  strong  contraction  of  the  muscle 
fibres  at  the  base  of  the  bladder,  especially  of  the  trigonum  and  of  the 
sphincter  triijoni.  When  these  nerves  are  stimulated  simultaneously  with 
the  pelvic  visceral  nerves  a  great  rise  of  intravesical  tension  may  be  induced 
without  any  flow  of  urine  taking  place.  In  some  cases  prolonged  stimulation 
of  these  nerves  in  the  dog  causes  apparently  an  active  relaxation  of  the 
sphincter  of  the  bladder.  On  the  other  hand,  in  the  rabbit  and  the  cat 
these  nerves  cause  an  inhibition  of  the  bladder  wall.  In  other  animals 
they  may  excite  either  contraction  or  relaxation  (or  both)  of  the  detrusor. 
They  always  contain  motor  fibres  to  the  sphincter  of  the  bladder  as  well  as 
to  the  constrictor  fibres  surrounding  the  urethra.  Where  this  effect  is 
tonic  micturition  must  be  associated  with  a  central  inhibition  of  their  tonic 
activity.  On  the  other  hand,  the  retention  of  urine  and  the  distension  of 
the  bladder  may  be  aided  by  a  reflex  dilatation  of  the  bladder  wall  and  a 
reflex  constriction  of  the  sphincter  in  each  case  excited  through  these  nerves. 
Normally,  therefore,  both  sets  of  nerves  are  called  into  play.  The  hypo- 
gastrics play  an  especially  active  part  during  the  accumulation  of  urine 
in  the  bladder,  while  the  pelvic  visceral  nerves  are  necessary  for  the  complete 
evacuation  of  the  bladder  which  occurs  at  micturition. 


THE  CENTRAL  CONTROL  OF  THE  BLADDER 

The  nerve-centre  which  presides  over  the  toiuis  and  contraction  of  the 
bladder  is  situated  in  the  lumbo-sacral  spinal  cord.  If  this  centre  and  its 
connections  be  intact,  micturition  may  be  carried  out  normally  even  after 
section  of  the  cord  in  the  doisal  region.  The  centre  can  be  excited  reflexly 
by  stimulation  of  almost  any  sensory  nerve,  such  as  the  sciatic  or  the  fifth 
nerve.  In  many  cases  where,  in  consequence  of  obstruction  to  the  passage 
of  impulses  from  the  higher  parts  of  the  central  nervous  system,  micturition 
is  delayed,  this  act  may  be  excited  by  the  application  of  cold  or  hot 
sponges  to  the  perineum,  and  it  is  well  known  that  almost  any 
irritation  of  the  ])elvic  organs  in  children  nuiv  give  rise  to  refle.x 
involuntarv  micturition. 

In  the  adult  the  processes  of  retention  and  evacuation  of  urine  are 
modified  and  controlltMl  bv  voluntaiv  effort.     The  normal   action   of  the 


1160  PHYSIOLOGY 

sphincter  mechanism  may  be  aided  by  the  contraction  of  the  perineal 
muscles  which  keep  the  urethra  closed.  The  reflex  process  of  evacuation 
may  be  set  in  motion  by  voluntary  contraction  of  the  abdominal  muscles, 
by  which  the  pressure  in  the  bladder  is  increased  and  the  normal  sphincter 
action  overcome.  It  is  probable  too  that  the  individual  has  a  certain  degree 
of  voluntary  power  over  the  unstriated  muscles  of  the  bladder,  and  that  the 
contraction  of  the  muscular  wall  may  be  directly  augmented  by  impulses 
proceeding  from  the  cortex  to  the  upper  part  of  the  lumbar  cord.  This  view 
is  favoured  by  the  fact  that  stimulation  of  the  crus  cerebri  has  been  observed 
to  cause  contraction  of  the  detrusor  urinse.  In  this  experiment  the  abdo- 
men was  opened,  so  there  could  be  no  question  of  the  contraction  of  the 
abdominal  muscles. 


CHAPTER   XVIII 

THE   SKIN   AND   THE   SKIN-GLANDS 

In  all  classes  of  animals  the  skin  performs  two  functions.  In  the  first  place, 
it  serves  to  protect  the  more  delicate  underlying  parts  from  injury  and 
from  penetration  or  invasion  by  foreign  organisms.  In  the  second  place, 
it  serves  as  a  sense-organ,  and  is  richly  supplied  with  nerves,  by  means  of 
which  the  activities  of  the  body  as  a  whole  may  be  brought  into  relation 
with  the  changes  going  on  in  the  environment  and  affecting  the  external 
surface  of  the  body.  In  warm-blooded  animals  the  skin  plays  an  important 
part  in  the  regulation  of  the  body  temperature,  since  the  loss  of  heat  to 
the  body  must  occur  almost  entirely  through  its  surface.  In  the  present 
chapter  we  have  to  deal  only  wath  the  first  and  third  of  these  functions. 

The  development  of  the  skin  as  an  organ  of  protection  shows  wide 
modification  in  various  classes  of  animals.  Thus  it  may  become  the  seat  of 
formation  of  horny  plates,  as  in  the  alhgator  ;  of  poisonous  glands,  as  in 
the  toad  ;  or  of  mucous  glands,  as  in  many  varieties  of  fishes.  In  warm- 
blooded animals  the  development  of  hair  from  the  deeper  layers  of  the 
epidermis  serves  to  diminish  the  loss  of  heat.  Since  the  hair-folhcles  are 
richly  supplied  with  nerve  fibres,  the  hairs  act  also  as  organs  of  sensation. 
In  man,  where  the  hairs  are  rudimentary,  except  in  certain  localities, 
practically  only  this  tactile  function  is  retained.  The  external  layer  of  the 
skin  in  man  consists  of  a  tough  horny  layer  formed  by  the  keratinisation  of 
the  external  layers  of  cells  of  the  epidermis.  The  skin  is  composed  of  two 
parts,  the  epidermis  and  the  cutis  (Fig.  542).  The  epidermis  is  a  stratified 
squamous  epithelium.  The  deeper  layers  form  the  rete  mucosum,  being  soft 
and  protoplasmic,  while  the  superficial  layers  forming  the  cuticle  are  hard 
and  horny.  The  most  superficial  layer  of  the  rete  mucosum  is  formed 
of  flattened  cells  filled  with  granules  of  a  material  staining  deeply  with  ha-ma- 
toxylin  and  eosin,  known  as  eleidin.  This  layer  is  called  the  stratum  (jranu- 
losum.  Inunodiately  superficial  to  this  layer  is  another  in  which  the  cells 
are  indistinct.  The  cells  are  clear  in  section  and  form  what  is  known  as  the 
stratum  hicidu))i.  The^e  two  layers  evidently  form  the  intermediate  stages 
in  the  transformation  of  the  cells  of  the  rete  mucosum  into  the  horny  scales 
which  make  up  the  superficial  cuticle.  The  cutis  or  corium  is  composed  of 
dense  connective  tissue,  wliich  becomes  more  open  in  texture  in  its  deeper 
part,  where  it  merges  into  tlic  subentaneous  connective  tissue.  The  most 
sirperficial  layer  of  the  coilum  is  prolonged  into  miiuite  papilla?  over  which 

llGl  37* 


1162 


PHYSIOLOGY 


the  epidermis  is  moulded.  These  papillae  contain  for  the  most  part  capillary- 
vessels  ;  a  few  contain  touch  corpuscles,  special  organs  of  tactile  sensation. 
The  blood-vessels  of  the  skin  form  a  close  capillary  network  immediately  at 
the  surface  of  the  cutis,  sending  up  loops  into  the  papillse.  All  parts  of  the 
skin,  except  the  palms  of  the  hands  and  the  soles  of  the  feet,  are  beset  with 
hair-folhcles.  The  hair- follicles  are  small  pits  which  extend  downwards  into 
the  deeper  part  of  the  corium,  being  down-growths  of  the  rete  mucosum. 
The  hair  grows  from  a  small  papilla  of  cells  at  the  bottom  of  the  follicle,  the 


stratum 
corneum 
Stratum 
lucidum 
Stratum 
sranulosum 


Eete 
mucosum 


r  Cutis  vera 


Fig.  542.  Vertical  section  through  the  skin  of  the  palmar  side  of  the  finger,  showing 
two  papillse  (one  of  which  contains  a  tactile  corpuscle)  and  the  deeper  layer  of 
the  epidermis.     Magnified  about  200  diameters.     (Schafer). 

part  of  the  hair  lying  within  the  follicle  being  known  as  the  hair-root.  The 
hair  itself  consists  of  long  tapering,  horny  cells,  the  nuclei  of  which  are 
still  visible,  though  the  cell  substance  has  been  almost  entirely  converted 
into  keratin. 

In  order  to  keep  the  cuticle  supple  and  preserving  it  from  the  drying 
effects  of  the  atmosphere,  it  is  kept  constantly  impregnated  with  a  fatty 
material  known  as  sebum.  This  material  is  formed  by  the  sebaceous  glands, 
which  are  distributed  all  over  the  surface  of  the  skin  wherever  hair-folhcles 
are  to  be  found,  the  mouths  of  the  glands  opening  into  the  hair-follicles.  A 
sebaceous  gland  is  a  pear-shaped  body,  consisting  of  a  secreting  part  and  a 
short  neck,  opening  into  the  folUcle.  The  gland  proper  is  composed  of  a 
solid  mass  of  cells.     The  outermost  cells  are  flattened  and  generally  show 


THE  SKIN  AND  THE  SKIN-GLANDS  1163 

signs  of  proliferation.  The  cells  lying  internal  to  these  are  much  larger, 
and  their  protoplasm  is  transformed  into  a  network  in  the  meshes  of  which 
are  granules  which  may  show  the  reaction  of  fat.  Further  inwards  the 
protoplasmic  network  diminishes  in  amount,  while  the  fatty  granules  increase 
in  size,  so  that,  in  the  lumen  adjoining  the  duct,  we  find  only  a  mass  of  cell 
debris  and  masses  of  fatty  material.  It  has  often  been  thought  that  the 
secretion  of  sebum  depended  simply  on  a  fatty  degeneration  of  the  cells. 
The  granules,  however,  when  they  first  appear,  stain  with  acid  fuchsin 
rather  than  osmic  acid,  and  one  must  regard  the  formation  of  sebum  as  an 
act  of  true  secretion  in  which  the  secretory  granules  are  gradually  trans- 
formed into  the  special  constituents  of  the  sebum.  For  it  must  be  noted 
that  the  sebum  is  not  a  true  fat,  nor  does  it  correspond  in  composition  with 
the  fat  found  in  other  parts  of  the  body.  It  is  true  that  it  contains  fatty 
acids,  but  these  are  for  the  most  part  in  combination,  not  with  glycerin,  but 
with  higher  alcohols,  including  cholesterol.  A  somewhat  similar  material 
may  be  extracted  from  wool,  and  is  known  as  wool-fat  or  lanoline,  as  well 
as  from  the  feather-glands  of  water  birds,  such  as  the  goose  and  duck.  It 
must  be  regarded  rather  as  a  wax  than  a  fat.  It  presents  many  advantages 
over  ordinary  fat  as  a  protective  salve  for  the  surface  of  the  body.  In  the 
first  place,  it  can  take  up  a  large  amount,  as  much  as  100  per  cent.,  of  water. 
In  the  second  place,  it  is  not  attacked  by  micro-organisms,  so  that  it  does 
not  tend  to  become  rancid  or  to  furnish  a  nidus  for  the  growth  of  these 
organisms  on  the  surface  of  the  body. 

The  secretion  of  sebum  is  a  continuous  process,  though  it  is  probably 
Cjuickened  in  conditions  of  increased  vascularity  of  the  skin.  The  extrusion 
of  the  products  of  secretion  is  determined  by  the  presence  of  unstriated 
muscle  fibres,  the  arrector  piH,  which  pass  from  the  surface  of  the  cutis 
obliquely  over  the  outer  surface  of  the  sebaceous  gland.  When  these  muscle 
fibres  contract  the  hair  is  erected  and  a  certain  amount  of  the  sebum 
squeezed  out  on  to  the  root  of  the  hair  and  the  surrounding  skin.  This  con- 
traction will  occur  whenever  cold  is  suddenly  applied  to  the  skin.  The  con- 
tracted condition  of  all  the  muscles  of  the  hair-follicles  is  shown  by  the 
'  goose-skin '  produced  under  such  circumstances.  There  is  no  evidence 
that  the  secretion  of  sebum  is  in  any  way  under  the  control  of  the  central 
nervous  system. 

THE  SWEAT-GLANDS.  Under  normal  circumstances  in  temperate 
climates  the  greater  part  of  the  water  taken  in  with  the  food  in  the  course 
of  the  day  is  excreted  by  the  kidneys,  a  smaller  proportion  leaving  by  the 
lungs  and  by  the  surface  of  the  skin.  On  an  average  we  may  say  that  about 
700  CO.  are  got  rid  of  through  the  skin.  The  excretion  of  water  by  the  skin 
is,  however,  mainly  determined  by  the  need  for  regulating  the  temperature 
of  the  body,  so  that  the  amount  leaving  in  this  way  depends  on  the  heat 
production  of  the  body  or  on  the  external  temperature,  and  is  very  little 
aft'ected  by  alterations  in  the  quantity  of  fluid  drunk.  A  certain  amount  of 
water  is  constantly  evaporated  from  the  surface  of  the  body  as  the  so-called 
'  insensible  perspiration.'     If  a  man's  body  be  enclosed  in  a  vessel  through 


1164  PHYSIOLOGY 

which  a  current  of  air  is  passed,  and  the  temperature  of  the  air  gradually 
raised,  it  will  be  noted  that  the  amount  of  water  given  off  rises  slowly  up 
to  a  certain  degree  and  then  rises  rapidly.  The  sudden  kink  in  the  curve  is 
due  to  the  setting  in  of  the  activity  of  the  sweat-glands,  and  we  are  there- 
fore justified  in  regarding  the  insensible  perspiration  as  being  determined 
by  evaporation  of  water^from  the  surface  of  the  cuticle  itself  apart  altogether 
from  the  sweat-glands.  The  sweat-glands,  which  are  distributed  over  the 
whole  surface  of  the  skin,  are  especially  abundant  on  the  palm  of  the  hand 
and  on  the  sole  of  the  foot.  They  are  composed  of  single  unbranched 
coiled  tubes,  which  he  in  the  subcutaneous  tissue  and  send  their  ducts  up 
through  the  cutis,  to  open  on  the  surface  by  corkscrew-hke  channels  which 
pierce  the  epidermis.  The  secreting  part  of  the  tube  consists  of  a  basement 
membrane  lined  by  a  double  layer  of  cells  ;  the  innermost  of  these  are 
cubical  and  represent  the  secreting  cells  proper.  Between  the  secreting 
cells  and  the  basement  membrane  is  a  layer  of  unstriated  muscle  fibres., 
The  duct  of  the  gland  has  an  epithehum,  consisting  of  two  or  three  layers  of 
cells  with  a  well-marked  internal  cuticular  lining,  but  there  is  no  muscular 
layer. 

The  sweat  formed  by  these  glands  is  the  most  dilute  of  all  animal  fluids. 
As  collected  it  generally  contains  epithelial  scales  and  some  admixture  of 
sebum.  After  filtration  it  forms  a  clear  colourless  fluid  of  a  specific  gravity 
of  about  1003.  It  contains  over  99  per  cent,  of  water.  Among  the  sohd 
constituents  sodium  chloride  is  the  most  prominent — it  may  contain  from 
0'3  to  0-5  per  cent,  of  this  salt.  It  is  generally  hypotonic  as  compared  with 
the  blood-plasma.  It  may  also  contain  small  traces  of  protein.  This 
constituent  is  especially  marked  in  the  horse.  It  generally  contains  also  a 
small  quantity  of  urea,  which  may  become  a  prominent  constituent  in  cases 
of  renal  disease.  The  quantity  of  sweat  excreted  in  the  day  is  very  variable. 
The  secretion  is  under  the  control  of  the  central  nervous  system  and  is 
almost  entirely  adapted  to  the  regulation  of  the  body  temperature.  The 
nervous  mechanism  can  be  set  into  activity  either  centrally  or  reflexly. 
The  most  usual  factor  is  a  rise  of  the  body  temperature.  If  a  man  sit  in  a 
warm  room,  e.g.  of  a  Turkish  bath,  the  secretion  of  sweat  commences  as  soon 
as  the  temperature  of  the  body  has  attained  a  height  of  0-5°  to  1°  C.  above 
normal.  In  the  case  of  muscular  exercise  the  temperature  will  generally  be 
found  to  be  raised  if  it  be  taken  at  the  instant  that  sweating  has  commenced. 
The  effect  of  rise  of  temperature  may,  however,  be  either  local  or  central, 
so  that  one  arm  enclosed  in  a  hot-air  bath  may  sweat  while  the  rest  of  the 
body  is  dry.  Under  ordinary  circumstances  the  central  stimulation  by  the 
warm  blood  is  the  predominant  factor.  This  is  shown  by  an  experiment 
of  Luchsinger.  In  the  cat  sweating  is  to  be  observed  only  on  the  hairless 
pads  of  the  front  and  hind  paws.  If  one  sciatic  nerve  be  cut  and  the  animal 
be  placed  in  a  warm  chamber,  sweating  will  commence  as  the  temperature  of 
the  animal  rises  in  the  three  intact  paws,  while  the  paw  with  the  nerve  cut 
will  be  quite  dry.  Sweating  moreover,  as  has  been  shown  by  Kahn,  may 
be  induced  in  the  cat's  paws  by  warming  the  blood  passing  through  the 


THE  SKIN  AND  THE  SKIN-GLANDS  1165 

carotid  arteries  on  its  way  to  the  brain,  at  a  time  when  the  temperature  of 
the  blood  circulating  through  the  rest  of  the  body,  including  the  paws  them- 
selves, has  undergone  no  alteration.  Sweating  may  also  be  aroused  by 
asphyxia,  and  this  result  is  found  even  in  the  spinal  cat,  i.e.  after  separation 
of  the  spinal  centres  from  the  medulla.  The  secretion  of  sweat  resulting 
from  stimulation  of  the  sweat- nerves,  although  generally  associated  with 
increased  vascularity  of  the  skin,  is  not  in  any  way  dependent  thereon. 
Thus  even  in  the  amputated  limb  stimulation  of  the  sciatic  nerve  may  cause 
the  appearance  of  drops  of  sweat  on  the  pad  of  the  foot.  If  the  sciatic  nerve 
be  stimulated  in  the  intact  animal,  the  secretion  of  sweat  which  is  produced 
is  associated  with  constriction  of  the  vessels  of  the  skin,  due  to  simul- 
taneous stimulation  of  the  vaso-constrictor  nerves  running  in  the  sciatic 
nerve. 

As  Langley  has  shown,  the  sweat-nerves  run  entirely  in  the  sympathetic 
system.  Leaving  the  cord  by  the  white  rami  communicantes  from  the 
second  dorsal  to  the  third  or  fourth  lumbar  nerves,  they  pass  into  the 
sympathetic  chain.  Here  the  first  relay  of  fibres  ends  in  connection  with  the 
cells  of  the  sympathetic  ganglia,  and  a  fresh  relay  of  fibres,  which  are  non- 
medullated,  pass  from  the  cells  along  the  grey  rami  into  the  various  spinal 
nerves,  to  be  distributed  to  the  whole  surface  of  the  skin.  The  secretion  of 
sweat  by  the  sweat-glands  may  be  roused  by  the  injection  of  pilocarpine  even 
after  division  of  the  sweat-nerves,  so  that  this  drug  must  act  peripherally 
on  the  glands.  The  action  of  pilocarpine,  as  well  as  the  efiects  of  artificial 
stimulation  of  the  sweat-nerves,  is  abolished  by  the  administration  of 
atropine. 

THE  GASEOUS  EXCHANGES  OF  THE  SKIN.  In  any  animal  with  a 
thin  moist  skin,  such  as  the  frog,  the  absorption  of  oxygen  and  the  excretion 
of  CO2  from  the  skin  may  be  sufficient  for  the  proper  aeration  of  its  blood, 
so  that  it  may  continue  to  live  after  the  extirpation  of  its  lungs.  In  man 
there  is  also  a  continuous  output  of  CO2  through  the  skin,  but  the  amount 
leaving  the  body  in  this  way  is  negligible  compared  with  that  which  is 
exhaled  through  the  lungs.  The  loss  of  CO2  by  the  skin  rises  with  increase 
of  external  temperature.  Thus  at  a  temperature  of  29°  to  33°  C.  the  CO2 
output  by  the  skin  is  about  0-35  grm.  per  hour,  i.e.  about  8-4  grm.  in  the 
twenty- four  hours.  When  the  external  temperature  rises  above  33°  C, 
the  COo  output  increases,  so  that  at  34°  it  is  doubled  and  at  38-5°  it  may 
amount  to  as  much  as  1-2  grm.  per  hour  (Schierbeck).  It  is  just  at  this 
temperature  of  33°  C.  that  a  secretion  of  sweat  begins  to  be  noticeable,  so  it 
has  been  suggested  that  the  increased  CO2  output  may  be  due  directly  to  the 
increased  work  and  metabolism  of  the  sweat-glands  during  their  activity. 

ABSORPTION  BY  THE  SKIN.  In  order  to  test  the  alleged  influence  of 
baths  containing  medicinal  substances  in  solution,  many  experiments  have 
been  made  to  determine  whether  absorption  is  possible  by  the  skin.  It 
may  be  regarded  as  established  that  the  uninjured  skin  is  impermeable 
for  watery  solutions  of  salts  or  other  substances.  On  the  other  hand,  it  is 
possible  to  produce  a  certain  amount  of  absorption  by  the  inunction  of 


1166  PHYSIOLOGY 

substances  dissolved  in  fatty  vehicles.  Thus  the  administration  of  mercury- 
is  often  carried  out  by  the  inunction  of  mercurial  ointments,  and  the  fact  that 
mercurial  salivation  may  be  produced  in  these  conditions  shows  that  a  certain 
amount  of  the  mercury  must  have  been  absorbed.  It  is  difficult  to  imagine 
that  any  appreciable  amount  of  cod  liver  oil  will  be  available  for  the  nutrition 
of  the  infant  when  this  substance  is  administered  by  rubbing  it  on  the  skin. 
On  the  other  hand,  the  moist  mucous  surfaces,  such  as  the  conjunctiva  or 
the  mucous  membrane  of  the  respiratory  passages,  as  well  as  raw  surfaces  of 
the  skin,  e.g.  which  have  been  deprived  of  their  epidermal  layer  by  the 
apphcation  of  bhsters,  permit  of  the  rapid  passage  of  substances  in  watery 
or  oily  solution. 


CHAPTER  XIX 

THE   TEMPERATURE  OF  THE   BODY   AND   ITS 
REGULATION 

In  dealing  with  the  chemical  changes  in  the  body  as  a  whole  we  have  seen 
that  the  sum  of  the  metabolic  processes  is  associated  with  the  evolution 
of  heat.  In  man,  under  normal  circumstances,  while  doing  moderate  work, 
the  total  energy  requirements  amount  to  about  3000  calories.     The  whole 


CO 


120 
110 
100 
90 

y 

\ 

/ 

/ 

\ 

/ 

\ 

/ 

\ 

BO 
70 
SO 
50 

1 

\ 

/ 

\ 

/ 

\ 

/ 

r 

\ 

/ 

40 

A 

i 

\ 

/ 

\ 

30 

y 

»' 

\ 

20 

10 

G      ' 

^ 

^ 

A 

— 

A 

^ 

''n 

zs 


35 


40 


46        SO 


55 


60 


TCMPERATUftC 

Fu;.  5-1:5.     Effect  of  tcniperaturo  on  the  COo  output  of  a  lui)in  seedling. 
Orclinatcs  ~  milligrammes  CO2  per  hour.  Abscissae  =  temperature  in  degrees  Centigrade. 

of  this  is  derived  from  the  oxidation  of  the  food,  the  combination  of  its 
carbon  and  hydrogen  with  oxygen  to  form  CO.2  and  water,  with  the  evolu- 
tion of  the  corresponding  amount  of  energy.  Of  this  energy  only  a  small 
proportion,  on  the  average  about  one-twentieth,  leaves  the  body  as  mechani- 
cal energy,  the  rest  being  evolved  in  the  form  of  heat  and  being  expended 
in  the  maintenance  of  the  body  temperature,  or  in  the  warming  of  the 
surrounding  medium. 

1167 


1168 


PHYSIOLOGY 


The  evolution  of  heat  is  not  confined  to  the  higher  animals,  but  is  com- 
mon to  all  hving  beings.  It  is  very  evident,  for  instance,  in  the  germina- 
tion of  peas  or  barley.  The  atmosphere  of  a  bee-hive  is  often  ten  degrees 
above  that  of  the  surrounding  atmosphere.  Whenever  we  can  excite 
increased  activity  in  an  organ,  we  are  able  to  show,  except  in  the  single  case 
of  the  nerve  impulse,  that  such  activity  is  associated  with  the  evolution  of 
heat.  This  heat  is  derived  from  the  chemical  changes  which  proceed  in  the 
living  cells.  Since  all  chemical  processes  are  quickened  by  rise  of  tempera- 
ture, we  should  expect  to  find  that  the  heat  produced  in  the  metabolic  pro- 
cesses of  organisms  would  tend  in  itself  to  quicken  these  processes.  In  most 
chemical  reactions  a  rise  of  about  10°  C.  would  increase  the  velocity  of 
reaction  from  two  and  a  half  to  three  times,  and  the  same  rule  is,  within 
the  hmits  of  stability  of  hving  tissues,  found  to  hold  good  for  them  also.  The 
diagram  (Fig.  543)  shows  the  influence  of  temperature  on  the  chemical 
changes  in  a  lupin  seedhng  as  measured  by  the  output  of  CO 2  per  hour  per 
100  grm.  of  plant.  A  marked  increase  in  the  rate  of  chemical  decomposi- 
tion is  shown  to  follow  a  rise  of  temperature  ;  but,  about  40°  C,  the  rate  of 
change  is  at  an  optimum,  and  thereafter  rapidly  declines,  owing  to  the  fact 
that  the  hving  tissues  are  being  killed  by  the  excessive  temperature. 

Hence  in  the  animal  organism  we  shall  expect  to  find  that  the  rate  of  the 
metabohsm  is  also  proportional  to  the  temperature  of  the  animal.  This 
is  universally  the  case  whether  we  are  dealing  with  warm-blooded  or  cold- 
blooded animals.  In  '  cold-blooded  '  animals  the  temperature  of  the  body, 
and  therefore  the  rate  of  its  metabohsm  and  the  amount  of  its  heat  produc- 
tion, is  proportional  to  the  external  temperature  (Fig.  544).  The  following 
Table  gives  the  average  CO2  output  per  hour  of  five  hzards  placed  in  a 
chamber  which  could  be  maintained  at  varying  temperature  : 


Temperature 

Temperature  of 

CO3  produced 

of  bath 

lizards  (average) 

in  one  hour 

5-0°  C. 

5-5°  C. 

•0246 

9-0°  a 

9-2°  C. 

•0790 

15-0°  C. 

15-2°  C. 

•0981 

20-5°  C. 

20-4°  C. 

•1023 

25-0°  C. 

24-5°  C. 

•1193 

30-0°  C. 

29-3°  C. 

•1440 

35-0°  C. 

34-8°  C. 

•1814 

39-0°  C. 

38-5°  C. 

•5454 

It  might  be  thought  that  such  a  reaction  in  change  of  temperature  would 
result  in  a  vicious  circle.  Since  the  animal  is  continually  producing  heat  and 
thus  raising  its  temperature  above  that  of  its  surroundings,  one  might  expect 
to  find  that  the  higher  the  external  temperature  the  greater  would  be  the 
difference  between  this  and  the  temperature  of  the  animal,  until  finally  the 
latter  would  rise  to  such  a  height  that  the  animal  would  die  of  heat-stroke, 
its  tissues  being  destroyed  by  the  actual  temperature  attained.     A  certain 


THE  TEMPERATURE  OF  THE  BODY  1169 

protection  is  afforded  to  most  cold-blooded  terrestrial  animals  by  the  fact 
that  their  surface  is  moist,  and  that  with  a  rise  of  external  temperature  the 
rate  of  evaporation  on  the  surface  increases,  so  that  the  increase  in  the  rate 
of  cooling  bv  evaporation  more  than  corresponds  to  the  rate  of  increase  in 
the  heat  production,  which  would  tend  to  raise  the  body  temperature.  Most 
of  these  animals,  however,  escape  from  any  extreme  rise  of  external  tempera- 
ture by  burrowing  underground  or  taking  to  the  water,  while  in  plants  a  rise 
of  external  temperature  assists  transpiration  to  such  an  extent  that  the 


30' 


40 


0  10"  20^ 

^»>-^  External  temp.  C° 

Fig.  544.     Effect  of  alterations  in  the  temperature  of  the  surrounding  medium 
on  output  of  COo  in  cold-blooded  (poikilothermic)  animals.     (C.  J.  Martis.) 

temperature  of  the  plant  is  generally  several  degrees  below  that  of  the 
surrounding  atmosphere.  The  extreme  variability  in  the  metabohsm  of 
such  animals  implies  a  state  of  dependence  of  all  the  activities  of  the  body  on 
the  environment,  which  would  prevent  the  utiUsation  to  the  full  of  the 
available  sources  of  energy.  An  animal  whose  metabolism  was  more  or 
less  independent  of  the  surrounding  temperature  must  have  a  great  ad- 
vantage over  an  animal  liable  to  have  his  activities  reduced  and  paralysed 
by  a  sudden  spell  of  cold  weather  ;  this  greater  independence  of  the  environ- 
ment which  is  characteristic  of  elevation  of  type,  has  been  achieved  by  the 
warm-blooded  animals,  including  man.  Such  animals  are  often  spoken  of  as 
homoiotliermic,  i.e.  animals  possessing  a  uniform  temperature,  in  contra- 
distinction to  the  cold-blooded  animals,  which  are  poikilothennic  and  possess 
a  temperature  varying  with  that  of  their  surroundings. 

Amongst  the  warm-blooded  animals  the  body  temperature  may  be 
very  different  according  to  the  species.  In  birds  it  is  generally  from  39° 
to  40°  C.  ;  in  mammals  it  varies  from  35°  to  40°  C.  The  temperature  of 
man  varies  within  slight  limits  about  37°  C.  (98-4°  F.). 


1170  PHYSIOLOGY 

THE   DIURNAL  VARIATIONS  IN  THE  BODY  TEMPERATURE 

In  any  animal  the  seat  of  heat  production,  e.g.  a  contracting  muscle, 
must  be  warmer  than  an  inactive  tissue,  and  this  again  than  a  tissue  from 
which  heat  is  being  rapidly  abstracted,  such  as  the  skin.  Owing,  however, 
to  the  rapidity  of  the  circulation  of  the  blood,  the  temperature  of  the  internal 
organs  can  be  regarded  as  approximately  uniform.  The  temperature  of  man 
is  usually  taken  in  the  mouth,  rectum,  or  axilla.  In  the  case  of  the  mouth 
the  temperature  is  liable  to  fluctuation  with  the  rate  of  breathing,  the  mouth 
being  cooled  by  the  passage  of  the  air  through  the  nasal  cavities.  There  is 
also  probably  loss  of  heat  through  the  cheeks.  In  order  to  determine  the 
temperature  in  this  situation  the  mouth  should  be  kept  closed  for  a  few 
minutes  and  then  the  bulb  of  the  thermometer  inserted  under  the  tongue, 
and  the  hps  kept  closed  on  the  stem  of  the  thermometer  for  five  minutes. 
Except  in  cases  where  the  cutaneous  vessels  are  much  dilated,  the  tempera- 
ture of  a  thermometer  in  the  axilla  takes  a  considerable  time  to  rise  to  that 
of  a  thermometer  in  the  mouth  ;  it  should  never  be  left  less  than  ten  minutes 
in  this  situation.  The  following  Table  represents  the  temperature  of 
different  parts  of  the  body  : 

Surface 

Skin  covered  with  clothes 33°  to  35°  C. 

Naked  skin  in  bath  at  5°  C 17°  G. 

„     25°C 26-5°  C. 

Muscles  12  mm.  below  the  Surface 

In  bath  at  5°  C .  36-3°  C. 

„       „     25°C 36-9°  C. 

The  body  temperature  of  man  shows  variations  of  several  tenths  of 
a  degree  according  to  the  time  of  day  at  which  the  temperature  is  taken. 
The  highest  temperature  is  obtained  about  six  or  seven  in  the  evening,  and 
the  lowest  at  about  four  or  five  o'clock  in  the  morning.  With  these  diurnal 
changes  in  temperature  are  associated  parallel  oscillations  in  the  rate  of 
metabohsm  as  shown  by  the  elimination  of  carbon  dioxide.  They  are 
probably  determined  by  the  changes  in  the  movement  and  tension  of  the 
muscles  occurring  during  the  waking  hours.  If  the  habits  of  a  man  or 
animal  be  reversed,  so  that  he  sleeps  in  the  daytime  and  performs  his  normal 
vocation  by  night,  it  is  possible  to  reverse  also  the  direction  of  the  diurnal 
variations  in  temperature.  The  temperature  may  be  also  affected  tem- 
porarily by  various  acts,  such  as  the  taking  of  food,  or  muscular  work  ;  the 
influence  of  the  latter  factor  is  often  very  marked.  In  many  individuals  a 
hard  game  at  tennis  suffices  to  raise  the  temperature  to  39°  C.  (102°  F.),  and 
even  the  healthiest  individual  will  show  some  change  in  his  temperature 
as  the  result  of  exercise.  Pembrey  found  that  the  act  of  marching  led  to  a 
considerable  rise  in  temperature,  a  rise  which  is  apparently  responsible  for 
the  discomfort  and  fatigue  observed  under  such  circumstances.  Such  a 
change  in  the  body  temperature  is  merely  temporary  in  its  effects,  and 
insignificant  in  comparison  with  the  wonderful  uniformity  of  temperature 


THE  TEMPERATURE  OF  THE  BODY  1171 

observed  in  men  of  all  races  and  of  all  climes  under  most  varying  conditions 
of  food  and  activity. 

Just  as  there  are  limits  to  the  power  of  the  organism  to  regulate  its 
temperature  when  there  is  an  excessive  formation  of  heat  in  the  body,  so 
there  are  limits  to  the  regulation  of  temperature  to  severe  alterations  in  the 
temperature  of  the  external  medium.  Thus  if  the  body  is  subjected  to 
excessive  external  cold,  or  the  loss  of  heat  be  increased  by  absence  of  clothes, 
by  depriving  an  animal  of  its  fur,  or  by  immersion  in  a  cold  bath,  the  tempera- 
ture of  the  body  may  sink  continuously.  This  fall  of  temperature  in  the 
higher  animals  is  very  soon  followed  by  paralysis  of  the  highest  nerve-centres 
and  loss  of  consciousness.  The  centres  in  the  medulla  are  later  on  affected, 
so  that  the  respiration  is  slowed  and  the  blood-pressure  falls.  If  the  tem- 
perature does  not  fall  too  low  it  is  possible  to  re^ave  the  animal  or  man  by 
checking  the  loss  of  heat  or  by  supplying  artificial  warmth.  Recovery  has  in 
fact  been  observed  in  men  in  whom,  as  a  result  of  exposure,  the  body  tem- 
perature had  fallen  to  24°  C.  In  the  same  way  exposure  to  extreme  heat, 
especially  associated  with  muscular  exercise  and  increased  production  of 
heat  in  the  body,  may  cause  a  rise  of  the  body  temperature.  A  man,  or 
animal,  whose  temperature  is  raised  above  the  normal,  is  said  to  be  in  a 
state  of  pyrexia.  A  rise  of  2°  or  3°  C.  is  associated  with  all  the  phenomena 
which  characterise  fever,  i.e.  quickening  of  pulse  and  respiration,  malaise, 
headache,  and  loss  of  muscular  power.  If  the  temperature  rise  to  a  greater 
degree  than  this  the  patient  may  lose  consciousness,  and  death  ensues  at  a 
temperature  of  about  44°  C. 

The  very  small  variations  presented  by  the  body  temperature  in  mam- 
mals, even  under  the  influence  of  considerable  variation  in  external  tempera- 
ture, or  in  the  production  of  heat  in  the  body,  connotes  an  accurate  adapta- 
tion between  the  production  of  heat  in  the  body  and  the  loss  of  heat  from 
the  body.  The  regulation  of  the  temperature  can  be  effected  either  by 
regulation  of  heat  production,  by  alteration  in  the  rate  of  loss  of  heat,  or  by 
a  combination  of  both  mechanisms.  It  will  be  convenient  to  deal  with 
these  two  methods  of  regulation  under  separate  headings. 

THE  PRODUCTION  OF   HEAT  IN  THE   BODY 
The  reactions  mainly  responsililo  for  heat  production  in  the  body  are 
those  associated  with  oxidation  ;  the  processes  of  disintegration,  such  as  are 
ciTected  by  means  of  hydrolytic  ferments,  accounting  for  a  very  small  part 
of  the  heat  evolved. 

In  these  processes  of  oxidation  all  the  organs  participate,  the  most 
important,  especially  in  relation  to  the  regulation  of  heat  production,  being 
the  skeletal  nuiscles.  These  represent  more  than  half  of  the  total  weight  of 
the  soft  ti8<iues  of  the  body,  and  even  during  rest  are  the  seat  of  oxidative 
processes  and  therefore  ot  heat  formation.  Heat  formation  varies  with  the 
state  of  tone  of  the  nuiscles,  and  is  largely  increased  with  every  active  con- 
traction. The  effect  of  muscular  activity  on  the  total  output  of  energy 
of  the  body  is  well  represented  in  the  Table  given  on  p.  039. 


1172 


PHYSIOLOGY 


It  is  probable  that,  in  relation  to  their  size  at  any  rate,  the  glands  are 
still  more  effective  as  heat  producers.  The  hver,  and  the  blood  flowing 
from  the  hver,  have  been  stated  to  present  a  higher  temperature  than  any 
other  part  of  the  body.  On  the  other  hand,  the  nervous  system,  although 
dependent  on  a  constant  supply  of  oxygen  for  its  activities,  does  not  appear 
to  be  the  seat  of  extensive  metaboHc  changes,  nor  does  the  heat  produced  in 
this  system  play  any  great  part  in  maintaining  the  temperature  of  the  body. 

The  skeletal  muscles  are  controlled  by  the  central  nervous  system ;  if 
separated  from  their  centres  in  the  cord  they  become  flaccid  and  rapidly 
atrophy.  The  heat  production  in  the  muscles  is  therefore  also  dependent  on 
their  connection  with  the  central  nervous  system.  If  this  connection  be 
severed  either  by  curare  or  section  of  the  cord,  or  if  the  reflex  play  of  impulses 
on  the  muscles  be  abolished  by  anaesthetics,  the  animal  will  react  like  a  cold- 
blooded animal.  The  total  metabolism  of  the  body  and  the  total  production 
of  heat  sink  to  a  minimum,  and  are  diminished  by  application  of  cold,  or 
increased  by  apphcation  of  warmth,  to  the  surface  of  the  body.  On  the 
other  hand,  in  the  intact  animal  changes  of  temperature  in  the  environment 
provoke,  reflexly  by  their  action  on  the  muscles,  changes  in  the  opposite 
direction.  Thus  exposure  to  cold  increases  and  to  heat  diminishes  muscular 
metabohsm  and  the  heat  production  of  the  body. 

The  effects  of  variations  in  the  external  temperature  on  the  metabohsm 
of  warm-blooded  animals  are  well  shown  in  the  experiment,  from  which 
the  following  Tables  are  taken,  on  the  CO 2  output  in  the  ornithorhynchus 
and  in  the  rabbit  (Martin)  : 

1.    ORNITHORHYNCHtrS.      WEIGHT.    693   GRM.  ;     SURFACE,    876   SQ.    CENTIMS. 


Temperature 

of 
environment 

Temperature 

of 

animal 

Difference  in 
temperature, 
animal  and 
environment 

CO2  per  hour, 
in  grammes 

CO2  per  hour 

per  1000 
sq.  centims., 
in  grammes 

5 

31-8 

26-8 

1-090 

1-2U 

10 

32-0 

22-0 

•722 

-825 

20 

32-6 

12-6 

•405 

•463 

32 

33-6 

b6 

•336 

•383 

35 

35-3 

•3 

•377 

•430 

2.  Rai 

!BiT,    Weight,  7 

50   GRM. 

Temperature 

of 
environment 

Temperature 

of 

animal 

Difference  in 
temperature, 
animal  and 
environment 

CO^  per  hour, 
in"  grammes 

COo  per  hour 

per  1000 
sq.  centims., 
in  grammes 

5 

37-5 

32-5 

1^426 

1^543 

10 

38-0 

28-0 

1^038 

1-124 

20 

38-7 

18-7 

•912 

•987 

35 

40-5 

5-5 

•766 

•829 

40 

41-6 

1-6 

•897 

•971 

THE  TEMPERATURE  OF  THE  BODY 


1173 


In  the  former  animal,  where  the  regulation  of  the  temperature  of  the 
body  is  effected  almost  entirely  by  changes  in  heat  production,  the  effect 
of  warming  the  environment  of  the  animal  on  the  CO2  output  is  extremely 
marked.  It  will  be  noticed  that  the  CO2  per  hour  sinks  continuously  with 
rising  temperature  up  to  32°  C.  When  the  temperature  of  the  chamber  was 
raised  to  35°  the  temperature  of  the  animal  rose  considerably,  i.e.  the 
regulatory  mechanism  was  failing,  so  that  the  same  effect  was  produced  on 
metabolism  as  is  observed  in  working  with   cold-blooded  animals.     The 


£-0 


10  ■"  ~ao^  30^ 

>» ■>  Eoct'-   Cemp.  de6.  CanC. 

Flo.  545.     Effect  of  variations  in  the  external  temperature  on  the  COo  output 
(per  1000  cm."  body  surface)  of  warm-blooded  animals.     (C.  J.  MAR-rrM.) 

same  change,  though  less  marked,  is  observed  on  exposing  the  rabbit  to  a 
gradual  rising  temperature.  Here,  however,  the  process  of  regulation  is 
aided  by  alterations  in  the  heat  lost  as  well  as  in  the  heat  production  (Fig. 
545).  If  the  animals  be  observed,  whilst  subjected  to  changes  of  tempera- 
ture, it  will  be  evident  to  any  one  that  the  regulation  is  associated  with 
changes  in  muscular  activity.  At  30°  to  35°  C.  the  animals  will  he  perfectly 
flaccid,  breathing  rapidly,  or  may  go  to  sleep.  On  cooling  they  at  once 
become  more  vigorous  and  perform  active  movements  in  their  cage.  The 
sam3  effects  of  changes  in  the  external  temperature  are  familiar  in  our- 
selves. The  slackness  and  extreme  disinclination  to  violent  exercise  ob- 
served in  hot  moist  weather,  contrasted  with  the  stringing  np  of  the  tone 
of  the  muscles  which  follows  exposure  to  cold,  and  which  may  be  associated 


1174  PHYSIOLOGY 

with  voluntary  exercise  to  keep  ourselves  warm,  are  indications  of  the 
important  part  played  by  the  muscles  in  determining  the  heat  production 
of  the  body.  As  a  rule  the  immersion  of  a  man  in  a  cold  bath  for  a  minute 
or  two  increases  considerably  his  output  of  CO 2-  It  is  possible,  however, 
to  sit  in  a  bath  and  by  an  act  of  the  will  keep  all  the  muscles  in  a  state  of 
relaxation.  Under  these  circumstances  the  temperature  of  the  body 
rapidly  falls,  and  with  it  the  rate  of  metabolism,  as  judged  by  the  output  of 
carbon  dioxide. 

This  process  of  adjustment  of  the  body  temperature  by  variations  in  the 
heat  production,  so  long  as  it  represents  the  only  method,  is  extravagant  of 
energy  directly  the  difference  in  temperature  between  animal  and  environ- 
ment attains  any  considerable  degree.  In  the  very  perfect  adjustment  of 
the  temperature  which  is  present  in  the  higher  mammals,  regulation  of  the 
heat  loss  plays  a  greater  part  than  regulation  of  heat  production.  The 
economy  of  adjustment  by  heat  loss  is  well  shown  if  we  compare  in  echidna 
and  rabbit  respectively  the  percentage  alteration  in  COg  production  when 
the  difference  in  temperature  between  animal  and  environment  varies  from 
10°  C.  to  20°  C.  This  is  for  echidna  72  per  cent.,  for  mammals  16  per  cent. 
In  echidna  variations  in  heat  loss  can  be  practically  neglected,  so  that  the 
whole  of  the  work  of  regulating  the  body  temperature  falls  on  the  heat 
production.  As  soon  as  the  external  temperature  falls  below  a  certain 
degree  the  mechanism  fails,  the  animal's  temperature  falls,  and  it  passes  into 
a  state  of  hibernation. 


THE  REGULATION  OF  HEAT  LOSS 

In  all  temperate  climates,  and  in  fact  in  all  climates  except  under 
certain  exceptional  conditions,  the  temperature  of  the  warm-blooded 
animal  is  higher  than  that  of  his  environment,  so  that  there  must  be  a  con- 
stant loss  of  heat  from  the  surface  of  the  body.  In  the  warm-blooded 
animals  in  the  arctic  regions,  and  in  those  which  have  adopted  an  aquatic 
existence,  the  thick  layer  of  fat  which  underlies  the  skin  protects  the  active 
portions  of  the  body,  the  muscles  and  internal  organs,  from  excessive  loss 
of  heat  to  the  surrounding  medium.  In  most  terrestrial  animals  the  loss 
of  heat  is  also  diminished  by  fur  and  feathers  with  which  these  animals  are 
clothed,  and  in  ourselves  the  same  office  is  performed  by  clothes,  which  are 
capable  of  voluntary  graduation  to  external  conditions.  The  value  of  these 
different  coverings  depends  on  the  fact  that  air  is  a  very  bad  conductor 
of  heat.  In  the  case  of  a  naked  man  the  layer  of  air  immediately  in  contact 
with  the  surface  of  the  body  is  warmed,  becomes  lighter,  and  rises,  its  place 
being  taken  by  fresh  cold  air.  Loss  of  heat  is  increased  by  a  draught, 
which  quickens  the  rate  at  which  the  layers  of  air  in  contact  with  the  surface 
are  renewed.  In  the  case  of  clothes  the  material  encloses  layers  of  air  and 
hinders  it  from  free  circulation,  and  it  is  the  air  enclosed  in  the  meshes  of 
the  garments  and  between  the  different  layers  of  garments  that  plays  the 
greater  part  in  preventing  loss  of  heat.     The  rapid  cooling  effect  of  wet 


THE  TEMPERATURE  OF  THE  BODY  1175 

clothes  is  partly  due  to  the  replacement  of  layers  of  air  by  water,  which  is  a 
much  better  conducting  fluid. 

In  addition  to  the  loss  of  heat  by  convection,  i.e.  by  warming  the  layers 
of  air  in  contact  with  the  body,  heat  is  also  lost  by  radiation,  i.e.  by  an 
exchange  of  heat  between  the  surface  of  the  body  and  that  of  surrounding 
cooler  objects.  This  loss  is  also  prevented  by  clothing.  Since  the  material 
of  which  clothes  are  made  does  not  allow  the  passage  of  radiant  heat,  they 
absorb  the  heat  leaving  the  body  and  become  warm.  This  warm  article  of 
clothing  may  in  its  turn  act  as  a  centre  for  the  loss  of  radiant  heat,  which 
may  again  be  prevented  by  putting  on  another  layer.  It  is  a  familiar 
experience  that  a  multiplication  of  garments  is  more  effective  in  retaining 
the  heat  of  the  body  than  merely  increasing  the  thickness  of  the  individual 
garments.  The  rate  of  loss  of  heat  by  radiation  is  diminished  by  a  rise  of 
the  amount  of  watery  vapour  in  the  air,  since  this  makes  the  air  more 
opaque  to  the  passage  of  radiant  energy.  Since  the  loss  of  heat  depends  on 
the  difference  of  temperature  between  the  surface  of  the  body  and  the 
surrounding  air,  or  objects,  it  will  be  largely  affected  by  the  temperature 
of  the  skin,  and  therefore  by  the  amount  of  blood  flowdng  through  the 
skin.  The  blood-flow  through  the  slrin  is  under  the  control  of  the  central 
nervous  system,  through  the  vaso-motor  and  vaso-dilator  nerves,  and  it  is 
by  altering  the  size  of  these  vessels  that  the  central  nervous  system  chiefly 
acts  in  regulating  heat  loss.  In  cold  weather,  or  when  the  heat  production 
in  the  body  is  low,  the  vessels  are  constricted,  the  skin  is  cold,  and  the  heat 
loss  is  small.  On  the  other  hand,  if  the  temperature  of  the  surrounding  air 
is  high,  or  a  large  amount  of  heat  is  being  produced  in  consequence  of 
muscular  exercise,  the  vessels  are  dilated  and  the  skin  is  hot.  In  hot 
weather  the  dilatation  in  the  cutaneous  vessels  is  associated  with  muscular 
inactivity,  so  that  there  is  a  derivation  from  the  muscles,  where  the  blood  is 
not  required,  to  the  skin,  where  a  considerable  circulation  is  necessary. 

Loss  of  heat  by  radiation  and  convection  can  only  happen  when  the 
temperature  of  the  surrounding  air  is  lower  than  that  of  the  body.  The 
body  temperature  can,  however,  be  maintained  at  its  normal  height  in  an 
atmosphere  with  a  temperature  much  higher  than  37-5°  C,  and  this  in  spite 
of  the  fact  that  the  production  of  heat  in  the  body  is  still  going  on.  In  this 
case  there  is  a  profuse  secretion  of  sweat  on  the  surface  of  the  body.  In  the 
evaporation  of  the  sweat,  especially  if  aided  by  a  draught  of  air,  a  large 
amount  of  heat  becomes  latent  and  is  abstracted  from  the  body,  which  is 
therefore  kept  at  a  temperature  below  that  of  the  surrounding  atmosphere. 
If  the  secretion  of  sweat  is  checked,  by  depriving  an  animal  or  man  of  water, 
or  if  its  evaporation  be  impeded  by  placing  him  in  an  atmosphere  already 
saturated  with  aqueous  vapour,  the  temperature  of  the  body  runs  up  rapidly 
and  death  ensues  from  hyperpyrexia,  or  heat-stroke.  Although  a  man  can 
stand  exposure  to  a  temperature  of  200°  or  even  250°  F.  for  a  considerable 
time,  provided  that  the  air  is  dry,  a  temperature  of  89°  F.  is  rapidly  fatal  if 
the  air  be  saturated  with  moisture.  The  same  mechanism  comes  into  play 
when  the  heat  production  in  the  body  is  very  largely  increased,  as  by 


1176  PHYSIOLOGY 

violent  exercise.     Under  these  conditions  a  man  may  sweat  profusely  when 
the  temperature  of  the  surrounding  atmosphere  is  at  0°  C. 

The  main  regulation  of  heat  loss  thus  takes  place  by  the  control  of  the 
nervous  system  over  the  cutaneous  circulation  and  the  sweat-glands. 
Besides  these  channels  of  heat  loss,  others  may  play  an  important  part  under 
certain  conditions.  Heat  is  lost  to  the  body  in  warming  the  food  and 
air  which  are  taken  in.  It  is  also  lost  in  respiration  in  the  evaporation  of 
w^ater  and  the  setting  free  of  COg  from  watery  solution  into  the  expired  air. 
The  following  estimate,  by  Tigerstedt,  represents  the  proportion  of  losses 
in  an  adult  man  by  these  different  ways  : 

A.    Warming  the  Food  and  Air 

(1)  1500  g.  water  di'unk  at  15°  C.  and  warmed  to  37-5° — raised  therefore  Cal. 

22-5° =    33-75 

(2)  1500  g.  food  eaten  at  25°  C.  (mean)  and  warmed  to  37-5°- — raised  therefore 

12-5;  specific  heat  0-8 =    15-00 

(3)  15,000  g.  (=  11,500  1.)  air  respired  at  15°  C.  and  warmed  to  37-5°— 

raised  therefore  22-5°  ;  specific  heat  0-237      .  .  .  .  .      =    79-95 


128-70 


B.    Loss  or  Water  and  CO2  in  the  Breath 

(4)  It  is  assumed  that  the  inspired  air  is  half  saturated  with  watery  vapour 

at  15°  C.  and  that  the  expired  air  is  fully  saturated  at  37-5°  C  Ap- 
proximately 450  g.  of  water  would  be  given  off  therefore  in  the  form  of 
vapour  from  the  respiratory  passages  ;  the  latent  heat  of  the  water 
vapour  is  0-537  Cal =241-70 

(5)  The  absorption  of  heat  in  the  liberation  of  CO2  from  the  lungs  (800  g.)  ; 

0-134  Cal.  per  g =  107-20 


348-90 
From  above        .  .  ...  .  128-70 


Total         .         .         .         .         .         .         .         477-60 

The  sum  of  heat  losses  specified  under  these  five  headings  amounts  to 
477-60  Cal.  Estimating  the  total  heat  loss  of  an  adult  man  at  2400  Cal., 
this  sum  represents  only  about  20  per  cent,  of  the  total.  The  remaining  80 
per  cent,  (in  round  numbers)  takes  place  through  the  skin. 

If  we  estimate  the  total  heat  loss  of  an  adult  man  at  2400  calories,  we 
may  say  that  about  5  per  cent,  of  the  total  heat  loss  takes  place  by  warming 
the  food  and  air,  about  15  per  cent.,  by  the  evaporation  of  water  and  CO2  in 
respiration,  and  about  80  per  cent,  by  radiation  and  convection  and  the 
evaporation  of  sweat  from  the  skin.  The  proportion  represented  by  the 
last  factor  will  increase  very  largely  in  the  presence  of  a  high  external 
temperature,  or  of  an  excessive  heat  production  in  consequence  of  violent 
muscular  exercise. 

THE  NERVOUS  MECHANISM  FOR  HEAT  REGULATION 

The  accurate  balance  between  heat  production  and  heat  loss  which  is 
responsible  for  the  nearly  constant  temperature  of  man,  indicates  the  active 


THE  TEMPERATURE  OF  THE  BODY  1177 

co-operation  of  the  central  nervous  system  in  every  step  of  the  process. 
Whether  this  function  of  temperature  regulation  can  be  specially  localised  at 
any  part  of  the  central  nervous  system,  so  that  it  would  be  possible  to  speak 
of  a  heat-centre  in  the  same  way  as  we  speak  of  a  respiratory  or  vaso-motor 
centre,  is  doubtful.  Many  observers  have  found  that  injury  to  the  cor'pus 
striatum  causes  a  rise  of  temperature  associated  with  increase  both  in  heat 
production  and  in  heat  loss.  On  the  other  hand,  injury  to  or  pathological 
lesions  of  the  pons  Varohi  often  lead  to  an  increased  production  of  heat  in  the 
body,  which  is  not  compensated  for  sufficiently  by  heat  loss,  and  so  causes 
death  by  hyperpyrexia.  It  has  been  suggested  that  the  thermogenic 
centre,  i.e.  that  responsible  for  regulating  heat  production,  is  situated  at  a 
lower  level  in  the  nervous  system  than  the  thermotaxic  system,  i.e.  that 
which  presides  over  and  determines  the  balance  between  heat  production  and 
heat  loss.  The  observations  of  Meyer  and  Barbour  that  local  coohng  of  the 
corpus  striatum  causes  increased  respiratory  exchanges  and  heat  production, 
while  warming  has  the  reverse  effect,  certainly  point  to  a  locahsation  of  the 
thermotaxic  centre  in  this  part  of  the  central  nervous  system.  The  centres 
for  heat  loss  must  be  placed  in  the  medulla,  at  any  rate  so  far  as  concerns 
control  of  heat  loss  by  alterations  in  the  blood-supply  to  the  skin  or  in  the 
secretion  of  sweat.  The  facts  at  our  disposal  are,  however,  too  meagre  to 
warrant  any  definite  locahsation  of  the  heat-regulating  function  in  the 
central  nervous  system,  or  any  such  accurate  analysis  of  the  regulating 
function  as  has  been  just  suggested. 

In  many  warm-blooded  animals  the  abihty  to  maintain  a  constant  tem- 
perature is  not  fully  developed  until  some  time  after  birth.  Pembrey  has 
shown  that  in  the  guinea-pig  and  chick,  in  which  the  nervous  system  is 
fully  functional  at  birth,  the  heat-regulating  mechanism  is  also  completely 
adequate,  whereas  animals  such  as  rats,  pigeons,  or  the  human  child,  which 
are  born  in  a  helpless  condition,  only  acquire  the  power  of  regulating  their 
own  temperature  some  time  after  birth.  As  we  should  expect,  the  develop- 
ment of  the  power  of  regulating  heat  production  runs  fari  passu  with  the 
acquisition  of  control  by  the  nervous  system  over  the  muscles  of  the  body. 


CHAPTER  XX 
THE  DUCTLESS  GLANDS 

INTERNAL  SECRETIONS 

In  unicellular  organisms,  as  in  the  rest  of  the  living  world,  activity  consists 
in  adaptation  to  external  conditions.  The  changes  in  the  environment 
which  determine  the  reactions  of  these  organisms  may  occur  at  their  surface 
or  at  some  distance.  Among  the  stimuli  which,  acting  from  a  distance, 
evoke  the  reaction  of  unicellar  organisms,  probably  the  most  important  are 
those  accompanied  by  chemical  changes.  The  interrelation  of  micro- 
organisms with  one  another  is  determined  almost  entirely  by  such  chemical 
stimuli.  Thus  the  antherozoids  of  ferns  are  attracted  to  the  ovule  in  con- 
sequence of  the  production  in  the  tissue  surrounding  the  latter  of  substances 
such  as  malic  acid.  Among  micro-organisms  we  find  some  which  leave 
places  rich  in  oxygen,  while  others  move  towards  any  spot  in  their  environ- 
ment where  oxygen  is  most  plentiful.  These  reactions  of  unicellular  organ- 
isms to  chemical  stimuli  are  classed  together  under  the  term  chemiotaxis. 
When  the  cells  are  united  together  to  form  cell  colonies,  or  when,  as  in  the 
metazoa,  the  multicellular  aggregate  is  formed  by  the  failure  of  the  products 
of  division  of  the  ovum  to  separate  one  from  another,  the  interrelations 
between  the  different  cells  forming  the  organism  are  still  largely  determined 
by  chemical  stimuli.  In  fact,  in  the  lowest  metazoa,  svich  as  the  sponge,  we 
know  of  no  other  means  of  correlating  the  reactions  of  different  parts  of  the 
cell  aggregate.  If  a  foreign  substance  be  introduced  into  the  living  tissue  of 
a  sponge  it  becomes  speedily  surrounded  with  a  collection  of  wandering 
phagocytic  cells,  called  from  the  surrounding  parts  by  the  diffusion  of 
chemical  substances  from  the  seat  of  the  lesion  into  the  fluids  of  the  body. 
The  same  chemical  sensibility  determines  the  aggregation  of  leucocytes 
around  bacteria  or  dead  tissue,  which  forms  the  essential  feature  of  the 
process  of  inflammation  in  higher  animals. 

When  the  reaction  of  distant  parts  of  the  body  to  a  change  occurring  in 
any  one  part  depends  on  the  diffusion  of  some  substance  from  a  stimulated 
part,  the  total  reaction  must  require  a  considerable  time  for  its  full  develop- 
ment. A  much  more  effective  method  of  correlation  was  acquired  by  the  evo- 
lution of  a  nervous  system,  by  means  of  which  the  consensus  f.artium  could  be 
maintained  by  the  rapid  propagation  of  molecular  changes  along  differen- 
tiated paths  in  the  protoplasm.     The  development  of  this  second  mode  of 

1178 


THE  DUCTLESS  GLANDS  1179 

correlation  ol  activities  ditl  not.  however,  do  away  witii  tlie  necessity  ior  the 
more  primitive  method.  Even  in  the  higher  animals,  where  rapidity  of 
reaction  is  not  required,  we  find  adaptatioiis  carried  out  in  response  to  some 
change  in  distant  parts  of  the  body,  the  message  having  been  chemical  and 
not  nervous  in  character  {e.g.  the  secretin  mechanism  for  pancreatic  secre- 
tion). 

When  we  speak  of  the  chemical  correlation  of  the  activities  of  the  different 
parts  of  the  body,  it  is  important  not  to  confuse  processes  which  have  little 
or  nothing  in  common.  In  one  sense  we  may  say  that  every  cell  in  the  body 
is  chemically  connected  with  and  dependent  on  all  the  other  cells  in  the  body. 
This  interdependence  is  a  necessary  consequence  of  the  differentiation  of 
function  associated  with  increased  complexity  of  the  organism.  Thus  the 
food-stuffs  are  digested  and  absorbed  by  the  cells  lining  the  ahmentary 
canal  and  are  then  transmitted,  more  or  less  changed  by  these  cells,  to  all  the 
other  tissues  of  the  body.  The  liver  stores  up  glycogen  and  is  ready  to  give 
of  its  store  to  any  tissue  in  need  of  carbohydrate.  All  the  tissues  probably 
produce  urea,  which  passes  to  the  kidneys  and  there  excites  the  act  of 
excretion.  All  tissues  produce  carbon  dioxide,  which  passes  to  the  lungs 
to  be  excreted,  but  as  it  traverses  the  respiratory  centre  it  arouses  respiratory 
movements  which  are  exactly  proportioned  to  the  tension  of  the  carbon 
dioxide  and  therefore  to  the  need  of  the  whole  body  to  eliminate  this  waste 
product.  The  liver  receives  ammonia  from  the  alimentary  canal  and  con- 
verts it  into  urea,  thus  shielding  all  the  other  tissues  from  the  poisonous 
effects  which  would  be  produced  by  the  entrance  of  the  ammonia  into  the 
general  circulation.  Thus  one  organ  may  receive  and  modify  any  substance 
or  food-stuff  so  as  to  prepare  it  for  more  ready  assimilation  by  other  tissues. 
It  may  shield  these  other  tissues  from  the  poisonous  effects  of  certain  waste 
products,  either  by  converting  these  into  harmless  substances  or  by  excreting 
them  from  the  body.  In  all  these  cases  the  tissues  are  dealing  with  some 
substance  which  is  utilised  in  bulk,  or  which,  by  its  accumulation,  could  exert 
a  toxic  influence  on  other  tissues.  We  are  probably  justified  in  treating 
apart  a  group  of  phenomena  in  which  the  substance  transmitted  from  one 
part  of  the  organism  to  another  is  significant  almost  entirely  as  an  excitatory 
agent,  and  has  little  or  no  value  as  a  source  of  energy.  When  the  adaptation 
to  a  change  of  a  consists  in  the  activity  of  an  organ  b,  the  activity  of  b  can  be 
evoked  either  by  a  nerve  impulse  passing  from  a  to  the  central  nervous 
system  and  from  this  to  b,  or  by  the  production  at  a,  as  a  direct  consequence 
of  the  stinnilus,  of  a  specific  chemical  substance,  which  passes  into  the 
circulating  blood  to  b,  where  in  its  turn  it  will  excite  the  required  state  of 
action.  Such  chemical  messengers  are  designated  hormones,  from  op/umio, 
'  I  excite.'  We  have  already  met  with  several  examples  of  such  bodies. 
It  may  be  interesting  here  to  consider  what  must  be  their  general  character 
if  they  are  to  fulfil  the  part  of  chemical  messengers. 

(1)  In  the  first  place,  they  must  not  be  antigens,  i.e.  their  injection 
into  the  blood-stream  must  not  evolve  the  production  of  an  anti-body. 
If  this  were  the  case,  the  hormone,  on  entering  the  blood-stream,  would  meet 


1180  PHYSIOLOGY 

its  anti-body  and  would  be  unable  to  exert  any  effect  ou  the  appropriate 
reacting  organ.  Practically  all  the  complex  colloid  bodies  allied  to  the 
proteins,  e.g.  ferments,  egg  albumin,  peptone,  sera  of  different  animals,  when 
injected  into  the  blood-stream,  cause  the  production  of  the  corresponding  anti- 
body. The  hormones  must  be  simpler  in  character  than  such  substances 
and  probably  have  a  precise  and  comparatively  simple  chemical  or  mole- 
cular constitution. 

(2)  Since  they  must  be  carried  by  the  blood-stream  to  the  reacting  organ 
they  must  in  most  cases  be  susceptible  to  easy  passage  through  the  walls  of 
the  blood-vessels  if  they  are  to  excite  a  reaction  within  a  fairly  short  space 
of  time.  This  consideration  would  also  tend  to  keep  their  molecular  weight 
comparatively  low. 

(3)  As  a  rule  the  chemical  messenger  must  excite  a  state  of  activity  in 
response  to  a  change  in  some  other  part  of  the  body.  When  the  primary 
change  passes  away,  the  action  of  the  hormone  should  also  disappear.  On 
this  account  it  is  necessary  that  the  hormone  should  either  be  susceptible 
of  easy  destruction,  by  oxidation  or  otherwise,  in  the  fluids  of  the  body, 
or  be  readily  excreted,  so  that  its  action  may  not  be  continued  indefinitely. 

In  previous  chapters  we  have  already  come  across  several  examples  of 
correlated  activities  of  different  tissues  effected  by  chemical  means.  It  is 
perhaps  questionable  whether  we  should  regard  carbon  dioxide,  or  the  lactic 
acid  produced  by  a  contracting  muscle,  as  a  hormone  in  the  strict  sense  of 
the  term,  since  both  these  products  are  produced  in  large  quantities  as  the 
final  product  of  oxidation  or  disintegration  of  the  food-stuffs.  Carbon 
dioxide  is,  however,  rapidly  eliminated  from  the  body,  and  lactic  acid  is 
equally  rapidly  oxidised  in  the  body,  and  there  is  no  doubt  that  the  activity 
of  the  respiratory  centre  is  determined  by  the  presence  of  this  substance  in 
the  blood  and  is  thereby  perfectly  co-ordinated  with  the  activities  of  the 
whole  of  the  rest  of  the  organism.  In  the  aUmentary  canal  the  secretion  of 
pancreatic  juice  at  the  precise  moment  when  it  is  required  in  the  duodenum 
for  the  digestion  of  the  food  arriving  there  from  the  stomach  is  evoked  by 
the  production  in  the  cells  of  the  intestinal  mucous  membrane  under  the 
agency  of  the  acid  of  the  gastric  juice  (the  specific  stimulus)  of  a  substance 
secretin.  This  substance,  which  is  heat  stable  and  diffusible,  but  is  easily 
destroyed  by  oxidation,  is  absorbed  into  the  blood  and  carried  to  the  pan- 
creas, where  it  acts  as  a  specific  stimulus  for  the  secretory  cells.  The  same 
substance  excites  also  the  secretion  of  bile  by  the  liver-cells  and  the  secretion 
of  intestinal  juice  by  the  glands  of  the  small  intestine.  These  are  perhaps 
the  two  best  examples  of  chemical  reflexes,  i.e.  adaptations  effected  by 
chemical  means  rather  than  by  impulses  passing  along  the  nerve- channels. 
There  are,  however,  many  other  examples  of  a  chemical  influence  exerted 
by  one  organ  on  another,  in  which  the  interaction  probably  depends  on  the 
production  of  minute  quantities  of  some  substance  acting  in  virtue  of  its 
excitatory  qualities  rather  than  of  its  value  as  a  source  of  energy.  For 
many  of  the  organs  of  the  body  we  know,  in  fact,  no  other  function  than  the 
production  of  some  substance  the  presence  of  which  in  the  blood  is  a  necessary 


THE  DUCTLESS  GLANDS  1181 

conditio)!  for  tiie  carrying  out  of  the  normal  functions  either  of  growth 
or  activity  of  many  other  parts  of  the  body.  In  other  cases  an  organ  may 
have  a  twofold  function.  Thus  the  pancreas  gives  an  external  secretion 
which  is  used  for  the  preparation  of  the  food  for  absorption,  and  an  internal 
secretion  which,  passing  into  the  blood,  exercises  an  important  influence  on 
the  metabolism  of  the  food-stuffs  after  absorption.  Other  instances  of 
these  chemical  correlations  may  be  cited.  The  secretion  of  gastric  juice, 
which  results  from  the  presence  of  peptones  or  other  substances  in  tha 
stomach,  has  been  ascribed  by  Edkins  to  the  production  in  the  pyloric 
nmcous  membrane  of  a  gastric  hormone,  which  travels  by  the  blood  to  the 
glands  of  the  fundus,  where  it  excites  secretion  of  gastric  juice.  According 
to  Frouin  the  injection  of  boiled  succus  entericus,  free  from  secretin,  provokes 
the  secretion  of  intestinal  juice.  In  the  reproductive  system  we  have 
many  examples  of  such  chemical  correlations.  The  pancreas,  by  its  internal 
secretion,  probably  influences  not  only  the  oxidation  of  the  carbohydrates 
but  also  the  assimilation  of  the  food-stuffs  by  all  parts  of  the  small  intestine. 
All  these  examples  are  discussed  in  fuller  detail  in  other  parts  of  this  book. 
There  is  one  class  of  organs  in  which  a  chemical  influence  exerted  on  the 
rest  of  the  body  is  the  only  function  with  which  we  are  acquainted.  These 
are  included  under  the  term  ductless  glands.  As  examples,  we  may  cite  the 
suprarenal  bodies,  the  thyroid  and  parathyroids,  the  thymus  and  the 
pituitary  body. 

THE  SUPRARENAL  BODIES 
The  suprarenal  capsules  in  mammals  are  two  small  masses  lying  on  the 
upper  or  oral  side  of  the  kidneys.  They  consist  of  two  parts,  the  cortex  and 
the  medulla.  The  cortex  is  composed  of  cells  arranged  in  columns  or  in  a 
reticular  fashion.  The  outermost  layer  of  cells  often  presents  an  alveolar 
structure,  the  lumen,  however,  being  but  little  marked.  According  to  the 
arrangement  of  the  cells  the  cortex  is  divided  into  three  zones,  the  zona 
glomerulosa,  zona  fasciculata,  and  zona  reticulata.  The  cells  themselves 
are  distinguished  by  the  large  amount  of  granules  they  contain,  which  give 
the  ordinary  reactions  for  fat,  but  consist  probably  of  lecithin  compounds. 
In  some  animals,  e.g.  the  guinea-pig,  the  cells,  especially  towards  the  inner 
part  of  the  gland,  contain  many  yellow  pigment  granules.  The  medulla, 
much  less  extensive  than  the  cortex,  presents  irregularly  shaped  cells,  the 
outlines  of  which  arc  but  slightly  marked.  These  cells  contain  granules 
which  stain  darkly  with  chromates  and  give  a  green  colour  with  salts  of  iron. 
It  is,  hence,  easy  to  deUmit  the  area  of  the  cortex  in  any  section  of  a  gland 
which  has  been  hardened  in  a  fluid  containing  chromates.  The  substance 
giving  this  reaction  is  known  as  chromophile  or  chromaffine  substance. 
The  suprarenals  are  richly  supplied  with  blood,  especially  in  the  medullary 
part,  the  cells  of  which  impinge  directly  on  the  endothehal  lining  of  dilated 
capillaries.  They  also  receive  an  abundant  nerve-supply  from  the  sym- 
pathetic system,  the  nerves  forming  a  thick  meshwork,  especially  in  the 
medulla,  and  presenting  at  intervals  ganglion-cells  which  may  be  isolated  or 
combined  to  form  small  ganglia. 


1182  PHYSIOLOGY 

A  study  of  the  development  of  the  suprarenal  glands  shows  that  we  have 
here  to  do  with  two  distinct  tissues,  probably  differing  in  the  part  they  play 
in  the  animal  economy.  Whereas  the  cortex  is  derived  from  that  portion 
of  the  mesoblast,  the  '  intermediate  cell  mass,'  from  which  the  mesonephros 
is  also  developed,  the  medulla  is  produced  by  an  outgrowth  from  the  sym- 
pathetic system  and  may  be  said  indeed  to  consist  of  profoundly  modified 
nerve-cells.  In  many  fishes  these  two  elements  of  the  suprarenal  gland 
remain  separated  throughout  hfe,  the  cortex  being  represented  by  a  series 
of  paired  interrenal  bodies  lying  on  the  front  of  the  spinal  column,  and  the 
medulla  by  a  number  of  collections  of  chromaffine  cells  lying  in  close  juxta- 
position to  the  spinal  nerves.  In  some  animals  accessory  suprarenals  are 
not  infrequent  in  which  both  cortex  and  medulla  may  be  represented.  In 
all  animals  we  find  masses  of  tissue,  the  so-called  paraganglia,  in  close  associa- 
tion with  the  sympathetic  system,  which  present  the  chromaffine  reaction 
typical  of  the  medulla.  Since  a  watery  extract  or  decoction  of  these  bodies 
has  the  same  influence  on  injection  into  the  blood-stream  as  an  infusion  of 
the  medulla  of  the  suprarenal  body  itself,  we  are  probably  justified  in 
regarding  these  bodies  as  equivalent  to  accessory  medullary  portions  of  the 
suprarenal.  They  have  the  same  origin,  the  same  staining  reactions,  and 
the  same  physiological  effect  as  the  latter. 

The  functions  of  the  suprarenal  bodies  were  a  matter  of  pure  hypothesis 
before  Addison  in  1855  drew  attention  to  the  coincidence  of  degenerative 
destruction  of  these  bodies  with  a  disease  which  has  been  known  since  that 
time  as  Addison's  disease.  The  three  cardinal  symptoms  of  this  disorder 
are  (1)  bronzing  of  the  skin,  (2)  vomiting,  (3)  excessive  muscular  weakness 
and  prostration.  The  disease  is  almost  invariably  fatal.  Addison's  observa- 
tions have  been  amply  confirmed  since  that  time,  but  we  are  not  yet  in  a 
position  to  account  for  the  occurrence  of  all  these  symptoms  as  a  result  of 
interference  with  the  cortex  and  medulla  of  the  suprarenals.  The  experi- 
mental destruction  or  extirpation  of  these  bodies  has  naturally  been  fre- 
quently carried  out.  The  operation  always  leads  to  the  death  of  the 
animal  within  twelve  to  twenty-four  hours.  Even  when  the  destruction  is 
carried  out  by  degrees  it  has  been  impossible  to  reproduce  the  bronzing 
which  is  so  characteristic  of  Addison's  disease.  The  one  symptom  which 
is  observed  as  a  result  of  the  experimental  extirpation  is  the  excessive  pros- 
tration, which  is  attended  with  muscular  weakness  and  a  lowered  blood 
pressure.  In  a  few  cases  it  has  been  found  possible  to  keep  rats  alive  after 
total  extirpation  of  these  organs,  but  this  result  is  probably  due  to  the 
frequent  presence  in  these  animals  of  accessory  suprarenals. 

Schafer  and  Oliver  in  1894  found  that  a  watery  extract  or  decoction  of 
the  suprarenal  bodies,  when  injected  into  the  circulation,  caused  a  very  great 
rise  of  blood-pressure,  brought  about  chiefly  by  constriction  of  all  the  blood- 
vessels of  the  body.  The  active  substance  responsible  for  this  rise  was 
limited  entirely  to  the  medulla,  infusions  of  the  cortex  being  without  influence 
on  the  blood-pressure.  Later  on  Takamine  succeeded  in  isolating  the  active 
substance,  to  which  he  gave  the  name  of  adrenaline,  and  since  that  time 


THE  DUCTLESS  GLANDS  1183 

physiological  chemists  have  succeeded  not  only  in  determining  the  consti- 
tution of  adrenaline  but  also  in  preparing  it  synthetically.  The  constitution 
of  adrenaUne  is  shown  by  the  following  formula  : 

HO 


H0<^  ^— CH(OH)— CH2XHCH3 


Since  it  possesses  an  asymmetric  carbon  atom,  a  substance  of  this  formula 
may  be  either  Isevo-  or  dextrorotatory.  Both  forms,  as  well  as  the  racemic 
modification,  have  been  prepared  synthetically.  The  substance  wliich 
occurs  in  the  suprarenal  gland  is  the  Isevorotatory  modification,  and  Cushny 
has  shown  that  it  is  only  this  modification  which  is  active,  injection  of  the 
dextrorotatory  compound  having  only  one-twelfth  the  effect  of  the  laevo- 
rotatory.  Adrenaline  is  active  in  excessively  minute  doses,  injection  of 
one  four-hundredth  of  a  milligramme  per  kilo  body  weight  sufficing  to  evoke 
a  definite  rise  of  blood-pressure.  On  injecting  it  into  the  circulation  there  is 
immediately  a  rise  of  blood-pressure  which,  if  the  vagi  are  intact,  is  only 
moderate  in  amount,  but  is  accompanied  by  a  marked  slowing  of  the  heart. 
This  excitation  of  the  vagus  is,  however,  probably  secondary  to  the  rise 
of  blood-pressure  and  is  not  due  to  direct  action  of  the  drug  on  the  vagus 
centre.  If  the  vagi  be  divided  the  injection  of  adrenaline  evokes  a  huge 
rise  of  pressure  which  may  amount  to  300  mm.  Hg.  It  may  indeed  be  so 
great  that  the  animal  dies  from  heart-failure  or  from  pulmonary  oedema. 
The  rise  of  pressure  is  observed  even  after  destruction  of  the  central  nervous 
system.  The  action  is  not  Hmited  to  the  blood-vessels.  It  has  been 
shown  by  Langley  and  by  Elliott  that  adrenahne  injected  into  the  circu- 
lation arouses  every  activity  which  can  be  normally  excited  by  stimulation 
of  the  sympathetic  system.  A  list  of  the  actions  of  adrenaline  is  therefore 
identical  with  a  list  of  the  chief  functions  of  the  sympathetic  nervous 
system.  In  the  head  it  causes  dilatation  of  the  pupil,  secretion  of  saliva, 
and  erection  of  the  hairs.  On  the  heart  it  has  a  strong  augmentor  and 
accelerator  influence,  so  that  the  heart  beats  more  effectively  as  a  rule 
even  against  the  enormously  increased  resistance  offered  by  the  constricted 
arterioles.  Whereas  a  rise  of  blood -pressure  generally  causes  increased 
systolic  volume  of  the  heart,  we  may  find  after  an  injection  of  adrenaline  and 
during  the  height  of  the  rise  of  blood-pressure  that  the  heart  empties  itself 
more  effectively  than  it  did  before  the  injection.  On  the  lung-vessels 
adrenaline  has  probably  a  slight  constrictor  influence.  With  regard  to  the 
vessels  of  the  brain,  we  find  the  same  divergence  of  opinion  as  in  the  case  of 
excitation  of  possible  vaso-motor  nerves  to  this  organ.  Some  observers, 
on  perfusing  the  brain  with  defibrinated  blood,  have  obtained  constriction 
on  adding  adrenaline  to  the  perfused  blood,  while  others  have  been  unable  to 
obtain  any  positive  results  in  this  direction.  In  the  abdomen  intravenous 
injection  of  adrenaline  causes  complete  relaxation  of  the  nmsculature  of 
the  stomach,  small  and  large  intestines,  but  contraction  of  the  ileocolic 
sphincter.     On  the  bladder  its  eifect  varies  according  to  the  animal  studied, 


1184  PHYSIOLOGY 

but  ill  every  case  is  identical  with  that  obtained  by  stimulting  the  hypogastric 
nerves.  It  has  been  shown  by  Dale  that  adrenaUne  may  also  excite  vaso- 
dilator fibres  or  produce  vaso-dilator  effects  when  such  effects  are  also 
obtained  from  stimulation  of  the  sympathetic  nerves.  In  order  to  evoke 
these  results  it  is  necessary  to  paralyse  the  vaso-constrictors  by  the  injection 
of  ergotoxin,  one  of  the  active  principles  of  ergot.  This  drug,  when  injected, 
causes  first  active  vaso-constriction  and  rise  of  blood-pressure,  followed  by 
paralysis  of  the  vaso- constrictor  mechanism.  Excitation  of  the  splanchnic 
nerves  or  injection  of  adrenahne  will  now  bring  about  a  fall  of  blood-pressure 
due  to  dilatation  of  the  vessels  in  the  splanchnic  area. 

The  point  of  attack  of  the  adrenahne  appears  to  be  in  the  muscular  or 
glandular  tissues  themselves,  since  it  may  be  obtained  not  only  after  destruc- 
tion of  the  cord  and  sympathetic  plexuses  but  even  after  time  has  been 
allowed  for  the  peripheral  (post-ganghonic)  fibres  to  degenerate  as  a  result  of 
extirpation  of  the  corresponding  ganglia.  Although  the  effect  is  not  altered 
under  these  circumstances,  and  it  may  still  produce  either  relaxation  or 
contraction  of  muscles  according  to  the  original  action  of  the  sympathetic 
on  these  fibres,  we  are  not  justified  in  regarding  it  as  acting  on  the  contractile 
material  of  the  cells  themselves.  Rather  must  we  assume  with  Langley  and 
EUiott  that  the  action  of  adrenahne  is  on  some  substance  mediating  between 
the  nerve  and  the  responsive  tissue.  We  may  speak  of  this  reactive  material 
as  the  receptor  substance  (Langley),  or  we  may  locate  it  in  the  situation 
where  the  nerve  joins  the  muscle  or  gland- cell  and  describe  adrenaline  as 
acting  on  the  myoneural  junction. 

Each  suprarenal  receives  a  number  of  filaments  from  the  splanchnic 
nerve  on  its  own  side.  These  pass  to  the  medulla  where  they  end  apparently 
without  the  interposition  of  any  ganglion  cells  on  their  course  (Elliott),  the 
cells  of  the  medulla  having  themselves  been  developed  by  a  modification  of 
sympathetic  ganghon  cells.  Stimulation  of  the  peripheral  end  of  the 
splanchnic  nerve  causes,  as  we  have  already  seen,  a  discharge  of  adrenahne 
into  the  blood-stream.  This  discharge  accounts  for  the  secondary  rise, 
often  accompanied  with  quickening  of  the  heart,  observed  on  a  blood- 
pressure  tracing  as  the  result  of  stimulating  the  splanchnic  nerve.  Through 
the  splanchnic  nerves  a  discharge  of  adrenaline  can  be  excited  by  many 
general  conditions,  such  as  pressure  on  the  brain,  puncture  of  the  fourth 
ventricle,  administration  of  anaesthetics,  mental  conditions  such  as  excite- 
ment or  fright.  Such  a  discharge  is  an  important  element  in  the  reaction  to 
environmental  stress  and  enables  the  animal  to  react  for  the  preservation  of 
its  life  either  by  offence  or  flight.  If  one  splanchnic  nerve  be  cut  before  the 
administration  of  anaesthetics  or  the  maintenance  of  a  condition  of  irritation 
or  fright,  the  suprarenal  gland  on  the  corresponding  side  will  be  found  to 
contain  two  or  three  times  as  much  adrenahne  as  the  gland  which  has  been 
left  in  connection  with  the  central  nervous  system.  It  is  interesting  that 
no  such  condition  of  exhaustion  can  be  produced  by  electrical  stimulation  of 
the  peripheral  end  of  the  divided  splanchnic.  It  has  been  suggested, 
therefore,  that  the  splanchnic  nerve  contains  two  sets  of  fibres,  anabolic 


THE  DUCTLESS  GLANDS  1185 

and  katabolic,  that  only  the  latter  are  stimulated  by  central  iriitation, 
whereas  electrical  stimulation,  exciting  both  sets  of  fibres,  causes  an  increased 
production  of  adrenaline  in  the  gland,  which  exactly  keeps  pace  with  the 
increased  output. 

When  adrenaline  is  injected  into  the  blood-stream  the  efltect  is  only 
temporary.  It  is  not  excreted  in  the  urine,  but  rapidly  disappears  from  the 
blood.  Since  it  is  easily  oxidised  and  is  extremely  unstable  in  alkaline 
solution,  we  may  conclude  that  after  performing  its  excitatory  function  it  is 
destroyed  by  oxidation  in  the  fluids.  Adrenaline  is  thus  a  typical  hormone, 
a  body  of  comparatively  low  molecular  weight,  having  a  drug-like  excitatory 
action  on  specific  tissues  of  the  body,  easily  diffusible,  and  rapidly  destroyed 
after  discharging  its  office. 

Owing  to  the  rai)id  destruction  of  adrenaline,  relativelj'^  enormous  doses  have  to  be 
given  by  the  mouth  in  order  to  produce  any  effect  on  the  blood-pressure.  There  is, 
however,  a  whole  series  of  substances,  more  or  less  allied  to  adrenaline  in  chemical  con* 
stitution,  which  undergo  less  rapid  destruction  and  can  therefore  be  administered 
as  drugs  in  the  usual  way.  Dale  and  Barger  have  recently  described  three  such  sub- 
.stances  as  occurring  in  infusions  of  putrid  meat  and  as  forming  the  most  important  of 
the  active  principles  of  ergot.  The  constitution  of  these  substances  is  shown  in  the 
following  formulae  : 

^S[*\cHCHoCHoNH,  Isoamylamine 

HO/^  \— CHoCHoNHo  p-hydroxyphenylcthylamino 

/  \ — CH2CH2NH2  phenylethylamine 

HO 


Hq/  >— CH(0H)CH2NHCH3  adrenaline 


The  formula  of  adrenaline  is  placed  below  in  order  to  show  the  relation  of  these 
substances  to  the  natural  hormone.  These  bodies  are  produced  from  the  amino -acids 
of  proteins  by  a  process  of  decarboxylation.  Leucine  would  yield  isoamylamine, 
tyrosine,  hydroxyphenylethylamine,  and  phenylalanine  would  give  phenylethylamine. 
Such  substances  may  be  formed  in  minute  quantities  during  the  normal  processes  of 
putrefaction  which  occur  in  the  alimentary  canal. 

There  seems  little  doubt  that  we  nuist  regard  adrenaline  as  a  true  internal 
secretion,  and  therefore  must  ascribe  to  the  medulla  of  the  suprarenal  capsules 
as  well  as  to  the  other  chromaffine  tissue  in  the  body,  the  function  of  main- 
taining the  normal  constriction  of  the  arterioles  and  of  facilitating  in  some 
way  or  other  the  functions  of  the  sympathetic  system  generally.  The 
absence  of  this  secretion  in  cases  of  destruction  by  disease  of  the  suprarenals 
would  serve  to  account  for  the  weakness,  prostration,  and  lowered  blood- 
pressure  of  Addison's  disease.  The  two  other  symptoms  of  this  disease, 
namely,  bronzing  aiul  vomiting,  still  remain  to  be  accounted  for.  It  is 
possible  that  the  latter  may  be  due  to  some  involvement  by  the  morbid 
process  of  the  mimberless  fibres  of  the  solar  plexus,  which  run  in  close 
proximity  to  the  suprarenals.  We  have  no  knowledge  whatsoever  of  the 
functions  of  the  cortical  portion  of  these  organs.     It  is  possible  that  future 

38 


1186 


PHYSIOLOGY 


work  may  show  some  connection  between  the  cortex  and  the  destruction  of 
pigment  in  the  body.  At  present  it  is  only  by  a  process  of  exclusion  that 
we  may  guess  at  a  causal  relationship  between  the  destruction  of  the  cortex 
and  the  bronzing  which  occurs  in  Addison's  disease. 

There  seems  Httle  doubt  that  the  rapidly  fatal  effects  of  extirpation  of 
both  suprarenals  is  to  be  ascribed  rather  to  the  removal  of  the  cortex  than  of 
the  medulla.  The  functions  of  the  latter  can  be  more  or  less  effectively 
maintained  by  the  other  chromaffine  tissues  found  at  the  back  of  the 
abdomen.  In  the  few  cases  where  animals  have  survived  double  extirpation 
small  masses  of  accessory  cortical  substance  have  been  found  embedded  in 
the  kidney  or  elsewhere  in  the  neighbourhood  of  the  suprarenals. 

THE  THYROID   GLAND  AND  THE  PARATHYROIDS 
The  thjrroid  gland  consists  of  two  oval  bodies  lying  on  either  side  of  the 
trachea,  joined  in  many  animals  across  the  trachea  by  an  isthmus.     Sur- 
rounded by  a  capsule  of  connective  tissue^  it  is  made  up  of  an  aggregation  of 

vesicles  varying  in  size  from  15  to 
150;>i.  The  vesicles  are  lined  by 
a  single  layer  of  cubical  epithelial 
cells,  and  are  filled  with  a  trans- 
lucent material  known  as  colloid 
(Fig.  546).  Of  the  cells,  some 
present  granules  and  resemble  the 
cells  of  a  secreting  gland,  while 
others  contain  masses  of  colloid, 
or  have  undergone  colloidal  de- 
generation. Between  the  vesicles 
may  be  seen,  here  and  there,  solid 
masses  of  cells  which  by  some 
observers  are  regarded  as  destined 
to  replace  vesicles  the  epithelium 
of  which  has  undergone  complete 
degeneration.  The  colloid  material  can  be  traced  between  the  cells  into 
the  lymphatics  lying  between  the  vesicles.  Since  the  gland  possesses 
no  duct  it  is  supposed  that  the  cells  furnish  an  internal  secretion, 
which  makes  its  way  into  the  blood  along  the  lymphatic  efferents  of  the 
gland.  The  thyroid  is  richly  supplied  with  blood  by  the  superior,  middle, 
and  inferior  thyroid  arteries,  and  is  surrounded  with  a  plexus  of  veins  lying 
immediately  under  the  capsule.  In  development  the  thyroid  is  formed  by 
an  outgrowth  from  the  fore-gut,  but  the  connection  with  the  gut  disappears 
long  before  the  end  of  foetal  life.  In  rare  cases  part  of  the  duct  may  persist, 
and,  becoming  gradually  filled  with  fluid,  give  rise  to  a  hyoid  cyst  which,  lies 
below  the  tongue  and  may  require  excision  by  the  surgeon. 

As  in  the  case  of  the  other  ductless  glands,  clinical  observations  have 
contributed  materially  to  our  knowledge  of  the  functions  of  the  thyroid. 
Although  the  gland  had  been  extirpated  in  animals  by  Astley  Cooper  and 


Fig.  546. 


Section  of  thyroid  gland  of  dog. 
(Swale  Vincent.) 


THE  DUCTLESS  GLANDS  1187 

by  Schift",  the  attention  of  physiologists  and  medical  men  was  especially 
directed  to  the  importance  of  this  organ  by  the  observations  of  surgeons, 
especially  Kocher,  on  the  untoward  and  even  fatal  effects  following  its 
complete  removal  in  man  in  operations  for  extirpation  of  goitre.  In  this 
country  attention  had  already  been  called  to  the  connection  of  a  disturbed 
condition  of  metabolism  known  as  myxoedema  with  atrophy  of  the  thyroid. 
A  patient  affected  with  myxoedema  presents  a  gradually  increasing  blunting 
of  his  or  her  mental  activities  ;  speech  is  slow,  cerebration  delayed.  With 
this  nervous  defect  are  associated  changes  in  the  connective  tissues,  the 
subcutaneous  connective  tissue  becoming  thickened,  so  that  the  face  and 
hands  appear  swollen  and  puffy,  looking  at  first  sight  as  if  oedema  were 
present.  The  swelling  is,  however,  due  to  newly  formed  connective  tissue, 
and  not  to  the  presence  of  an  excess  of  interstitial  fluid  in  the  tissues.  The 
patient  often  presents  a  yellow,  waxy  appearance  with  a  patch  of  colour  on 
the  cheeks.  The  hair  falls  out,  the  pulse  is  slowed,  and  the  temperature 
tends  to  be  subnormal  owing  to  the  diminution  of  the  rate  of  metabolism  in 
the  body.  The  intake  of  food  and  the  excretion  of  urea  are  diminished. 
If  the  atrophy  of  the  thyroid  occurs  in  early  hfe  during  the  period  of  growth, 
e.g.  in  young  children,  the  growth  of  the  skeleton  practically  ceases.  The 
bones  of  the  limbs  may  grow  in  thickness  but  not  in  length.  There  is 
early  synostosis  of  the  bones  of  the  skull  and  complete  cessation  of  develop- 
ment of  mental  powers.  Children  so  affected  may  hve  for  many  years,  but 
when  twenty-five  or  thirty  present  still  a  childish  appearance  (Fig.  547,  c). 
Stunted,  pot-bellied,  and  ugly,  they  have  the  intelligence  of  a  child  of  four 
or  five.  They  often  present  fatty  tumours  above  each  clavicle,  and  similar 
subcutaneous  tumours  of  fat  or  loose  fibrous  tissue  are  found  in  cases  of 
myxoedema  in  the  adult. 

When  the  thyroid  is  extirpated  in  man  the  result  is  often  the  production 
of  typical  myxoedema.  In  some  cases,  especially  in  young  individuals,  the 
results  are  more  severe,  a  condition  of  tetany  being  set  up  in  which  there  are 
tonic  spasms  of  the  muscles  of  the  body,  especially  of  the  extremities.  When 
the  thyroid  gland  is  extirpated  in  animals  the  results  more  closely  resemble 
these  acute  cases.  In  certain  cases  a  chronic  condition  of  malnutrition  is 
set  up,  but  a  typical  myxoedema  with  thickening  of  the  subcutaneous  tissues 
by  new  growth  of  connective  tissue  has  only  been  described  by  Horsley  in 
monkeys.  The  effects  are  more  pronounced  in  carnivora  than  in  herbivora. 
In  the  former  a  condition  of  tetany  is  produced  accompanied  with 
muscular  tremors  and  clonic  convulsions  which  come  on  at  intervals  and 
may  be  accompanied  with  severe  dyspnoea  leading  to  death  within  fourteen 
days.  In  herbivora,  wasting,  diminution  of  respiratory  exchange,  and 
disorders  of  nutrition  are  often  the  most  prominent  symptoms.  These 
results  were  ascribed  by  Munk  to  interference  with  the  recurrent  laryngeal 
nerves  during  the  operations,  but  the  observations  on  man  leave  very 
little  doubt  that  they  are  due  entirely  to  the  removal  of  the  chemical 
influence  of  the  thyroid  gland.  Many  authorities  were  at  first  inclined  to 
ascribe  these  results  in  man  and  animals  to  the  circuIatio)i  in  the  blood  of 


1188 


PHYSIOLOGY 


toxic  substances  which  would  normally  undergo  destruction  in  the  thyroid 
gland.  This  theory  is  put  out  of  court  by  the  results  of  administration  of 
thyroid  gland  to  patients  with  myxoedema  or  to  animals  deprived  of  their 
thyroids.  SchifE  first  showed  that  the  effects  of  extirpation  of  the  thyroid 
might  be  prevented  if,  at  the  same  time,  the  thyroid  from  another  animal 
were  transplanted  into  the  subcutaneous  tissue  to  take  the  place  of  the  one 
removed.  On  removing  the  transplanted  thyroid,  the  typical  symptoms 
of  thyroid  destruction  at  once  ensued.  It  was  later  found  that  similar 
good  results  could  be  obtained  by  subcutaneous  injection  of  the  expressed 
juice  of  the  thyroid,  and  later  that  even  this  was  not  necessary,  and  that  it 

A  EC 


^  :*-r 


FiG.  547.     A,  a  cretin,  23  months  old.     b,  the  same  child,  34  months  old,  after  ad- 
ministration of  sheep's  thyroids  for  1 1  months,    c,  a  cretin,  untreated,  15  years 

old.       (W.  OSLEE.) 

was  sufficient  to  administer  the  thyroid  gland,  either  fresh,  dried,  or  partially 
cooked,  by  the  mouth.  The  administration  of  the  thyroid  gland  in  this  way 
is  indeed  one  of  the  therapeutic  triumphs  of  the  last  twenty  years.  An 
ugly  and  idiotic  cretin  can  be  converted  in  this  way  into  a  child  of  ordinary 
intelligence  with  normal  powers  of  growth  (Fig.  547).  Given  to  myxoedemic 
patients,  the  thyroid  gland  reduces  the  swelling  of  the  subcutaneous  tissues, 
causes  a  new  growth  of  hair,  and  restores  the  patient  to  his  or  her  former 
state  of  mental  health.  Nor  is  the  thyroid  gland  without  influence  on  the 
healthy  individual.  If  given  in  large  doses  either  to  man  or  animals,  it  quickens 
the  pulse,  even  causing  violent  palpitation,  and  increases  the  metabolic 
activities  of  the  body,  so  that  the  appetite  is  increased,  the  nitrogenous  output 
rises  above  the  intake,  and  the  subcutaneous  fat  is  diminished  or  disappears. 
It  is  possible  that  a  moderate  degree  of  thyroid  inadequacy  is  not  infrequent 
and  that  the  beneficial  effects  on  general  health,  in  removing  excessive 


THE  DUCTLESS  GLANDS  1189 

corpulence  and  in  promoting  the  growth  of  hair,  which  are  observed 
on  administering  the  drug  to  people  of  middle  life,  may  be  due  to 
the  actual  replacement  of  a  function  which  is  being  insufficiently 
discharged.  The  symptoms  caused  by  excessive  doses  of  thyroid  gland 
are  strikingly  similar  to  those  occurring  in  the  disease  known  as 
exophthalmic  goitre,  where  there  is  a  true  hypertrophy  of  the  gland 
associated  with  cardiac  palpitation,  proptosis  (bulging  of  the  eyes),  wasting, 
and  muscular  weakness. 

All  these  facts  warrant  us  in  including  the  thyroid  body  among  the 
glands  with  an  internal  secretion,  the  presence  of  which  in  the  blood-stream 
is  a  necessary  condition  for  the  normal  growth  and  functions  of  almost  all 
the  tissues  of  the  body.  If  this  secretion  is  lacking  we  obtain  the  condition 
known  as  myxoedema  in  adults,  as  cretinism  in  young  children.  If  it  be 
present  in  excess  the  symptoms  of  exophthalmic  goitre  are  produced. 
The  exact  character  of  the  internal  secretion  cannot  be  regarded  yet  as 
definitely  established.  It  seems  possible  that  it  is  identical  with  a  substance 
containing  iodine  in  organic  combination,  which  was  isolated  by  Baumann 
from  the  thyroid  gland  and  is  known  as  iodothyrin.  In  certain  experiments 
the  results  of  administration  of  iodothyrin  were  found  to  be  identical  with 
those  obtained  by  giving  the  whole  gland.  Doubt  has  been  thrown  on  the 
specific  nature  of  this  body  on  account  of  the  fact  that  iodine  may  be 
wanting  in  the  thyroid  gland  in  certain  animals,  though  Reid  Hunt  has 
shown  that  the  physiological  effects  of  thyroid  extract  are  proportional  to 
the  amount  of  iodine  contained  therein. 

SIGNIFICANCE  OF  THE  PARATHYROIDS.  The  parathyroids  are 
small  bodies,  varying  in  number,  situated  on  the  border  of  the  thyroid  gland 
or  actually  embedded  in  its  substance.  In  histological  appearance  they 
differ  widely  from  the  thyroid,  and  consist  of  sohd  masses  or  columns  of 
epithelial  cells  surrounded  with  connective  tissue  and  richly  supplied  with 
blood-vessels  (Fig.  548).  Considerable  divergence  of  opinion  still  exists  as  to 
the  significance  of  these  bodies.  In  some  animals,  e.g.  in  the  dog,  where 
they  are  embedded  in  the  gland,  they  will  be  necessarily  removed  in  any 
operation  for  the  extirpatio}i  of  the  thp'oid.  In  others,  such  as  the  rabbit, 
where  they  lie  outside  the  gland,  it  is  easy  to  avoid  them  in  the  excision  of 
the  thyroid.  To  this  varying  distribution  of  the  parathyroids  have  been 
ascribed  the  different  results  of  extirpation  of  the  thyroid  in  carnivora  and 
herbivora  respectively.  Forsyth  has  shown  that,  in  man,  the  situation  of 
the  parathyroids  corresponds  almost  exactly  with  the  places  in  which  are 
found  occasionally  accessory  thyroids  ;  and.  according  to  Ednumds,  after 
excision  of  the  thyroid,  the  parathyroids  undergo  histological  alteration  and 
are  converted  into  thyroid  tissue,  the  cells  taking  on  an  alveolar  arrangement 
and  producing  colloid  material.  According  to  this  view  the  parathyroids 
would  represent  simply  immature  thyroid  tissue.  On  the  other  hand,  it  has 
been  suggested  (Biedl)  that  the  parathyroids  have  a  function  entirely  dis- 
tinct from  that  of  the  thyroid  gland,  removal  of  the  thyroids  producing 
simply  a  condition  of  cachexia  and  the  changes  associated  with  myxoedema, 


1190  PHYSIOLOGY 

while  removal  of  the  parathjrroids  is  responsible  for  the  nervous  disturbances 
and  tetany  observed  after  total  extirpation  of  these  organs.  The  matter 
cannot  yet  be  regarded  as  definitely  settled. 


en& 


end. 


Fig.  548.     Section  of  parathyroid.     (Kohn.) 
ep,  secreting  epithelium  ;  pig,  cells  containing  pigment ;  cuf,  sinus-like 
capillaries  ;  enA,  endothelial  cells. 


THE  PITUITARY  BODY 
The  pituitary  body  consists  of  two  parts  which  have  separate  modes  of 
origin.  An  outgrowth  from  the  buccal  cavity  in  the  embryo  meets  a  hollow 
extension  of  the  anterior  cerebral  vesicle.  The  buccal  ectoderm  gives  rise  to 
the  anterior  lobe  and  pars  intermedia  of  the  pituitary,  while  the  neural  epiblast 
becomes  developed  into  the  posterior  lobe  (Fig.  549).  In  some  animals  the 
posterior  lobe  remains  hollow  and  retains  its  primitive  connection  with  the 
third  ventricle  of  the  brain,  but  in  man  it  becomes  entirely  sohd.  The 
anterior  lobe  in  the  adult  consists  of  nests  of  epithelial  cells  (Fig.  550),  many 
of  which  are  filled  with  granules,  and  is  richly  supplied  with  large,  thin- 
walled  capillary  blood-vessels.  The  anterior  lobe  is  separated  from  the 
posterior  lobe  by  a  cleft  which  is  the  remains  of  the  original  hollow  outgrowth 
from  the  buccal  cavity.  The  epithelial  tissue  immediately  surrounding  this 
cleft  differs  somewhat  from  that  constituting  the  anterior  lobe.  The  cells, 
which  present  but  few  granules,  are  arranged  in  islets,  separated  by  an 
intervening  tissue  continuous  with  the  main  mass  of  the  posterior  lobe. 
Many  of  the  islets  are  hollow  and  enclose  a  colloid  material.  The  colloid 
material  has  been  traced  by  Herring  into  the  interalveolar  connective  tissue 
and  into  the  prolongation  of  the  infundibulum  which  enters  the  posterior 


THE  DUCTLESS  GLANDS 


1191 


lobe.  One  must  therefore  conclude  that  the  colloid  material  secreted  by 
the  cells  of  this  part  passes  directly  into  the  third  ventricle.  The  amount  of 
colloid  material  increases  in  animals  which  have  undergone  extirpation  of 
the  thyroid  gland. 

Our  first  clue  to  the  importance  of  this  organ  in  the  normal  processes 
of  the  body  was  furnished  by  the  observations  of  Pierre  Marie,  who  found  that 
the  morbid  condition  of  '  acromecjoly  '  is  associated  with  tumours  of  the 


Fig.  S-tO.     Mesial  sagittal  section  through  the  pituitary  body  of  an  adult  monkey 
(semi-diagrammatic).     (After  Herring.) 

a,  optic  chiasma  ;  h,  third  ventricle ;  c,  tongue-like  process  of  pare  intermedia  ; 
d,  epithelial  investment  of  posterior  lobe ;  e,  anterior  lobe  ;  /,  epithelial  cleft ; 
g,  pars  intermedia  ;  h,  posterior  lobe. 


pituitary  gland.  This  disease  consists  in  an  increased  growth  of  certain 
parts  of  the  skeleton,  especially  the  lower  jaw  and  the  extremities  of  the 
limbs.  Headache  is  often  present,  and  there  may  be  polyuria  and  affection 
of  the  eyesight.  When  this  disease  occurs  during  the  period  of  active  growth 
there  may  be  an  increase  in  length  both  of  the  limb-bones  and  of  the  trunk, 
and  most  of  the  giants,  which  are  shown  from  time  to  time,  are  examples  of 
this  pathological  condition  of  '  gigantism.'  It  seems  probable  that  this 
condition  is  due  to  an  over-action  of  the  gland.  In  cases  of  acromegaly  the 
tumour  is  generally  an  adenoma,  i.e.  an  enlargement  of  the  ordinary  gland 
tissue.  Total  extirpation  of  the  pituitary  body  is  generally  followed  by 
death  within  a  few  days,  death  which  cannot  be  attributed  to  shock  or  any 
accidental  features  of  the  operation.  One  must  regard  the  pituitary  there- 
fore as  essential  to  the  maintenance  of  life.  It  has  not  been  possible  by 
transplantation  to  replace  a  removed  pituitary  body,  since  the  transplanted 
organ  has  hitherto  always  undergone  degeneration.  In  a  certain  number 
of   cases  animals,  especially  if  young,   have  survived  extirpation  of  the 


1192 


PHYSIOLOGY 


pituitary  body.  In  these  the  operation  was  followed  by  arrest  of  develop- 
ment— the  animals  remaining  in  an  infantile  condition,  small  with  an  excess 
of  fat,  and  absence  of  sexual  development. 

The  most  definite  evidence  we  have  as  to  the  mode  of  action  of  the 
different  parts  of  the  pituitary  gland  has  been  furnished  by  experiments  on 
administration  or  injection  of  the  dried  gland  or  its  extracts.  The  posterior 
lobe  seems  to  be  practically  inactive,  extracts  made  from  this  lobe  having 


Fig.  550.     Section  of  cat's  pituitary  body,  passing  through  the  cleft  in  the  gland. 

(P.  T.  Herring.) 
a,  pars  anterior  ;   b,  cleft ;   c,  pars  intermedia  :   d,  pars  nervosa  (posterior  lobe). 

the  same  influence  as  extracts  from  nervous  tissue  generally.  If,  however, 
the  intermediate  epithelial  substance  is  included  in  the  posterior  lobe, 
marked  effects  may  be  obtained  from  the  intravenous  injection.  An 
extract  of  the  posterior  lobe  (including  pars  intermedia)  produces,  as  was 
shown  by  Schafer,  a  rise  of  blood-pressure  and  diuresis.  The  latter  result 
also  follows  administration  of  the  posterior  lobes  by  the  mouth.  Dale  has 
shown  that  the  active  principle  exercises  a  direct  excitatory  effect  on  all 
unstriated  muscle,  the  effect  being  unaltered  whether  the  nerve-supply  to  the 
muscle  be  present  or  not.  Thus  it  produces  contraction  of  the  blood-vessels, 
of  the  intestinal  muscle,  and  of  the  uterus,  and  will  act  upon  muscular 
tissues,  such  as  the  arteries  of  the  lungs  or  heart,  which  do  not  receive  con- 
strictor impulses  from  the  sympathetic  system.  The  active  principle  is 
much  more  stable  than  the  other  hormones  we  have  already  studied.  It 
is  not  destroyed  by  boiling,  and  after  injection  into  the  blood-stream  can  be 


THE  DUCTLESS  GLANDS  1193 

recovered  from  the  urine.  It  is  possible  that  the  polyuria,  which  is  not 
infrequently  observed  in  association  with  head  injuries  or  tumours  of  the 
brain,  may  be  occasioned  by  an  increased  escape  of  this  material  into  the 
general  circulation. 

Extracts  from  the  anterior  lobe  have  no  definite  effect  when  injected 
into  the  blood-stream.  Schafer  found  that  the  addition  of  the  anterior 
lobe  of  the  pituitary  body  to  the  food  of  young  gro\ving  animals  causes 
an  increased  rate  of  growth.  In  this  experiment  eight  rats  of  a  htter 
were  taken  :  four  were  fed  with  bread  and  milk  to  which  the  anterior  lobes 
of  pituitary  bodies  had  been  added,  while  the  other  four,  which  served  as 
controls,  received  bread  and  milk  with  a  corresponding  quantity  of  testis  or 
ovary.  Later  experiments  have  not  however  confirmed  these  results. 
According  to  Mackenzie  extracts  of  the  pituitary  body  have  a  marked 
excitatory  effect  on  the  secretion  of  milk  by  the  mammary  glands. 

It  is  evident  that  much  further  work  is  necessary  before  we  can  regard 
the  functions  of  the  pituitary  body  as  definitely  ascertained.  The  evidence 
we  have  at  present  would  seem  to  point  to  the  following  conclusions  : 

(a)  The  anterior  lobe  furnishes  some  substance  to  the  circulation  which 
promotes  growth,  especially  of  the  bony  and  connective  tissues  of  the  body. 

(6)  The  intermediate  part  surrounding  the  cleft  between  anterior  and 
posterior  lobes,  in  addition  to  the  production  of  some  substance  which  is  a 
general  excitant  for  unstriated  muscle  and  produces  diuresis,  also  furnishes 
a  colloid  secretion  which  passes  directly  into  the  ventricles  of  the  brain  and 
may  be  assumed  to  have  some  influence  on  the  growth  or  functions  of  the 
central  nervous  system.  Schafer  regards  the  principle  giving  rise  to  diuresis 
as  distinct  from  that  causing  contraction  of  unstriated  muscle,  since  diuresis 
may  occur  without  corresponding  rise  of  blood-pressure.  The  independence 
of  the  two  phenomena,  renal  and  vascular,  cannot  be  regarded  as  proved. 

(c)  The  posterior  lobe  consists  mainly  of  neurogha.  We  have  no  clue  to  its 
functions  apart  from  the  masses  of  intermediate  cells  which  it  may  contain. 

Very  httle  can  be  said  as  to  the  other  ductless  glands.  The  thymus 
forms  two  large  masses  in  the  anterior  mediastinum  which  in  man  grow  up 
to  the  second  year  of  life  and  then  rapidly  diminish  so  that  only  traces 
are  to  be  found  at  puberty.  It  contains  a  large  amount  of  lymphatic  tissue 
and  is  therefore  often  associated  with  the  lymphatic  glands  as  the  seat  of 
formation  of  lymph-corpuscles.  The  epithelial  remains  of  Hassell's  cor- 
puscles found  in  the  medullary  part  of  its  globules  have  not  had  any  func- 
tion assigned  to  them.  In  certain  cases  of  arrested  development  or  of 
general  weakness  in  young  people  the  thynuis  has  been  found  to  be  per- 
sistent. The  effect  of  extracts  made  from  the  thymus  do  not  differ  from 
those  of  extracts  made  from  any  other  cellular  organ. 

The  pineal  gland  has,  so  far,  not  been  proved  to  have  any  function  in 
metabolism.*  It  is  interesting  as  a  vestigial  remnant  of  a  primitive 
dorsal  eye.     In  certain  lizards  this  organ  still  presents  traces  of  its  original 

*  Cases  have  been  recorded  in  wliith  tumours  of  the  pineal  body  have  been  asso- 
ciated with  obesity,  premature  sexual  development  and  early  matiu-ity. 

38* 


119^ 


PHYSIOLOGY 


structure,  and  is  found  to  conform  to  the  invertebrate  type  of  eye.  It  is 
doubtful  whether  at  any  time  in  the  history  of  vertebrates  the  pineal  eye 
has  been  functional. 

The  carotid  and  coccygeal  glands  have  often  been  grouped  with  the 
collections  of  chromaffine  cells  already  described  as  associated  with  the 
sympathetic  system.  Their  structure  resembles  more  nearly  that  of  the 
parathyroid  bodies  or  the  anterior  lobe  of  the  pituitary  gland.  They  con- 
sist of  a  small  collection  of  columns  or  masses  of  cells  bound  together  by 
connective  tissue  with  a  rich  supply  of  blood-capillaries.  Nothing  is 
known  as  to  their  function. 

The  lymph  and  heemolymph  glands,  and  the  spleen,  are  often  grouped 
with  these  ductless  glands.  The  essential  activity  of  these  bodies,  however, 
Hes  in  the  production,  not  of  a  diffusible  chemical  substance,  but  of  formed 
elements,  e.g.  lymph-corpuscles,  and  they  do  not  properly  fall  within  the 
scope  of  this  chapter.  As  a  matter  of  convenience,  we  may  deal  shortly  here 
with  the  functions  of  the  spleen. 


THE  SPLEEN 
This  organ  is  similar  in  many  respects  to  a  lymphatic  gland.     It  is 
formed  of  a  framework  of  connective  tissue  and  unstriated  muscular  fibres, 
in  the  interstices  of  which  is  contained  the  splenic  pulp.     This  consists  of  a 


Carotid 


VA./s,,^/v^y\/^..■■^/vW^-A^-^ 


.■^J'^y^J"vAA.''\AAA./ 


Dog:8.5  Kilo. all  connections  with  splelen 

SEVERED   EXCEPT  one:  ARTERY  &   VEIN  -^^ 
0   PRESSURE 


Fig.  551.     Pleth3\smographic  tracing  of  spleen  (upper  curve)  from  a  dog,  showing 
the  spontaneous  contractions  of  this  organ  (reduced  from  a  tracing  by  Schafer). 

fine  fibrillar  network,  on  the  fibrils  of  which  lie  endothehal  cells.  The 
meshes  contain  the  cells  of  the  splenic  pulp,  which  are  fairly  large  polygonal 
cells,  and  leucocytes.  Just  as  in  a  lymphatic  gland  the  cellular  elements  of 
the  tissues  are  bathed  by  the  lymph  which  flows  through  the  gland,  so  in  the 
spleen  the  walls  of  the  capillaries  become  discontinuous,  and  the  blood  is 
poured  out  into  the  interstices  of  the  tissue.  The  spleen  is  therefore  the 
only  tissue  in  the  body  where  the  blood  comes  in  actual  contact  with  the 
tissue-elements  themselves.  The  blood  from  the  splenic  pulp  is  collected  into 
large  venous  sinuses,  which  run  along  the  trabeculse  to  the  hilum,  where 
they  unite  to  form  the  splenic  vein.  The  arteries  to  the  spleen  are  beset  in 
their  course  along  the  trabecular  with  small  nodules  of  lymphoid  tissue,  which 
are  known  as  the  Malpighian  folhcles. 


THE  DUCTLESS  GLANDS 


lli)5 


It  is  evident  that  the  blood  must  meet  with  considerable  resistance  in 
passing  through  the  close  meshwork  of  the  splenic  pulp.  Li  order  to  ensure 
a  constant  circulation  through  the  gland,  the  muscular  tissue  of  the  capsule 
and  trabeculse  has  the  property  of  rhythmic  contraction.  If  the  spleen  be 
enclosed  in  a  plethysmograph,  or  splenic  oncometer,  and  its  volume  be 
recorded  by  connecting  this  with  an  oncograph,  it  will  be  seen  to  be  subject 
to  a  series  of  large,  slow  variations,  each  contraction  and  expansion  lasting 
about  a  minute,  and  recurring  with  great  regularity  (Fig.  551).  Superposed 
on  these  large  waves  are  smaller  undulations  due  to  the  respiratory  variations 
of  the  blood-pressure,  and  on  these  again  the  Uttle  excursions  corresponding 
to  each  heart- beat.  The  contractile  power  of  the  spleen  is  under  the 
control  of  the  nervous  system,  and  a  rapid  contraction  may  be  induced  by 
stimulation  of  the  splanchnic  nerves. 


FUNCTIONS  OF  THE  SPLEEN 

The  structure  of  this  organ  suggests  that  the  splenic  cells  must  exercise 
a  constant  influence  on  the  blood  which  surrounds  them,  and  that  this 
influence  is  not  purely  of  a  chemical  nature.     In  the  liver  and  kidneys. 


Fig.  5.52.     ("ells  from  a  scraping  of  the  spleen.     (Kolliker.) 
A,  splenic  pvilp-cell  containing  red  blood-corpuscles,  h  (k  =  nucleus) ;   b,  leucocyte 
with  ])nlynif)rphous  nucleus;  c,  pulp-cell  containing  disintegrated  red  corpuscles; 
n.  lyiniihocyte  ;  E.  giant  cell ;  f,  nucleated  red  corpuscles  ;  o,  normal  red  corpuscle  ; 
H.  multi nuclear  leucocyte  ;  j,  eosinophile  cell. 

which  exercise  so  powerful  an  ofToct  on  the  composition  of  the  blood  passing 
through  them,  the  proper  cells  of  the  organs  are  separated  from  the  blood- 
stream by  the  capillary  wall.  Microscopic  examination  of  the  cells  of  the 
splenic  pulp  shows  us  that  these  are  full  of  particles  of  brown  pigment 
or  fragments  of  red  corpuscles  (Fig.  552).  In  many  cases  of  infectious 
disease,  such  as  recurrent  fever,  the  splenic  cells  are  observed  towards  the 
end  of  the  attack  to  be  full  of  the  organism—  spirillum — which  is  the  cause  of 
the  disease.  In  fact,  these  cells  are  so  arranged  that  they  can  take  up  solid 
particles  hold  in  suspension  in  the  blood-plasma.  We  must  indeed  look 
upon  the  spleen  as  the  great  blood-filter,  purifying  the  blood  in  its  passage  by 


1196  PHYSIOLOGY 

taking  up  particles  of  foreign  matter  and  effete  red  corpuscles.  The  process 
of  phagocytosis,  which  was  described  under  the  cellular  mechanisms  of 
defence  (p.  1022),  is  in  the  spleen  a  normal  occurrence, 

A  function  has  also  been  assigned  to  the  spleen  in  the  formation  of  red 
blood-corpuscles,  but  the  evidence  is  not  sufficient  to  determine  whether 
such  a  process  occurs  normally. 

Chemical  analysis  of  the  spleen  reveals  the  presence  of  a  large  number  of 
what  are  called  extractives,  such  as  succinic,  formic,  butyric,  and  lactic 
acids,  inosit,  leucine,  xanthine,  hypoxanthine,  and  uric  acid.  There  is  also 
a  protein,  combined  with  iron,  as  well  as  several  pigments  probably 
derived  from  the  haemoglobin  of  the  red  corpuscles  destroyed  by  the 
cells  of  the  splenic  pulp.  The  fact  that,  in  cases  where  the  spleen  is 
pathologically  enlarged  as  in  leucocythsemia,  the  uric  acid  in  the  urine 
is  largely  increased  points  to  a  connection  between  the  spleen  and  the 
formation  of  uric  acid  in  the  body.  The  numerous  extractives  which  are 
formed  probably  owe  their  origin  to  the  destructive  changes  effected  on 
the  effete  constituents  of  the  blood  by  the  agency  of  the  splenic  pulp-cells. 


BOOK  IV 
REPKODUCTION 


CHAPTER   XXI 
THE   PHYSIOLOGY   OF   REPRODUCTION 

SECTION  I 
THE  ESSENTIAL  FEATURES  OF  THE  SEXUAL  PROCESS 

The  two  fundaniental  characteristics  of  protoplasm,  which  distinguish  it 
above  all  others  from  unorganised  matter,  are  growth  and  activitij.  Growth 
occurs  at  the  expense  of  surrounding  non-living  material,  while  activity  is 
in  every  case  an  adapted  reaction  to  changes  in  the  environment.  The 
second  characteristic  would  seem  to  involve  a  limitation  of  the  first,  and 
does,  in  fact,  determine  the  conditions  under  which  it  may  occur.  In  the 
process  of  growth  of  a  minute  spherical  mass  of  protoplasm  its  bulk  and 
mass  increase  as  the  cube,  while  the  surface  only  increases  as  the  square,  of 
the  radius.  Thus  the  proportion  of  surface  to  mass  diminishes  with  in- 
creased size  of  the  protoplasmic  unit,  and  since  activity  is  a  function  of  the 
surface  the  larger  the  unit  the  smaller  must  be  its  activity.  It  follows  that 
there  must  be  a  limiting  size  to  the  living  protoplasmic  unit,  and  it  is  on 
this  account  that  practically  no  unicellular  animal  or  plant  exceeds  a  fraction 
of  a  millimetre  in  diameter.  If  an  organism  is  to  attain  any  larger  size,  this 
can  only  be  by  a  multiplication  of  units,  each  presenting  the  same  relative 
amount  of  surface  as  a  complete  unicellular  organism,  thougli  the  surface 
may  be  exposed  to  an  internal  and  not  to  an  external  medium.  Another 
factor,  limiting  the  size  of  the  unicellular  organism  or  of  the  unit  of  the 
nmlticellular  organism,  is  the  necessity  for  maintaining  a  certain  proportion 
between  the  size  of  the  nucleus  and  that  of  the  cytoplasm  composing  the 
body  of  the  cell.  Observations  on  artificial  division  of  cells  have  shown 
us  that  the  functions  of  digestion,  assimilation,  and  growth  depend  upon  the 
presence  of  a  nucleus.  Hence,  when  for  any  reason  it  is  advantageous  that 
a  cell  should  attain  a  large  size,  such  a  cell  is  almost  always  found  to  contain 
many  nuclei.  All  the  '  giant  cells  '  found  in  the  body  of  man  under  normal 
or  pathological  conditions  are  also  multi nuclear. 

Thus  the  continuous  display  of  the  functions  of  assimilation  and  dis- 
similation, of  growth  and  activity,  is  only  possible  so  long  as  cell  division 
keeps  pace  with  growth.  In  unicellular  organisms,  under  favourable  condi- 
tions, this  growth  and  nuiltiplieation  occur  with  prodigious  rapidity.  It 
has  been  computed  that  a  paramccciuni.  freelv  supplied  with  food  material, 

1199 


1200  PHYSIOLOGY 

Avould,  by  growth  and  division,  in  the  course  of  a  year  form  a  mass  of  proto- 
plasm the  size  of  the  earth,  assuming  of  course  that  no  accidents  or  destruc- 
tive agencies  intervened  to  destroy  the  paramoecia  which  were  being  formed. 
This  computation,  which  may  seem  a  fanciful  one,  is  useful  as  indicating  the 
enormous  number  of  individuals  brought  under  the  action  of  natural  selec- 
tion, which  very  few  survive.  In  unicellular  organisms,  such  as  para- 
moecium  or  amoeba,  death  cannot  be  regarded  as  a  natural  process.  They 
may  be  eaten  by  higher  organisms  or  serve  as  food  to  vegetable  parasites, 
but  so  long  as  conditions  are  favourable  and  food-supply  sufficient,  they 
will  continue  to  grow  and  reproduce  themselves  eternally.  In  the  course 
of  its  existence  each  individual  may  be  brought  under  many  varieties  of 
conditions  ;  some  of  these  may  be  so  harmful  that  the  individual  is  destroyed 
and  its  race  comes  to  an  end.  Other  individuals,  under  circumstances  of 
less  severity,  may  undergo  modifications  in  their  molecular  structure  which 
will  serve  to  neutrahse  the  effect  of  the  injurious  invironment.  Any  such 
modification  in  structure,  morphological  or  molecular,  must  be  transmitted  to 
the  next  generation,  so  that  with  slowly  varying  external  conditions  there  is 
a  possibihty  of  a  corresponding  slow  variation  in  type,  which  may  finally 
attain  a  form  altogether  different  from  that  with  which  it  set  out.  A  new 
species  may  in  this  way  be  formed  by  gradual  alteration  of  environment. 
It  is  not  therefore  difficult  to  understand  in  the  case  of  such  organisms  either 
the  maintenance  of  type  by  heredity  under  constant  conditions,  or  the 
change  of  type  with  gradually  varying  conditions. 

Reproduction  by  continuous  growth  and  division  is  not,  however,  the 
only  means,  even  in  the  unicellular  animals,  by  which  new  generations  may 
be  produced.  If  protozoa,  such  as  paramoecia,  be  kept  for  a  long  time  in 
nutrient  solutions  their  rapidity  of  reproduction  after  a  time  falls  off,  while 
many  die,  and  others  become  the  easy  prey  to  infectious  diseases.  Under 
these  conditions  a  new  phenomenon  makes  its  appearance,  viz.  '  conjuga- 
tion,' which  is  the  analogue  of  the  sexual  reproduction  of  the  higher  animals. 
Infusoria  contain  two  kinds  of  nuclei,  a  large  and  a  small,  known  as  the 
macro-nucleus  and  the  micro-nucleus  respectively.  During  conjugation  the 
macro-nucleus  breaks  up  and  disappears  in  two  cells,  which  become  closely 
applied  together,  while  in  each  the  micro-nucleus  divides  twice  to  form  four 
spindle-shaped  bodies.  Three  of  these  degenerate  (hke  the  polar  bodies  of 
the  ovum),  while  the  fourth  divides  into  two.  This  is  followed  by  an 
exchange  of  micro-nuclei,  one  micro-nucleus  from  a  passing  into  b,  while 
one  micro- nucleus  from  b  passes  into  a.  The  two  cells  then  separate,  a  single 
micro-nucleus  being  formed  in  each  by  the  amalgamation  of  the  two.  This 
micro-nucleus  then  divides  three  times,  so  that  eight  nuclei  are  formed,  while 
the  cell  itself  divides  into  four,  two  nuclei  passing  into  each  of  the  daughter 
cells.  Of  these  one  enlarges  to  form  the  macro-nucleus,  while  the  other 
remains  as  the  micro- nucleus.  After  conjugation  has  occurred,  the  colony  of 
infusoria  takes  on,  so  to  speak,  a  new  lease  of  life,  and  there  is  a  rapid 
production  of  new  generations  by  simple  division  of  the  cells,  in  which  both 
macro-nucleus  and  micro-nucleus  take  part.     Conjugation  apparently  only 


ESSENTIAL  FEATURES  OF  SEXUAL  PROCESS  1201 

occurs  in  the  presence  of  adverse  coiulitions,  and  may  be  prevented  almost 
indefinitely  by  maintaining  the  colonies  in  as  favourable  conditions  as 
possible.  In  certain  organisms,  especially  in  Alga>,  in  which  similar  pheno- 
mena take  place,  each  organism  after  conjugation  may  surround  itself  with 
a  thickened  wall  and  remain  for  a  considerable  length  of  time  in  a  state  of 
suspended  animation.  It  is  very  difficult  to  understand  the  advantage  of 
this  interchange  of  nuclear  material  either  to  the  individual  or  to  the  race. 


Second  fission 

First  fission,  after  separation 
Differentiation  of  micro-  and 
macro-nuclei 

Separation  of  the  gametes 
>  Division  of  the  cleavage-nucleus 


Cleavage-nucleus 
Exchange  and  fusion  of  the  germ- 
nuclei 
Oerm-nuclei 


►  Formation  of  the  polar  bodies 


Union  of  the  gametes 


Fia.  553.     Diagram  showing  the  history  of  the   micro-nuclei   during   the 
conjugation  of  paramcccium.     (From  Wilson  after  INIatjpas.) 
X  and  Y  represent  the  opposed  macro-  and  micro-nuclei  in  the  two  gametes 
circles  represent  degenerating  and  black  dots  persisting  nuclei. 

It  has  been  suggested  that  as  soon  as  each  individual  concerned  in  the  pro- 
cess receives  the  nuclear  material  from  organisms  which  may  have  been 
exposed  to  slightly  different  circumstances,  corresponding  changes  will  be 
introduced  into  the  tendencies  to  growth  of  the  product  of  the  union.  Some 
of  these  tendencies  may  be  more  advantageous  than  before,  while  others  may 
be  the  reverse.  Increased  possibility  of  variation  is,  however,  intro- 
duced by  this  admixture  of  nuclear  material,  and  this  may  be  the  advantage 
of  the  process  to  the  race.  It  should  be  noted  that  the  half  of  the  micleus 
lost  by  each  conjugating  organism  is  qualitatively  different  from  that  which 
it  retains  and  probably  from  that  which  it  receives.  A  gamete  in  which 
the  micleus  can  be  represented  by  ab,  and  which  by  simple  division  will 
produce  similar  organisms  with  nucleus  ab,  conjugates  with  an  organism 


1202  PHYSIOLOGY 

of  slightly  dift'ereiit  structure,  and  therefore  with  a  nucleus  which  can 
be  represented  as  cd.  After  conjugation,  the  ah  gamete  will  contain  a 
nucleus  represented  by  ac,  while  the  cd  gamete  will  contain  a  nucleus 
represented  by  hd.  ac  or  hd  may  be  better  or  worse  combinations  than 
ah  or  cd.  If  either  of  them  is  better,  that  organism  will  survive  under  the 
less  favourable  conditions,  and  the  race  will  continue  with  a  slight,  and  to  us 
inappreciable,  change  of  type. 

REPRODUCTION  IN  THE  METAZOA 
The  numberless  cells  forming  the  bodies  of  the  higher  animals  are  all 
produced  by  a  series  of  divisions  from  a  single  cell,  the  fertilised  ovum. 
This  cell  is  the  result  of  a  process  of  conjugation  between  two  cells  derived 
from  different  individuals.  With  the  multiplication  of  cells  forming  a  single 
organism  there  is  of  course  an  increased  size  of  the  organism.  It  is  doubt- 
ful whether  this  of  itself  would  be  of  any  advantage,  were  it  not  that  the 
multiphcation  of  cells  goes  hand  in  hand  with  differentiation,  groups  of 
cells  being  modified  structurally  and  set  aside  for  one  or  other  function  of  the 
body.  Differentiation  of  function  implies  higher  functional  capacity. 
As  a  motor  organ  or  as  a  means  of  locomotion,  the  differentiated  muscle- 
cells,  with  their  attached  parts,  must  be  more  effective  than  the  undif- 
ferentiated protoplasm  of  the  amoeba.  Specialisation  of  function  involves 
changes  of  type  in  the  cells  resulting  from  the  division  of  the  primitive  un- 
cUfferentiated  ovum.  In  most  cases  this  change  of  type  is  permanent.  An 
epithehal  cell  such  as  that  forming  the  epidermis  or  the  liver,  when  it  divides, 
produces  another  cell  of  the  same  kind.  One  might  almost  speak  of  the 
evolution  of  a  new  species  of  cell  but  that  it  takes  place  within  the  short 
period  of  the  development  of  the  multicellular  individual,  instead  of  occupy- 
ing a  long  space  of  time,  and  involving  the  destruction  of  countless  indi- 
viduals, as  is  the  case  when  a  change  of  type  gradually  occurs  in  unicellular 
organisms.  Differentiation  necessarily  brings  with  it  a  limitation  of  the 
powers  of  reproduction.  Any  one  of  the  descendants  of  a  unicellular 
organism  is  in  all  respects  equivalent  to  its  ancestor,  and  can  reproduce  the 
same  type  of  individual.  The  specialised  liver-  or  muscle-cell  can  only 
produce  a  cell  of  the  same  type,  one,  that  is  to  say,  incapable  of  independent 
existence  or  of  forming  the  divergent  series  of  types  necessary  for  the  forma- 
tion of  an  individual.  Differentiation  of  function  therefore  involves  the 
setting  aside  of  certain  cells,  germ-cells,  which  retain  their  primitive  character 
and  are  capable  of  indefinite  division  to  form  new  generations  each  capable 
of  developing  into  a  complete  individual.  These  germ-cells  can  often  be 
recognised  from  the  very  earliest  divisions  of  the  fertilised  ovum,  which  lead 
to  the  production  of  the  mature  individual.  Thus,  in  Ascaris,  the  progenitor 
of  the  germ-cells  differs  from  the  somatic  cells  both  by  the  greater  size  of 
its  nucleus  and  in  its  mode  of  division  (Fig.  554).  In  the  cells  destined  to 
produce  the  somatic  cells  a  portion  of  the  chromatin  is  cast  out  into  the 
cytoplasm,  where  it  degenerates,  so  that  only  in  the  germ-cells  is  the  sum 
total  of  the  chromatin  retained.     Thus  in  the  two-celled  stage,  in  one  cell 


ESSENTIAL  FEATURES  OF  SEXUAL  PROCESS  1203 

all  the  chromatin  is  preserved,  while  in  the  other  cell  the  thickened  ends  of 
the  chromosomes  are  cast  off  into  the  cytoplasm  and  degenerate,  only  the 
thinner  central  portions  being  preserved.  When  these  divide  again,  the 
same  process  is  repeated  in  only  one  of  the  daughter  cells  derived  from  a 
germ-cell,  and  the  process  is  repeated  during  five  or  six  divisions,  after 
which  the  chromatin  elimination  ceases  and  the  two  primordial  germ-cells 


Fig.  554.     Origin  of  the  primordial  germ-cells  and  casting  out  of  chromatin  in 
the  somatic  cells  of  Ascnris.    (Wilson  and  Boveki.) 

A,  two-cell  stage  dividing  ;  s,  stem-cell,  from  which  arise  the  germ-cells.  B,  the 
same  from  the  side,  later  iu  the  second  cleavage,  showing  the  two  types  of  mitosis 
and  the  casting  out  of  chromatin  (c)  in  the  somatic  cell,  c,  resulting  four-cell 
stage  ;  the  eliminated  chromatin  at  c.  d,  the  third  cleavage,  repeating  the  foregoing 
process  in  the  two  upper  cells. 

thenceforward  give  rise  only  to  other  germ-cells  in  which  the  entire  chromatin 
is  preserved.  Thus  "  the  original  nuclear  constitution  of  the  fertilised  egg  is 
transmitted,  as  if  by  a  law  of  primogeniture,  only  to  one  daughter  cell,  and 
by  this  again  to  one,  and  so  on,  \\liile  in  other  daughter  cells  the  chromatin  in 
part  degenerates,  in  part  is  tran.sformed,  so  that  all  of  the  descendants  of 
these  side-branches  receive  small  reduced  nuclei  "  (Boveri,  quoted  by 
Wilson). 

The  innnortality,  which  was  the  property  of  all  the  unicellular  ancestors 
of  the  metazoa.  has  in  the  latter  descended  only  to  the  germ-cells.  All  the 
other  cells  of  the  body,  which  form  the  nervous  and  muscular  tissues, 
glands,  skin,  &c.,  are  mortal.  They  ])ass  through  a  certain  number  of 
divisions  ;  but  although  this  number  is  large,  it  is  limited,  and  on  the  number 


1204  PHYSIOLOGY 

of  divisions  which  are  possible  depends  the  normal  duration  of  life  of  the 
organism  to  which  the  cells  belong.  We  may  thus  regard  the  egg-cell  as 
dividing  into  two  parts.  From  one  part  will  be  formed  by  differentiation 
all  the  complex  somatic  mechanisms  of  the  adult  animal ;  the  other  part 
will  divide,  but  will  remain  in  an  undifferentiated  form,  until  its  descendants 
can  conjugate  with  germ-cells  from  other  individuals  and  form  fertilised 
egg-cells,  destined  to  undergo  the  same  series  of  changes. 

The  metazoan  individual  thus  consists  of  a  mortal  host  holding  within  itself  the 
immortal  sexual  cells  or  gonads.  Gaskell  has  pointed  out  that  the  development  of 
the  fertilised  ovum  involves  two  parallel  processes — on  the  one  hand,  the  elaboration 
of  the  elements  forming  the  host  ;  on  the  other,  of  those  derived  from  the  free-living 
independent  germ-cells.  From  the  very  beginning  the  somatic  part  of  the  organism, 
the  host,  is  a  reacting  individual  in  which  the  nervous  system  acts  as  the  integrator  of 
all  the  activities  of  the  body  and  as  the  middleman  between  the  internal  and  external 
epithelial  surfaces  and  the  muscular  system.  The  host  may  thus  be  regarded  as  a 
neuro-epithelial  syncytium,  every  step  in  its  evolution  and  differentiation  being  attended 
by  increased  control  of  all  the  units  by  a  central  nervous  system. 

The  gonads  were  placed  at  first  within  the  interstices  of  this  syncytium,  and  escaped 
to  form  a  new  generation  only  after  the  death  and  disintegration  of  the  host.  But 
differentiation  and  division  of  labour  affect  also  the  free-living  gonads.  Some  of  these 
form  a  germ  epithelium  surrounding  the  body  cavity,  of  which  a  few  only  of  the  elements 
pass  out  of  the  host  as  perfect  germ-cells,  while  the  others  are  subordinated  to  the 
metabolic  needs  of  these  germ-cells  and  are  transformed  into  various  elements,  such  as 
nurse-cells,  wandering  mesoderm  cells  or  phagocytes,  yolk-cells,  and  so  on.  Gaskell 
regards  the  greater  part,  it  not  the  whole,  of  the  connective-tissue  framework  of  the 
body,  as  well  as  the  wandering  corpuscles  of  the  blood  and  tissue-fluids,  as  derived  from 
these  primitive  germ -cells.  All  these  tissues,  though  useful  to  the  host  as  well  as  to 
the  finally  successful  germ-cells,  present  the  common  feature  of  an  absolute  independence 
of  the  central  nervous  system.  Thus  the  evolution  of  the  animal  kingdom  means 
essentially  the  evolution  of  the  host,  and  must  therefore  be  closely  connected  with  the 
evolution  of  the  central  nervous  system,  the  ruling  element  in  the  neuro-muscular 
syncytium.  On  these  grounds  Gaskell  has  used  the  comparative  morphology  of  the 
central  nervous  system  as  a  means  of  tracing  the  origin  of  the  vertebrate  from  the  in- 
vertebrate type,  and  has  come  to  the  conclusion  that  the  immediate  ancestor  of  the 
vertebrate  must  be  sought  in  the  invertebrate  group  presenting  the  most  highly  developed 
central  nervous  system,  namely,  the  Arthropoda. 

All  the  complex  mechanisms  which  are  concerned  in  maintaining  the 
life  of  the  individual  have  apparently  been  developed  in  order  to  give  the 
potentially  immortal  germ-cells  a  better  chance  of  survival  in  the  struggle 
for  existence.  From  the  broad  biological  standpoint,  as  Foster  points  out, 
all  the  toil  and  turmoil  of  human  existence  may  be  regarded  simply  as  the 
by- play  of  an  ovum-bearing  organism.  From  the  same  standpoint  one  must 
acknowledge  that  the  mortality  of  the  individual,  resulting  from  the  absence 
of  an  indefinite  power  of  multiplication  among  the  somatic  cells,  must  be 
an  advantage  to  the  race.  Throughout  the  living  world  the  welfare  of  the 
individual  is  subordinated  to  that  of  the  species.  With  each  new  genera- 
tion there  are  possibilities  of  variation  and  of  the  production  of  individuals 
better  or  worse  fitted  for  the  maintenance  of  the  race  than  those  of  the 
previous  generation.  Immortality  of  the  individual  would  handicap  the 
survival  of  the  younger  generations,  and  we  should  have  the  same  retardation 


ESSENTIAL  FEATURES  OF  SEXUAL  PROCESS  1205 

of  progress  in  a  race  that  we  see  in  many  civilised  communities,  where  the 
power  and  the  conduct  of  affairs  are  in  the  hands  of  the  older  members. 


THE  FORMATION  OF   GERM-CELLS 

In  multicelkilar  organisms  the  cells  which  conjugate  to  form  a  new  cell, 
capable  of  developing  into  an  individual,  are  of  two  kinds.  One,  which 
has  generally  a  certain  amount  of  reserve  material  stored  up  in  its  cytoplasm, 
is  the  female  element  and  is  called  the  ovum.  The  other  cell,  which  consists 
of  little  more  than  nuclear  material,  is  the  male  element,  and  is  called  the 
spermatozoon.  Both  kinds  of  cells  are  derived  from  a  mass  of  undifEerentiated 
cells,  the  germ  epithelium,  which,  as  we  have  seen,  can  often  be  traced  directly 
back  to  the  first  divisions  of  the  fertilised  egg.  The  use  of  the  reserve 
material  in  the  ovum  is  to  serve  as  food  for  the  developing  individual.  The 
ovum  and  spermatozoon  caimot  be  regarded  as  corresponding  to  complete 
cells.  Before  their  union  or  conjugation  both  male  and  female  germ-cells 
undergo  certain  important  changes  which  differentiate  them  from  the 
ordinary  somatic  cells  of  the  indi^^dual.  The  essential  differences  between 
a  germ-cell  and  a  somatic  cell  can  be  best  seen  by  a  study  of  the  nuclear 
changes  which  precede  their  formation.  In  division  the  nuclei  of  all  somatic 
cells,  whether  of  plants  or  animals,  undergo  a  series  of  changes  which,  in 
their  broad  outlines,  are  identical  throughout  both  animal  and  vegetable 
kingdoms  (Fig.  555).  The  nucleus  of  the  resting  cell  in  its  vegetative  condi- 
tion is  generally  separated  from  the  cytoplasm  by  a  nuclear  membrane,  and 
contains  irregular  masses  of  a  material  staining  deeply  with  basic  dyes,  and 
known  as  chromatin.  In  the  cytoplasm  of  most  animal  cells  may  be  seen  a 
small  particle  known  as  the  centrosome.  When  division  is  about  to  take 
place  the  clumps  of  chromatin  arrange  themselves  into  a  filament  which 
forms  a  continuous  skein,  the  '  spireme  stage.'  This  then  breaks  up  into 
a  number  of  segments,  often  V-shaped,  the  chromatin  filaments  or  chromo- 
somes. Each  of  the  filaments,  in  large  nuclei,  may  often  be  seen  to  be  com- 
posed of  rows  of  granules.  While  this  change  has  been  occurring  the  nuclear 
membrane  in  most  cases  disappears,  and  the  centrosome  outside  the  nucleus 
divides  into  two  parts,  which  travel  to  opposite  ends  of  the  nucleus.  Round 
each  centrosome  the  cytoplasm  is  modified  and  presents  a  radiate  appearance, 
the  aster,  while  joining  the  two  centrosomes  is  a  spindle  of  fine  fibres,  the 
achromatic  spindle.  The  V-shaped  segments  of  chromatin  arrange  them- 
selves in  a  circle  at  the  equator  of  the  spindle  midway  between  the  two 
centrosomes.  Each  of  the  loops  then  splits  longitudinally,  and  each  half 
travels  towards  one  or  other  of  the  centrosomes,  thus  forming  two  daughter 
nuclei.  The  half-loops  then  join  to  form  a  skein,  and  may  return  to  the  form 
of  a  resting  nucleus.  These  different  phases  in  division  are  presented  by  all 
somatic  cells,  and  have  received  the  following  names  : 

(1)  Prophase  (the  formation  of  the  spireme  and  of  the  achromatic  spindle, 
and  the  breaking  up  of  the  spireme  into  chromatin  loops  or  chromosomes). 

(2)  Metaphase  (the  splitting  of  the  chromosomes). 


1206  PHYSIOLOGY 

(3)  Anaphase  (the  travelling  of  each  half-chromosome  to  the  extremity 
of  the  spindle). 

(4)  Telophase  (the  retrogressive  changes  leading  to  the  conversion  of 


Pf:  1 


Fig.  555.     Diagram  showing  the  changes  which  occur  in  the  centrosomes 

and  nucleus  of  a  cell  in  the  process  of  mitotic  division.     (Schafeb.) 

The  nucleus  is  supposed  to  have  four  chromosomes. 

the  chromatin  filaments  into  an  ordinary  resting  nucleus,  which  are  accom- 
panied or  preceded  by  a  division  of  the  cytoplasm  across  the  equatorial  part 
of  the  spindle). 

When  the  spireme  has  broken  up  into  separate  chromatin  loops,  it  is 
possible  to  count  them,  and  it  is  found  that  the  number  present  in  any  cell 
is  constant  for  the  species.     Thus  every  human  somatic  cell  has  sixteen 


ESSENTIAL  FEATURES  OF  SEXUAL  PROCESS  1207 

cliromosomes  in  its  nucleus.  The  same  number  is  found  in  types  so  far 
apart  as  the  ox,  the  guinea-pig,  and  the  onion.  In  the  mouse,  the  sala- 
mander, and  the  lily  the  number  is  twenty-four.  Other  types,  such  as  the 
crustacean  Artemia,  are  said  to  have  as  many  as  168  chromosomes,  while 
in  Ascaris  the  cells  only  contain  two  or  four  chromosomes.  All  these  changes, 
which  are  included  under  the  term  mitosis  or  'karyohnesis,  seem  to  be 
adapted  to  ensuring  an  equal  qualitative  as  well  as  quantitative  distribution 
of  the  nuclear  chromatin  among  the  daughter  cells  resulting  from  the 
division  of  any  cell.  As  we  have  seen  in  an  earlier  chapter,  the  nucleus,  by 
its  interaction  with  the  cytoplasm,  determines  the  processes  of  assimilation 


\m\ 


\ 


Fig.  556.    Three  stages  of  hetcrotypc  mitosis  in  spermatocyte  of  triton.     (Moofe.) 
rt,  germinal  condition  of  chromosomes  ;   h,  gemini  arranged  in  quadrate  loops  or 
tetrads;    c,  separation  of  tetrads  into  the  duplex  chromosomes  of  the  daughter 
nuclei. 

and  growth  of  the  whole  cell.  For  the  preservation  of  type  in  cell  division 
it  is  therefore  essential  that  the  nuclei  of  the  daughter  cells  shall  be  identical 
in  all  respects  with  the  nucleus  of  the  mother  cell. 

Sexual  reproduction  involves  the  conjugation  of  two  cells,  with  union 
of  their  nuclei.  If  each  of  these  nuclei  consisted  of  the  normal  number  of 
chromosomes,  the  fertilised  egg-cell  would  contain  double  the  number 
characteristic  of  the  species,  and  since  these  chromosomes  would  divide  by 
splitting,  the  number  of  chromosomes  in  each  cell  would  be  doubled  with 
each  generation.  This  doubling  is  obviated  by  the  fact  that,  in  the  forma- 
tion of  the  germ-cells,  the  ovum  and  spermatozoon  nuclei  undergo  a  special 
type  of  division,  which  leads  to  the  reduction  of  the  chromosomes  in  the 
sexually  mature  cell  to  one-half  of  the  number  characteristic  of  the  species. 
This  mode  of  cell  division  is  often  called  '  division  by  reduction,'  or  '  hetero- 
type  '  mitosis,  or  '  meiosis  '  (Fig.  556).  We  may  take  as  an  example  the 
development  of  spermatozoa.     The  mother  cells  of  the  spermatozoa,  the 


1208 


PHYSIOLOOY 


spermatocytes,  divide  twice,  giving  rise  to  four  daughter  cells,  the  spermatids, 
each  of  which  develops  into  a  functional  spermatozoon.  In  the  nuclear 
changes  preparatory  to  the  first  division,  the  spireme,  when  it  breaks  up, 
gives  rise  to  only  half  the  normal  number  of  chromosomes.  Thus  if  the 
somatic  number  of  chromosomes  were  four  we  should  find  in  the  spermato- 
cyte, after  the  breaking  up  of  the  spireme,  only  two  chromosomes.  These 
take  up  their  position  at  the  equator  of  the  achromatic  spindle  and  then 
divide,  but  the  division  is  effected,  not  by  splitting  of  the  double  chromo- 
some, but  by  transverse  division.  Each  chromosome  breaks  into  half, 
one  half  going  to  each  daughter  cell.  Since  each  of  the  reduced  number  of 
chromosomes  can  be  regarded  as  made  up  of  two  normal  chromosomes 


Primordial  CTcrm-cell. 


Spermatogonia. 


Primary  spermatocyte. 
Secondary  spermatocytes. 

Spermatids. 
Spermatozoa. 


Division-period  (the  number  of  divi» 
sions  is  much  greater) . 


Growth-period. 


M  aturation-period, 


Fig.  557. 


placed  end  to  end  or  joined  to  form  a  ring,  as  in  Fig.  556,  h,  the  division  in 
the  middle  provides  for  a  quahtative  difference  between  the  two  daughter 
cells.  If  we  indicate  the  four  normal  chromosomes  as  a,  h,  c,  d,  in  ordinary 
somatic  division  each  daughter  cell  will  also  contain  chromosomes  which 
may  be  represented  as  al.  61,  cl,  dl,  and  a2,  &2,  c2,  d2.  In  the  sperma- 
tocvte  the  two  chromosomes  may  be  represented  as  ah  and  cd.  When  they 
divide  one  daughter  cell  receives  a  and  c,  while  the  other  daughter  cell 
receives  b  and  d.  The  second  division  of  these  daughter  cells  takes  place 
generally  by  splitting  of  the  filaments,  so  that  finally  four  spermatids  are 
produced  (Fig.  557),  each  containing  two  chromosomes,  two  of  them  con- 
taining a  and  c,  while  the  other  two  contain  h  and  d.  In  the  ovum,  during 
maturation,  analogous  changes  take  place.  Two  successive  cell  divisions 
occur  as  in  the  formation  of  spermatozoa,  but  the  daughter  cells  are  of  very 
unequal  size.  In  the  first  division,  the  heterotypical  division,  the  chromo- 
somes fuse  in  pairs  and  then  divide  as  in  the  spermatocytes  so  that  each  of 
the  daughter  cells  contains  one  half  the  somatic  number  of  chromosomes. 
The  larger  of  the  two  resulting  cells,  which  retains  most  of  the  cytoplasm, 


ESSENTIAL  FEATURES  OF  SEXUAL  PROCESS  1209 

is  still  called  the  ovum,  while  the  smaller  one  is  spoken  of  as  the  '  first  polar 
body.'  The  ovum  now  divides  again  and  throws  off  a  second  polar  body, 
the  division  being  of  the  homotypical  variety.  The  first  polar  body  may 
also  divide,  so  that  from  the  original  ovum  three  cells  are  produced,  one  of 
which  retains  the  greater  part  of  the  cytoplasm,  while  the  others  are  extruded, 
and  degenerate  (Fig.  558).  The  mature  ovum  has,  however,  only  half  the 
normal  number  of  chromosomes,  so  that  its  nucleus  is  equivalent  to  the 
nucleus  forming  the  head  of  the  spermatozoon.  The  only  difference  there- 
fore between  the  formation  of  ovum  and  spermatozoon  is  that  in  the  former 
case  three  of  the  cells  formed  by  the  division  of  the  primitive  ovum  are 

primordial  gcnn-cel\. 


Ocigonia. 


Primary  oocyte  or  ovarian  egg. 

Secondary  oocytes  (egg  and 

first  polar  body ) 


Mature  egg  and  three  polai  bodies 


•  Division-period  fthe  number  of  divi- 
sions is  much  greater). 


.   Growth-period. 


M  aturation-period. 


Fig.  558. 

abortive,  whereas  in  the  spermatozoon  all  four  daughter  cells  produced 
from  the  spermatocyte  remain  functional.  The  production  of  these  two 
kinds  of  sexual  cell  is  represented  in  Figs.  557  and  558. 

Since  the  nuclei  of  the  mature  ovum  and  spermatozoon  only  contain  half 
the  normal  number  of  chromosomes,  they  are  generally  spoken  of  as  pro- 
tiuclei. 

FERTILISATION 

The  essential  features  of  fertilisation,  i.e.  the  union  of  the  sexual  cells, 
are  best  studied  in  some  of  the  lower  invertebrates,  such  as  ascaris  or  echino- 
dernis.  In  the  latter  fertilisation  takes  place  in  the  sea- water,  into  which 
both  ova  and  spermatozoa  are  extruded.  The  ovum  of  the  echinoderm 
consists  of  a  naked  mass  of  protoplasm.  Of  the  countless  hordes  of  sperma- 
tozoa which  may  be  in  the  neighbourhood  of  a  given  ovum  only  one  as  a 
rule  enters.  As  soon  as  the  spermatozoon  has  entered  the  ovum  a  tough 
membrane  is  rapidly  formed  round  the  latter,  so  preventing  the  entrance  of 
any  further  spermatozoa.  The  head  of  the  spermatozoon  enters  the  egg, 
while  the  tail  atrophies  and  disappears.  The  head  of  the  spermatozoon 
enlarg(>s  and  assumes  the  character  of  a  nucleus,  the  dense  mass  of  chro- 
niatin  broakii\g  up  first  into  a  thread  and  then  into  the  characteristic  number 


1210 


PHYSIOLOGY 


of  chromosomes  (Fig.  559).  The  egg  now  contains  two  nuclei  or  pro-nuclei, 
exactly  similar  in  appearance,  one  derived  from  the  male  and  the  other 
belonging  to  the  egg  itself.     The  two  nuclei  approach  one  another  and  join. 


^  Fig.  559.  Fertilisation  and  first  division  of  ovum  of  Ascaris  megalocephala.  (Slightly 
modified  from  Boveri  and  Wilson.) 
A,  second  polar  globule  just  formed  ;  the  head  of  the  spermatozoon  is  becoming 
changed  into  a  reticular  nucleus  (  5  ),  which,  however,  shows  distinctly  two  chromo- 
somes ;  just  above  it,  its  archoplasm  is  shown  :  the  egg- nucleus  (  ?  )  also  shows  two 
chromosomes,  b,  both  pro-nuclei  are  now  reticular  and  enlarged  ;  a  double  cen- 
trosome  {a)  is  visible  in  the  archoplasm  which  lies  between  them,  c,  the  chromatin 
in  each  nucleus  is  now  converted  into  two  filamentous  chromosomes  ;  the  centro- 
somes  are  separating  from  one  another,  d,  the  chromosomes  are  more  distinct  and 
shortened  ;  the  nuclear  membranes  have  disaj^peared  ;  the  attraction- spheres  are 
distinct,  e,  mingling  and  splitting  of  the  four  chromosomes  (c) ;  the  achromatic 
spindle  is  fully  formed,  r,  separation  (towards  the  poles  of  the  spindle)  of  the 
halves  of  the  split  chromosomes,  and  commencing  division  of  the  cytoplasm.  Each 
of  the  daughter  cells  now  has  four  chromosomes ;  two  of  these  have  been  derived 
from  the  ovum  nucleus,  two  from  the  spermatozoon  nucleus. 

In  many  cases  there  is  an  apparent  fusion  of  the  substance  of  the  two 
nuclei.  In  others  the  chromatin  filaments  of  male  and  female  simply  lie 
side  by  side,  forming  a  complete  nucleus  with  the  somatic  number  of  chromo- 
somes.    Fertilisation  is  rapidly  followed  by  cell  division.     Each  of  the 


ESSENTIAL  FEATURES  OF  SEXUAL  PROCESS  1211 

chromosomes  splits  longitudinally,  half  going  to  each  of  the  daughter  cells, 
and  this  process  is  repeated  throughout  the  succeeding  divisions  which  result 
in  the  formation  of  the  new  individual.  Thus  every  cell  of  the  body  con- 
tains a  nucleus  of  which  exactly  one  half  is  paternal  and  the  other  maternal  in 
origin.  In  ascaris  it  is  often  possible,  in  the  first  few  divisions  of  the  fertihsed 
ovum,  to  distinguish  in  the  daughter  nuclei  the  chromatin  filaments  derived 
from  the  male  from  those  derived  from  the  female. 

The  strong  impetus  to  cell  division  given  by  the  process  of  fertihsation 
has  naturally  aroused  much  curiosity  as  to  its  intimate  character.  It  might 
be  thought  that  for  cell  division  to  take  place  a  normal  number  of  chromo- 
somes is  essential.  As  against  this  explanation  may  be  adduced  the  fact 
that  in  many  animals  parthenogenesis  occurs.  The  female  pro-nncleus 
may,  under  certain  conditions  of  en\dronment  or  nutrition,  start  dividing 
and  give  rise  to  an  embryo,  each  cell  of  which  contains  only  half  the  normal 
number  of  chromosomes.  In  other  cases  of  parthenogenesis  only  one 
polar  body  is  extruded,  or  the  second  polar  body  joins  again  \\ith  the  female 
pro-nucleus.  In  either  case  the  ovum  contains  a  nucleus,  with  a  normal 
number  of  chromosomes,  which  divides  and  produces  an  individual  resembhng 
that  resulting  from  the  union  of  ovum  and  spermatozoon.  It  has  been 
suggested  that  the  impetus  to  division  is  given  by  the  entry  of  the  sperma- 
tozoon itself.  In  the  series  of  divisions  which  precede  the  formation  of  the 
female  pro-nucleus  the  centrosome  of  the  ov^um  generally  disappears,  whereas, 
in  the  formation  of  the  spermatozoon,  the  centrosome  persists  ana  forms  the 
middle  part  of  the  spermatozoon.  In  many  cases  the  centrosomes  divide 
in  the  spermatozoon  itself,  so  that  this  contains  two  centrosomes  when  it 
enters  the  egg.  These  two  centrosomes  then  become  the  centres  of  attrac- 
tion spheres.  They  diverge,  and  between  them  is  formed  an  achromatic 
spindle,  along  the  equator  of  which  the  chromatin  filaments  of  male  and 
female  pro-nuclei  arrange  themselves.  It  is  doubtful,  howev^er,  how  far 
the  centrosome  can  be  regarded  as  a  permanent  cell  structure.  In  echino- 
derm  eggs  various  modes  of  treatment  will  lead  to  the  appearance  of  attrac- 
tion spheres  in  the  cytoplasm,  and  even  to  division  of  the  non-fertilised 
egg.  Loeb  has  suggested  that  the  action  of  the  spermatozoon  is  essentially 
chemical  in  character.  By  alteration  of  the  medium  in  which  the  eggs  are 
contained,  Loeb  has  succeeded  in  imitating  exactly  the  changes  which 
normally  need  the  entrance  of  a  spermatozoon  for  their  occurrence.  On 
immersing  the  eggs  in  a  weak  solution  of  formic  or  lactic  acid,  a  membrane 
is  formed.  The  eggs  are  then  taken  from  the  acid,  placed  in  concentrated 
sea-water  for  a  short  time,  and  then  removed  to  ordinary  sea-water.  Division 
rapidly  occurs  with  the  production  of  a  normal  larva.  He  suggests  that  the 
spermatozoon  brings  with  it  ferments,  or  other  chemical  substances,  which 
excite  the  egg-iuicleus  and  cytoplasm  in  the  same  way  as  the  chemical 
measures  adopted  for  this  artificial  induction  of  segmentation. 


SECTION  II 

DEVELOPMENT   AND    HEREDITY 

There  is  perhaps  no  phenomenon  which  is  so  impressive  as  the  development 
from  a  minute  speck  of  protoplasm,  the  fertihsed  egg,  of  an  individual 
partaking  of  the  minutest  characteristics  of  both  its  parents.  An  egg- cell 
has  much  the  same  appearance  whether  it  belong  to  an  echinoderm,  a  fish, 
or  a  man.  In  the  process  of  development,  by  a  simple  repetition  of  a  series 
of  cell  divisions,  this  undifferentiated  protoplasm  is  formed  into  the  complex 
organs  with  the  potentialities  and  habits  which  distinguish  the  type  from 
which  the  protoplasm  has  been  derived.  We  cannot  wonder  that  the 
intimate  nature  of  this  process  has  been  the  subject  of  speculation  from  the 
very  birth  of  science.  Running  through  these  speculations  are  two  main 
ideas,  which  have  been  labelled  the  theories  of  '  evolution '  and  of  '  epi- 
genesis.'  By  the  '  evolutionists  '  the  egg  was  believed  to  contain  an  embryo 
fully  formed  in  miniature,  as  the  bud  contains  the  flower  or  the  chrysalis 
the  butterfly.  Development  was  therefore  only  the  unfolding  of  something 
already  existing.  If,  however,  this  theory  be  pushed  to  its  utmost  and  if  the 
egg  contain  a  complete  embryo,  this  must  itself  contain  eggs  for  the  next 
generation,  and  so  on  ad  infinitum,  a  conclusion  which  is  of  course  absurd. 
According  to  the  theory  of  epigenesis,  the  structure  of  the  egg  is  wholly 
different  from  that  of  the  adult,  its  development  consisting  in  the  continual 
formation  one  after  the  other  of  new  parts  previously  non-existent  as  such. 
There  is  no  doubt  that  this  view  is  fundamentally  correct.  The  difiiculty 
with  which  we  have  to  contend  is  the  understanding  of  the  orderly  sequence 
and  correlation  of  the  cell  divisions  and  differentiations  which  result  in  an 
adult  individual  of  the  same  type  as  the  parents.  The  fact  that,  under 
approximately  identical  conditions,  one  mammalian  ovum  will  give  rise  to 
a  mouse  and  the  other  to  a  man  indicates  that  there  must  be  some  difference 
in  structure,  organisation,  or  composition  of  the  primitive  egg-cell  in  each 
case,  and  the  theory  of  '  evolution  '  has  reappeared  in  later  days  in  a  some- 
what modified  form,  according  to  which  the  differentiation  of  the  ovum 
is  causally  connected  with  a  preformed  differentiation  in  the  nuclear  struc- 
tures, e.g.  chromosomes,  of  the  ovum  itself.  We  have  already  seen  that  the 
germ-cells  in  some  types  are  separated  off  from  the  rest  of  the  embryo  at  a 
fairly  early  stage.  If  in  the  two-celled  stage  of  the  frog's  egg  one  cell  be 
destroyed  by  means  of  a  hot  wire,  the  other  cell  develops  to  form  half  an 
embryo,  thus  suggesting  that  each  cell  of  the  two-celled  embryo  could  give 

1212 


DEVELOPMENT  AND  HEREDITY  1213 

rise  only  to  the  corresponding  half  of  the  body.  This  limitation  of  develop- 
ment, however,  only  occurs  if  the  intact  cell  be  left  in  coimection  with  the 
cell  that  has  been  injured.  If,  in  echinoderm  larvae,  the  cells  be  entirely 
separated,  even  as  late  as  the  eight-celled  stage  of  division,  each  cell  will  give 
rise  to  a  whole  embryo,  differing  from  a  normal  embryo  only  in  respect  of 
size.  This  difference  suggests  that  the  number  of  divisions  that  each  cell  can 
undergo  is  predetermined  in  the  egg-cell  itself,  but  shows  also  that  the  cells 
into  which  the  egg  divides  are,  at  first  at  any  rate,  equipotential.  We  must 
assume  therefore  that  the  reason  why  one  cell  under  ordinary  circum- 
stances only  forms  one  half  of  the  embryo  is  that  its  development  is  regu- 
lated and  determined  by  the  presence  of  the  other  cell  in  connection  with 
it  forming  the  other  half  of  the  embryo.  That  is  to  say,  the  development 
of  the  egg  involves  the  reaction  to  environment  of  a  protoplasm  of  certain 
properties  and  powers  of  reaction.  The  final  product  of  development 
depends  (1)  on  the  nature  of  the  protoplasm  (including  the  nucleus)  of  which 
the  egg  is  composed,  and  (2)  on  the  environmental  conditions  to  which  the 
egg  is  subjected  during  the  rapid  growth  and  multiplication  attending  its 
development.  We  could  therefore  speak  of  a  morphology  of  inheritance, 
but  the  morphology  would  be  ultra-microscopic  and  have  relation  to  the 
molecular  structure  of  the  protoplasm  of  which  the  egg  was  composed. 

In  the  transmission  of  the  potentiahties  of  development  from  parent 
to  fertilised  egg  we  must  regard  the  nucleus  as  the  essential  structure.  In 
ordinary  development  the  spermatozoon  furnishes  only  a  nucleus  and 
centrosome,  the  ovum  supplying  the  whole  of  the  cytoplasm.  There  seems, 
however,  no  grounds  for  assigning  any  directive  power  to  the  latter  struc- 
ture. In  echinoderm  ova  it  is  possible  to  get  rid  of  the  nucleus  and  then  by 
the  introduction  of  spermatozoa  to  have  an  individual  entirely  paternal  in 
origin,  which,  on  development,  produces  a  larva  of  the  paternal  character. 
In  division  of  the  egg  the  only  part  of  the  cell  which  divides  so  that  each 
daughter  cell  shall  include  an  equal  part  of  both  parental  germs  is  the 
nucleus.  The  constant  number  of  the  chromosomes  in  each  species,  and 
their  accurate  division  on  mitosis,  suggest  that  the  hereditary  transmission 
of  the  potentialities  of  the  cell  is  bound  up  with  the  chromosomes.  It  has 
been  suggested  that  every  character  is  located  in  a  chromosome  or  part  of 
a  chromosome.  If  this  be  the  case  one  might  regard  the  differentiation 
into  various  tissues,  which  occurs  in  the  process  of  development,  as  occa- 
sioned by  an  actual  loss  or  degeneration  of  the  constituent  parts  of  one  or 
more  chromosomes.  There  is  no  doubt  that  many  tissues  do  become  thus 
differentiated  at  a  fairly  early  period  in  development,  having  undergone  in 
the  process  an  absolute  modification  of  their  potentiahties,  which  must  be 
at  any  rate  shared  by  the  chromosomes  of  their  constituent  cells.  The 
extent  to  which  this  limitation  of  powers  of  development  occurs  varies 
widely  in  different  animals.  In  the  higher  animals,  such  as  man,  epithehum 
will  reproduce  epithelium,  and  hver-cells  will  reproduce  liver-cells,  while 
nerve-cells  are  absolutely  incapable  of  multiplication  On  the  other  hand, 
in  Crustacea  a  whole  limb  may  be  torn  off  and  be  regenerated  from  the 


1214  PHYSIOLOGY 

tissues  of  the  stump.  Destruction  of  the  optic  lens  in  the  salamander  is 
followed  by  its  regeneration  from  the  anterior  part  of  the  optic  cup,  a  tissue 
which  had  no  part  in  its  primary  formation.  Worms  will  form  a  new  head 
after  decapitation.  In  these  animals  therefore  the  cells  in  many  parts  of  the 
body  possess  the  power  of  directed  growth,  if  need  arise,  in  case  of  injury, 
and  are  able  to  form  tissues  of  many  different  kinds. 

I  have  mentioned  the  small  size  of  the  larva  formed  from  isolated  cells 
of  the  segmenting  egg  as  a  proof  that  the  number  of  cell  divisions  of  the 
somatic  part  of  the  developing  animal  is  predetermined  and  limited.  This 
conclusion  must  not  be  taken  too  absolutely.  Many  of  the  tissues,  even  of 
the  highest  animals,  possess  the  power  of  almost  unlimited  regeneration  by 
cell-multiphcation  as  a  response  to  injury.  Under  normal  conditions  the 
growth  of  such  tissues  is  limited,  not  by  absence  of  power  to  divide,  but  as 
a  result  of  a  mutual  interaction  between  them  and  the  surrounding  cells. 
We  might  almost  speak  of  a  struggle  for  existence  between  the  various  tissues 
of  the  body,  which  in  the  healthy  organism  results  in  an  equihbrium,  or 
balance  of  multipHcative  powers.  If  this  balance  is  upset  by  any  means, 
such  as  stimulation  of  certain  cells  by  the  presence  of  intra-cellular  parasites, 
or  their  destruction  by  irritants  or  other  abnormal  conditions  {e.g.  exposure 
to  X-rays),  one  tissue  may  enter  into  active  growth  at  the  expense  of  the 
surrounding  tissues,  and  the  result  is  a  morbid  growth  such  as  cancer.  It  is 
possible  that  in  the  latter  case  a  new  factor  comes  into  play.  All  tissues 
of  the  body,  as  we  have  seen,  begin  to  die  from  the  time  that  they  are 
born.  They  have  a  certain  span  of  life,  a  certain  limitation  to  their  genera- 
tions, which  results  in  the  phenomenon  of  senescence,  such  as  occurs  in  a 
culture  of  protozoa.  In  protozoa  this  phenomenon  is  the  signal  for  rejuvena- 
tion by  conjugation.  It  is  possible  that  in  cancer  something  of  the  same 
nature  occurs.  It  is  at  any  rate  significant  that  in  a  rapidly  growing 
cancer  many  of  the  dividing  cells  present  the  phenomenon  of  heterotype 
mitosis,  a  phenomenon  which  is  otherwise  found  only  in  the  sexual  cells 
preparing  for  conjugation  and  for  the  production  of  a  new  individual.  Given 
adequate  conditions  of  nutrition,  there  seems  to  be  no  limit  to  the  growth  of 
cancer-cells.  In  mice  a  cancer  may  be  transferred  from  one  individual  to 
another  by  inoculation^  and  this  process  may  apparently  go  on  indefinitely, 
so  that  finally  a  mass  of  cancer-cells  may  have  been  produced  equal  in  volume 
to  many  thousands  of  mice,  and  persisting  long  after  the  mouse  from  which 
it  was  first  taken  would  have  died  under  natural  conditions. 

In  sexual  reproduction  the  new  individual  partakes  of  characteristics 
of  both  its  parents.  It  therefore  resembles  neither  of  its  parents  in  all 
details.  The  conjugation  of  the  two  parent  cells  from  which  it  is  derived  has 
been  preceded  by  a  throwing  out  of  half  the  chromosomes  from  each  parent 
cell.  It  is  therefore  natural  to  ascribe  the  variations  which  occur  among  the 
members  of  one  family  to  a  qualitative  difference  in  the  chromosomes  which 
have  been  ehminated  in  the  formation  of  their  respective  egg-cells.  Can 
we  regard  the  chromosomes  as  representing  separate  qualities  of  the  individual 
or  must  we  assume  that  all  qualities  are  represented  to  a  greater  or  less 


DEVELOPMENT  AND  HEREDITY  1215 

extent  in  every  chromosome  ?  In  the  case  of  many  quaUties,  especially 
those  which  distinguish  the  species  as  apart  from  the  individual  variation 
or  family  characteristic,  we  must  probably  accept  the  latter  idea  as  correct. 
In  this  case  the  child  can  be  regarded  as  representing  an  arithmetical  mean 
of  both  its  parents.  In  certain  respects,  however,  a  quality  seems  to  be 
transmitted  from  parent  to  oifpsring  either  completely  or  not  at  all.  This 
is  specially  apphcable  to  those  characteristics  which  have  been  rapidly 
produced  by  artificial  selection,  characters  which,  if  artificial  selection  be 
abandoned,  rapidly  disappear,  with  reversion  to  the  type  from  which  the 
special  strain  was  ultimately  produced.  The  way  in  which  these  charac- 
teristics are  transmitted  was  first  studied  by  Mendel  and  has  been  formulated 
as  Mendel's  law.  Mendel's  first  experiments  were  carried  out  on  peas. 
On  crossing  a  tall  plant  with  a  dwarf  plant  seeds  were  obtained  from  which 
all  the  plants  were  tall.  On  recrossing  the  plants  of  this  generation  among 
one  another  a  third  generation  was  obtained  in  which  25  per  cent,  of  the 
plants  were  dwarfs  and  75  per  cent,  were  tall.  Crossing  the  dwarf  plants 
among  themselves  led  to  the  production  of  dwarf  plants  through  successive 
generations.  Of  the  tall  plants  25  per  cent,  and  all  their  descendants  con- 
tiimed  to  produce  tall  plants  when  self-fertihsed,  whereas  of  the  remaining 
50  per  cent,  of  the  tall  plants  25  per  cent,  produced  dwarfs  and  the  remaining 
75  per  cent,  produced  tall  plants.  On  continuing  the  process  of  breeding,  the 
dwarf  plants  when  self-fertihsed  always  produced  dwarfs,  whereas  of  the 
tall  plants  25  per  cent,  produced  tall  plants,  which  bred  true,  while  the 
remaining  50  per  cent,  produced  the  same  percentage  of  tall  and  dwarf  as  in 
the  preceding  generations.  Mendel  explained  these  results  by  the  assump- 
tion that  a  character  could  be  dominant  or  recessive.  If  both  characters 
were  present  together  in  one  plant  it  would  partake  of  the  dominant  type  ; 
the  fact  that  this  plant  possessed  the  recessive  character  would  only  be  shown 
by  the  results  of  breeding.  In  the  case  of  the  peas  the  tall  character  was 
dominant  over  the  dwarf.  Thus  when  the  tall  and  dwarf  pea  were  crossed 
the  first  generation  of  plants  would  exhibit  the  dominant  character  and  be 
tall.  In  the  second  generation,  however,  25  per  cent,  of  the  individuals 
would  be  pure  dominants  (D  +  D),  25  per  cent,  would  be  pure  recessive 
(R  +  R),  while  50  per  cent,  would  be  mixed  (D  +  R).  The  pure  dominants 
bred  together  would  always  give  rise  to  nothing  but  pure  dominants,  the 
recessive  to  recessive,  while  the  mixed  type  would  always,  as  before,  give  rise 
to  25  per  cent,  pure  dominants,  50  per  cent,  mixed,  and  25  per  cent,  pure  reces- 
sives.     These  results  may  perhaps  be  made  clearer  by  the  following  Table  : 

D  -t-  R 

I 
DR 

I 

25%  D  50%  DR  25%  R 

I  I  _  I 

D       25%  D  50%  DR  25%  R  R 


D  D     25%  D     60%  DR  25%  R       R  R 


1216  PHYSIOLOGY 

It  has  been  suggested  that  a  very  large  number,  if  not  all,  of  the  charac- 
ters of  an  individual  might  be  brought  under  this  law.  This  might  be  done 
by  indefinitely  subdividing  the  characters,  but  the  question  would  then 
become  beyond  the  hmits  of  analysis  or  experimental  investigation.  There 
is  no  doubt  that  many  qualities  are  subject  to  Mendel's  law,  and  that  their 
study  will  be  of  considerable  assistance  in  guiding  the  efforts  of  our  breeders 
and  horticulturists  in  the  formation  of  new  varieties  desirable  for  their 
value  to  man.  In  respect  of  many  quahties  the  Mendelian  law  seems  to 
fail.  Thus  in  man  the  progeny  of  a  cross  between  a  white  and  black  race 
are  more  or  less  intermediate  between  the  two  and  vary  according  to  the 
amount  of  black  and  white  blood  introduced  in  succeeding  generations. 
Definite  black  and  white  individuals  are  not  produced,  but  merely  individuals 
of  various  degrees  of  brownness. 


SECTION  III 
REPRODUCTION   IN   MAN 

THE   DEVELOPMENT  OF  THE  REPRODUCTIVE  ORGANS 

The  most  marked  example  of  chemical  correlation  is  found  in  the  influence 
exerted  by  the  genital  glands  upon  the  other  parts  of  the  reproductive 
apparatus  and  upon  the  body  generally.  Thus  castration,  i.e.  removal  of 
the  testes  or  ovaries,  if  carried  out  before  the  time  of  puberty,  prevents  the 
development  of  the  secondary  sexual  characters,  which  normally  occurs 
at  this  epoch  in  both  sexes.  Puberty  denotes  the  period  at  which  ripe 
spermatozoa  and  ova  are  produced  in  the  testis  and  ovary  respectively.  In 
the  human  species  this  period  is  marked  or  preceded  in  the  male  by  in- 
creased growth  of  the  skeleton,  by  growth  of  the  larynx,  leading  to  a  lower- 
ing in  pitch  of  the  voice,  by  the  growth  of  hair  on  the  face  and  pubes,  and 
by  the  development  of  sexual  desire.  In  the  female  we  find  at  puberty 
enlargement  of  the  breasts,  attended  by  some  growth  of  the  mammary 
glands  and  by  a  moulding  of  the  whole  form,  making  it  more  fit  for  the 
bearing  of  children.  The  chief  sign  of  puberty  in  the  female  consists  in  the 
periodic  changes  in  the  uterus,  which  give  rise  to  menstruation,  i.e.  a  flow 
of  blood  and  mucus  from  the  genital  organs,  lasting  three  to  five  days  and 
repeated  every  four  weeks.  Menstruation  persists  so  long  as  the  ovary  is 
functional,  and  is  producing  ripe  ova.  The  activity  of  the  ovary  comes  to 
an  end  between  the  forty- fifth  and  fiftieth  year  ('  the  climacteric  '  or  '  change 
of  fife ').  With  the  cessation  of  its  activity  menstruation  also  stops,  and 
the  uterus  undergoes  a  process  of  atrophy.  These  secondary  sexual  charac- 
ters must  be  ascribed  to  the  influence  of  chemical  substances  produced  in  the 
ovary  and  testis  respectively.  Castration  after  puberty,  though  not  causing 
any  change  in  the  skeleton,  which  has  already  assumed  its  permanent  form, 
brings  about  retrogressive  changes  in  the  other  genital  organs,  analogous 
to  those  occurring  in  the  female  at  the  climacteric.  In  animals  the  pheno- 
mena of  '  coming  on  heat '  or  '  rut '  seem  to  be  analogous  with  menstrua- 
tion in  the  human  female,  and  like  this  depend  on  the  normal  activity  of  the 
ovary.  They  are  permanently  abolished  by  extirpation  of  the  ovaries, 
but  may  be  reinduced  by  implantation  in  the  peritoneum  of  an  ovary  from 
another  animal  of  the  same  species.  This  fact  shows  that  the  changes  in 
the  uterus  responsible  for  rut,  as  well  as  for  menstruation,  are  independent 
of  any  nervous  connections  between  the  ovaries  and  the  rest  of  the  body,  and 
must  therefore  be  brought  about  by  the  circulation  in  the  blood  of  specific 

1217  39 


1218  PHYSIOLOGY 

chemical  substances  produced  in  tlie  ovaries.  According  to  some  authors, 
the  essential  factors  for  the  production  of  these  genital  hormones  are  the 
'  interstitial  cells  '  found  both  in  the  testes  and  ovaries  of  various  animals. 
These  interstitial  cells  are  not,  however,  universally  present.  It  has  been 
shown  that,  by  means  of  the  Eontgen  rays,  it  is  possible  to  destroy  the 
germ-cells  in  either  testes  or  ovaries,  so  rendering  the  animal  sterile.  The 
interstitial  cells,  when  present,  are  not  destroyed  by  these  rays,  yet  the 
effects  on  the  accessory  genital  organs  are  stated  to  be  as  marked  as  after 
complete  extirpation  of  either  ovaries  or  testes. 

The  chemical  correlations  between  the  ovaries  and  the  other  organs 
concerned  in  reproduction  are  perhaps  best  marked  in  the  changes  which 
attend  pregnancy.  In  this  case  the  fertihsation  of  the  ovum  by  a  sperma- 
tozoon is  followed  by  a  great  development,  first  of  the  mucous  membrane 
and  later  on  of  the  muscular  wall  of  the  uterus.  The  mucous  membrane 
thickens,  apparently  in  order  to  form  a  bed  for  the  developing  fertilised 
ovum.  With  this  growth  of  the  uterus  there  is  a  corresponding  growth  of 
the  other  parts  of  the  genital  tract,  e.g.  the  vagina.  At  the  same  time  rapid 
changes  take  place  in  the  mammary  glands.  These  changes  may  be  studied 
experimentally  in  the  rabbit,  in  which  animal  gestation  lasts  only  about 
twenty- nine  days.  In  a  virgin  rabbit  of  a  year  old  it  is  difl&cult  with  the 
naked  eye  to  see  any  trace  of  the  mammary  gland  in  the  tissue  lying  under 
the  nipples.  Each  gland  is  limited  to  an  area  not  more  than  1  cm.  broad, 
and  consists  entirely  of  ducts  lined  with  a  single  layer  of  flattened  epithehal 
ceUs.  With  the  occurrence  of  conception  a  marked  change  takes  place. 
Four  or  five  days  after  fertihsation,  when  it  is  still  impossible  with  the 
naked  eye  to  discover  any  embryos  in  the  swollen  uterine  horns,  on  reflecting 
the  skin  from  the  abdomen  each  mammary  gland  appears  as  a  circular  pink 
area,  about  3  cm.  in  diameter.  On  section  the  gland  consists  of  ducts 
which  are  in  an  active  state  of  proHferation,  their  epithehal  lining  being 
two  or  three  cells  thick  and  presenting  numerous  mitotic  figures.  By  the 
ninth  day  the  whole  abdomen  is  covered  with  a  thin  layer  of  glandular 
tissue  ;  by  the  twenty- fifth  day  this  tissue  is  \  cm.  in  thickness  and  consists 
for  the  greater  part  of  secreting  alveoli,  hned  with  cells  containing  numerous 
fat-globules.     At  full  term  the  alveoli  contain  ready-formed  milk. 

This  hypertrophy  of  the  mammary  glands  occurs  during  pregnancy 
after  complete  division  of  all  possible  nervous  paths  between  the  glands  of 
the  ovaries  or  uterus.  In  the  guinea-pig  a  mammary  gland  has  been  actually 
transplanted  to  another  part  of  the  body,  thus  severing  all  its  normal  nervous 
connections,  and  yet  it  enlarged  as  usual  during  a  subsequent  pregnancy. 
Ancel  and  Bouin  have  brought  forward  evidence  that  the  corpus  luteum — 
the  tissue  produced  in  the  ovary  as  a  result  of  the  discharge  of  an  ovum — 
is  intimately  concerned  with  the  growth  of  the  mammary  glands,  and  may 
indeed  cause  a  certain  degree  of  hypertrophy  of  these  glands  in  the  entire 
absence  of  any  product  of  conception  within  the  uterus.*    The  hmited 

*  According  to  Ancel  and  Bouin,  in  the  rabbit  discharge  of  an  ovum  and  formation 
of  a  corpus  luteum  only  occur  as  a  result  of  copulation.     The  same  effect  may  be  pro- 


REPRODUCTION  IN  MAN  1219 

growth  of  the  glands,  which  occurs  at  puberty,  can  certainly  not  be  ascribed 
to  the  presence  of  a  foetus  in  the  uterus,  and  must  be  connected  with  the 
growth  of  ripe  ova,  or,  as  suggested  by  the  two  French  authors,  with  the 
growth  of  the  tissue  of  the  corpus  luteum.  resulting  from  the  discharge 
of  ova. 

There  seem  also  to  be  obscure  relationships  between  the  activity  of  the 
sexual  organs  and  that  of  certain  so-called  ductless  glands.  Thus  castra- 
tion at  an  early  age  leads  to  persistence  of  the  thymus  gland,  whereas 
normally  this  gland  atrophies  just  before  the  sexual  organs  commence  their 
functional  activity.  The  existence  of  a  connection  between  the  thyroid 
and  the  ovaries  has  been  a  popular  beUef  for  2000  years.  In  many  individuals 
the  thyroid  is  perceptibly  enlarged  at  each  menstrual  period.  On  the  other 
hand,  extirpation  of  the  thyroid  before  puberty  brings  about,  among  the 
other  signs  of  cretinism,  failure  of  development  of  the  ovaries,  so  that 
puberty  is  delayed  partially  or  completely. 

We  must  thus  regard  the  germ-cells  not  only  as  representing  the  cells 
from  which  the  individuals  of  the  new  generation  may  be  developed,  but 
also  as  concerned  in  the  formation  of  chemical  substances  which,  dis- 
charged into  their  hosts,  affect  many  or  all  of  the  functions  of  the  latter, 
with  the  object  of  finally  subordinating  the  activities  of  the  individual 
to  the  preservation  and  perpetuation  of  the  species. 

THE  MALE  REPRODUCTIVE  ORGANS 

In  all  the  higher  animals  we  may  divide  the  reproductive  organs  into 
the  essential  organs,  which  form  the  germ-cells,  the  spermatozoa  and  ova 
respectively,  and  the  accessory  organs,  which  have  as  their  office  the  faciUta- 
tion  of  the  access  of  the  spermatozoa  to  the  ova  (fertihsation),  and  in  the 
female  the  nutrition  of  the  product  of  fertilisation  during  the  early  period 
of  its  development. 

The  essential  sexual  organ  of  the  male  is  represented  by  the  testis. 
This  is  made  up  of  a  collection  of  convoluted  tubules,  the  seminal  tubules, 
which  are  contained  in  a  number  of  compartments  separated  by  fibrous 
septa.  The  tubules  present  few  or  no  branches,  each  one  being  about 
500  mm.  long.  The  testis  is  formed  in  the  first  instance  in  the  peritoneal 
cavity  from  the  germinal  epithelium,  but  early  in  fife  leaves  the  abdominal 
cavity  by  the  abdominal  ring  to  lie  in  a  pouch  of  skin— the  scrotum.  Several 
tubules  unite  to  form  a   straight    tubule,    which    leads  by  a  series  of 

duced  by  artificial  rupture  of  a  ripe  follicle.  Whenever  this  occms  there  is  a  develop- 
ment of  the  niaminary  glands.  If  no  impregnation  has  taken  i)lace  {e.ff.  if  the  buck  has 
been  sterilised  by  ligatme  of  the  vas  deferens),  the  glands  develop  for  fourteen  days 
and  then  begin  to  atrophy.  Tliis  period  corresponds  to  the  period  of  active  growth 
of  the  corpus  luteum.  The  continued  growth  during  the  latter  half  of  pregnancy  these 
authors  ascribe  to  the  production  of  another  hormone  by  a  special  glandular  tissue 
('  myometrial  gland  ')  which  makes  its  appearance  about  the  fourteenth  day  in  the  wall 
of  the  uterus,  at  the  site  of  implantation  of  the  placenta,  and  lasts  until  the  end  of 
pregnancy. 


1220 


PHYSIOLOGY 


commiiiiicating  spaces,  the  rete  testis,  into  the  vasa  eff  erentia  (Fig.  560).  These 
unite  to  form  the  duct  of  the  epididymis,  which  forms  a  mass  lying  at  the  back 
of  the  testis.  The  epididymis  is  composed  of  the  convolutions  of  this  single 
duct,  which  is  about  20  feet  long.  From  the  lower  end  of  the  epididymis 
the  vas  deferens,  a  tube  with  thick  muscular  walls,  leads  by  the  abdominal 
ring  to  the  base  of  the  bladder,  where  it  opens  into  the  beginning  of  the 
urethra  in  its  prostatic  part.     Just  before  it  joins  the  urethra  each  vas 


Appendix 


Epididymis 


Tunica  vaginalis 
Tunica  albuglnea 

Septum 
Seminal  tubules   — 

Lobule 
Mediastinum 

Testis 


-     Vas  deferens 


Paradidymis 


.■^:^_  Vasa  efferentia 


Appendix  of  rete 
testis 

Vas  aberrans 


Rete 
testis 


Fig.  560. 


Diagrammatic  representation  of  the  course  of  the  seminal  tubules  in  the 
testis  and  epididymis.     (After  Nagel.) 


deferens  presents  a  diverticulum,  the  seminal  vesicle,  which  Hes  along,  and 
is  attached  to,  the  base  of  the  bladder.  The  prostate  itself,  which  surrounds 
the  first  part  of  the  urethra,  is  composed  of  a  matrix  of  unstriated  muscular 
fibres,  enclosing  numerous  branched  racemo-tubular  glands.  From  the 
point  of  entry  of  the  vasa  deferentia  to  its  orifice,  the  urethra  represents 
a  common  passage  for  the  urine  and  for  the  sexual  products — the  semen. 
It  passes  therefore  through  tissues,  forming  the  penis,  which  are  especially 
adapted  for  the  purpose  of  intromission,  i.e.  the  introduction  of  the  semen, 
containing  the  spermatozoal  into  the  female.  In  the  urethra  we  distinguish 
the  prostatic,  the  membranous,  and  the  penile  portions.  Into  the  beginning 
of  the  penile  portion,  the  bulb  of  the  urethra,  open  the  ducts  of  the  two 
glands  of  Cowper.  In  the  penis  itself  the  urethra  is  surrounded  with 
erectile  tissue,  forming  the  corpus  spongiosum,  and  Hes  between  the  two 
corpora  cavernosa,  which  consist  of  the  same  kind  of  tissue.  The  erectile 
tissue  is  a  spongy  mesh  work  of  elastic  and  unstriated  muscle  fibres,  enclosing 
spaces  in  free  communication  with  the  efierent  veins  of  the  organ.  The 
arterioles  also  open  into  these  spaces,  but  under  normal  circumstances  both 
the  arterioles  and  the  muscle-tissues  of  the  framework    are  contracted,  so 


REPRODUCTION  IN  MAN  1221 

that  the  blood  trickles  only  slowly  from  the  arterioles  into  the  spaces, 
whence  it  escapes  readily  by  means  of  the  veins.  If  the  muscle  fibres  be 
relaxed,  so  that  blood  can  escape  readily  into  and  distend  the  spaces,  the 
tissue  swells  and  becomes  harder,  causing  '  erection  '  of  the  organ. 

In  the  immature  testis,  i.e.  from  birth  up  to  puberty,  the  seminal  tubules 
are  filled  with  cells  with  large  nuclei.  Some  of  ttese  are  the  spermatogonia, 
the  mother  cells  of  the  future  spermatozoa,  while  the  others  form  the  cells 
of  Sertoli,  whose  function  it  is  to  act  as  nurse  cells  to  the  developing  sper- 
matozoa. The  actual  formation  of  spermatozoa  begins  at  puberty,  when 
the  spermatogonia  divide  many  times  to  form  the  spermatocytes,  which 
in  their  turn  undergo  heterotype  mitosis  to  form  the  spermatids,  as  already 
described.  By  a  modification  of  the  latter  the  fully  formed  spermatozoa  are 
formed.  These,  when  mature,  pass  by  the  tubules  of  the  testis  and  of  the 
epididymis  into  the  vas  deferens,  whence  they  make  their  way  into  the  seminal 
vesicles.  Their  movement  is  probably  facilitated  by  the  cells  lining  the  tubule 
of  the  epididymis  as  well  as  by  the  secretion  of  the  lining  membrane  of  the 
seminal  vesicles.  It  has  been  noted  that  the  spermatozoa  are  practically 
motionless  while  in  the  seminiferous  tubules  of  the  testis,  but  become 
actively  motile  in  the  vas  deferens,  or  when  mixed  with  prostatic  secretion. 
It  is  difficult  to  understand  how  the  spermatozoa  are  conveyed  through  the 
resistance  which  must  be  offered  by  the  huge  length  of  the  tubule  of  the 
epididymis,  unless  their  onward  motion  is  facihtated  by  the  cilia-like 
structures  attached  to  some  of  the  cells  lining  this  tubule.  The  formation 
of  the  spermatozoa  is  continuous,  though  the  rate  at  which  this  occurs  is 
variable  and  regulated  by  the  sexual  activity  of  the  individual.  In  the  fully 
formed  semen  the  spermatozoa  formed  by  the  testis  are  mixed  not  only  with 
the  fluid  secreted  by  the  lining  membrane  of  the  epididymis  and  of  the 
seminal  vesicle  but  also  with  the  mucous  secretions  of  the  prostatic  glands 
and  of  Cowper's  glands.  Nevertheless  it  contains  spermatozoa  in  enormous 
numbers,  the  semen  emitted  at  a  single  act  of  coitus  containing  as  many  as 
226,(KX),()00  spermatozoa.  Though  the  vast  majority  of  these  are  probably 
capable  of  fertilising  an  ovimi,  this  act  is  carried  out  by  only  one — a  fact 
characteristic  of  the  prodigality  of  nature  when  deahng  with  the  perpetua- 
tion of  the  type. 


THE  FEMALE   REPRODUCTIVE  ORGANS 

The  essential  organ  of  reproduction  in  the  female  is  the  ovary,  the  seat 
of  production  of  the  ova.  The  accessory  organs  include  the  oviducts  or 
Fallopian  tubes,  the  uterus,  in  which  the  fertilised  ovum  is  retained  during 
the  first  nine  months  of  its  development,  and  the  vagina,  which  is  especially 
adapted  for  the  reception  of  the  male  organ  in  the  act  of  impregnation. 

Among  the  accessory  organs  we  may  also  reckon  the  mammary  glands, 
which  undergo  a  special  development  during  pregnancy,  and  serve  for 
the  nourishment  of  the  young  individual  during  the  first  period  of  extra- 
uterine life. 


1222  PHYSIOLOGY 

OVULATION.  At  birth  the  ovary  consists  of  a  stroma  of  spindle-shaped 
cells,  and  is  covered  by  a  layer  of  cubical  epithehum  (the  germ-epithehum) 
continuous  with  the  endothehum  lining  the  general  peritoneal  cavity.  Em- 
bedded in  the  stroma,  but  especially  numerous  just  underneath  the  epithe- 
lium, are  a  vast  number  of  '  primordial  follicles.'  These  are  formed  during 
foetal  life  by  down-growths  of  the  germinal  epithehum.  Of  the  cells  pro- 
longed in  this  way  from  the  germinal  epithehum,  some  undergo  enlargement 
to  form  the  primordial  ova,  while  the  others  are  arranged  as  a  single  layer 
of  flattened  nucleated  cells,  the  '  folhcular  epithelium,'  as  a  sort  of  capsule 
to  the  ovum.  Of  the  primordial  folhcles,  about  70,000  are  to  be  found  in 
the  ovary  of  the  new-born  child.  During  the  first  twelve  to  fourteen  years  of 
life  they  remain  in  a  quiescent  condition.  With  the  onset  of  puberty  one  or 
more  of  the  primordial  follicles  begin  to  develop.  Indeed,  this  development 
may  be  regarded  as  the  causative  factor  in  the  various  phenomena  which 
are  characteristic  of  puberty  in  the  female  [v.  p.  1217).  The  first  stage  in 
the  growth  of  the  folhcle  is  a  prohferation  of  the  follicular  epithelium,  the 
cells  of  which  become  cubical  and  are  arranged  in  several  layers  round  the 
ovum.  At  one  point  in  the  mass  of  cells  surrounding  the  ovum  a  cavity 
appears  filled  with  fluid,  the  liquor  folUcuU.  The  epithelium  thus  becomes 
separated  into  two  parts,  i.e.  the  membrana  granulosa,  several  layers  thick, 
lining  the  whole  folhcle,  and  the  discus  proligerus,  a  mass  of  cells  attached  to 
one  side  of  the  folhcle,  in  which  is  embedded  the  ovum  (Fig.  561).  Round 
the  growing  folhcle  the  stroma  assumes  a  concentric  arrangement  and  forms 
a  capsule,  of  which  the  internal  layer  consists  chiefly  of  spindle-shaped  cells 
richly  supplied  with  blood-vessels,  while  the  outer  layer — the  theca  externa 
— ^is  made  up  of  a  tough  fibrous  tissue.  With  the  growth  of  the  follicle 
the  ovum  also  becomes  larger  and  surrounds  itself  with  a  distinct  membrane, 
known  as  the  zona  'pellucida.  This  membrane  presents  a  fine  radial  striation, 
which  is  supposed  to  indicate  the  existence  of  canals  through  which  the 
ovum  can  obtain  sustenance  from  the  surrounding  cells  of  the  follicular 
epithehum.  The  nucleus  also  becomes  larger,  and  forms  the  germinal 
vesicle  containing  one  or  two  well-marked  nucleoU^ — the  germinal  spot.  The 
mature  Graafian  folhcle  projects  from  the  surface  of  the  ovary  as  a  trans- 
parent vesicle  about  the  size  of  a  pea.  (Its  diameter  is  about  15  mm.)  In 
the  process  of  growth  the  ovum  has  increased  from  a  diameter  of  25^  to 
200/x.  Before  the  ovum  can  undergo  fertihsation  the  double  division  of 
the  nucleus,  or  germinal  vesicle,  has  to  take  place,  which  leads  to  the  forma- 
tion and  extrusion  of  the  two  polar  bodies.  This  process  probably  occurs 
just  before  or  just  after  the  discharge  of  the  ovum  from  the  ovary. 

With  increasing  size  of  the  Graafian  follicle  the  membrane  covering  it 
becomes  progressively  thinner.  At  certain  periods,  or  under  certain  condi- 
tions, the  membrane  ruptures,  and  the  ovum  is  discharged  in  the  hquor 
folliculi,  still  surrounded  by  an  adherent  mass  of  the  cells  of  the  discus 
proligerus.  In  some  animals  this  process  of  ovulation  occurs  at  definite 
periods  of  the  year.  In  others,  such  as  the  rabbit,  the  occurrence  of  ovula- 
tion depends  upon  coitus  taking  place  during  the  period  of  sexual  activity. 


REPRODUCTION  IN  MAN  1223 

We  shall  have  later  to  discuss  the  relation  of  o\nilation  in  the  human  female 
to  the  periodic  changes  occurring  in  the  other  parts  of  the  reproductive 
apparatus. 

After  the  discharge  of  the  ovum  the  remaining  portions  of  the  follicle 
undergo  a  characteristic  series  of  changes,  which  result  in  the  production 


-  <?2r 


dp 


Fig.  561.     Graafian  follicle  of  niaminaiian  u\ar\ .     (^i'KE.NANT  and  BouiN.) 

ov,  ovum  ;    dp,  discus  proligcrus  ;    ?<?./,  liquor  folliculi ;    cli.  thcca  ; 
Qr,  mcmbrana  granulosa. 

of  the  corjpus  luteum.  Immediately  after  the  rupture  the  follicle  becomes 
filled  with  blood,  apparently  resulting  from  the  sudden  release  of  the  pressure 
on  the  capillaries  in  the  walls  of  the  folhcle.  The  cells  of  the  membrana 
granulosa  rapidly  increase  in  size,  a  few  of  them  undergoing  mitotic  division, 
so  that  a  dense  mass  of  cells  is  formed,  nearly  fiUing  the  original  follicle.  At 
the  same  time  the  cells  of  the  internal  theca  prohf crate,  with  the  formation 
of  connective  tissue,  which  grows  in  among  the  cells  filling  the  Graafian 
follicle.  These  cells  finally  attain  a  size  four  or  five  times  that  of  the  cells 
of  the  membrana  granulosa  in  the  mature  follicle.  Blood-vessels  grow  from 
the  external  theca  towards  the  centre  of  the  follicle.  The  cells  within  the 
follicle  then  undergo  fatty  degeneration  and  present  a  yellow  colour  due  to 


1224  PHYSIOLOGY 

a  fatty  pigment  known  as  lutein.  The  corpus  luteum,  as  the  body  so 
formed  is  called,  attains  its  greatest  size  about  a  week  after  ovulation^  and 
then  gradually  undergoes  regressive  changes.  If,  however,  the  ovum, 
which  has  been  discharged,  undergoes  fertihsation,  and  pregnancy  results, 
the  corpus  luteum  continues  to  grow  for  a  considerable  time  and  attains  its 
largest  size  at  about  the  third  month  of  pregnancy.  It  does  not  entirely 
disappear  until  after  the  end  of  pregnancy.  The  big  corpus  luteum  found 
in  pregnancy  is  often  spoken  of  as  the  '  true '  corpus  luteum,  and  is  dis- 
tinguished from  the  corpus  luteum  spurium  of  menstruation  or  of  ovulation 
without  fertilisation.     There  is,  however,  no  essential  difference  other  than 


Fig.  562.     Fully  developed  corpus  luteum  of  the  mouse.     (Sobotta.) 

that  of  size  between  these  two  kinds  of  corpus  luteum.  It  must  not  be 
imagined  that  all  the  70,000  primordial  folhcles  found  in  the  ovary  of  a 
new-born  child  undergo  this  series  of  changes  ;  it  is  probable  that  in  the 
human  female  ovulation  occurs,  as  a  rule,  once  every  four  weeks  during  the 
thirty-five  years  of  sexual  Ufe.  A  vast  number  of  the  Graafian  folhcles, 
after  developing  to  a  certain  extent,  undergo  regressive  changes,  both  during 
childhood  and  during  adult  Hfe.  The  cellular  elements  degenerate,  leuco- 
cytes wander  into  the  folhcle  and  attack  the  degenerating  ovum,  so  that 
finally  the  folhcle  is  replaced  by  connective  tissue,  without  the  formation  of 
any  corpus  luteum. 

MENSTRUATION.  Puberty  in  the  girl  is  marked  by  the  onset  of 
menstruation.  Under  this  term  is  understood  a  flow  of  blood  and  mucus 
from  the  uterus,  which  recurs  every  four  weeks  and  lasts  each  time  from  four 
to  five  days.  Before  the  first  menstrual  period,  other  signs  of  puberty,  i.e. 
of  approaching  sexual   maturity,   are  usually   observed.     These  include 


REPRODUCTION  IN  MAN  1225 

rapid  growth,  with  changes  in  the  skeleton,  leading  to  the  typically  feminine 
type  of  pelvis,  a  development  of  the  mammary  glands,  and  the  growth  of 
hair  on  the  pubes.  At  the  same  time  there  is  increased  development  of  the 
mental  characteristics  which  are  typical  of  the  sex.  The  amount  of  blood 
lost  at  each  menstrual  period  varies  between  lUO  and  300  grm.  During  the 
'  period  '  there  are  often  disturbances  of  other  functions  of  the  body,  which 
are  so  common  that  to  be  '  unwell '  is  the  recognised  polite  description  of 
the  menstrual  period.  Thus  it  is  often  attended  with  pains  in  the  abdomen, 
a  feeling  of  weight  and  fulness,  disturbance  of  digestion,  headache,  and 
neuralgias  of  various  distribution.  At  the  same  time  there  is  a  general 
disinclination  for  exertion. 

Menstruation  is  due  to  periodic  changes  in  the  uterine  mucous  membrane. 
During  the  few  days  previous  to  the  period  the  mucous  membrane  undergoes 
a  rapid  hypertrophy,  increasing  in  thickness  from  2  mm.  to  6  mm.  At  the 
same  time  there  is  increased  vascularity  of  the  membrane  in  consequence  of 
dilatation  of  its  blood-vessels.  At  the  commencement  of  the  menstrual 
period  there  is  an  escape  of  the  red  blood-corpuscles,  chiefly  by  diapedesis, 
but  partly  by  actual  rupture  of  the  blood-capillaries  into  the  spaces  between 
the  uterine  glands.  At  this  period  sections  of  the  uterine  mucous  mem- 
brane show  numerous  collections  of  red  blood-corpuscles,  Ipng  immediately 
under  the  superficial  epithelium.  In  some  cases  this  stage  is  followed  by 
an  almost  complete  desquamation  of  the  superficial  epithelium.  Generally 
the  desquamation  is  only  partial,  but  in  either  case  the  blood  escapes  into 
the  cavity  of  the  uterus,  where  it  becomes  mixed  with  the  increased  secre- 
tion from  the  uterine  glands  and  is  discharged  into  and  from  the  vagina  as 
the  menstrual  fluid.  With  the  occurrence  of  the  menstrual  flow  the  mucous 
membrane  begins  to  diminish  in  thickness.  The  vascularity  decreases,  and 
much  of  the  blood  in  the  deeper  parts  of  the  mucosa  becomes  reabsorbed. 
The  desquamated  epithelium  is  replaced  by  proliferation  of  the  cells  which 
remain  intact,  so  that  finally  the  mucosa  is  completely  regenerated  and 
brought  back  to  its  original  condition.  This  period  of  regeneration  lasts 
about  fourteen  days.  Dvuing  the  next  few  days  the  condition  of  the  mem- 
brane is  stationary,  but  this  period  of  rest  lasts  but  a  short  time,  since  signs 
of  the  pre- menstrual  swelling  can  be  detected  as  early  as  three  days  before 
the  onset  of  the  next  menstrual  period. 

THE  RELATION  OF  OVULATION  TO  MENSTRUATION 
There  is  no  doubt  that  menstruation  depends  on  the  functional  activity 
of  the  ovary.  Its  onset  coincides  with  the  first  production  of  ripe  ova  in  the 
ovary,  and  it  ceases  with  the  cessation  of  ovulation  at  the  climacteric  or 
menopause.  In  cases  where  the  ovaries  have  been  removed  before  puberty 
menstruation  never  occurs.  Removal  of  both  ovaries  during  adult  life 
generally  brings  about  a  premature  menopause.  It  seems  probable  that 
the  ripening  of  the  ova  in  tlie  human  ovary  occurs  at  periods  corresponding 
to  those  of  menstruation.  But  there  has  been  much  division  of  opinion  as  to 
the  exact  relation  between  the  two  processes.     Fairly  definite  clinical  and 

39* 


1226  PHYSIOLOGY 

post-mortem  evidence  has  been  brought  forward  for  the  theory  that  ovula- 
tion precedes  the  menstrual  flow.  On  this  theory  the  degeneration  of 
the  uterine  mucous  membrane,  which  occurs  at  each  period,  represents,  so 
to  speak,  the  undoing  of  a  preparation  for  the  reception  of  a  fertihsed  ovum. 
The  ovum  has  been  discharged,  the  mucous  membrane  has  been  prepared 
for  its  reception,  but  fertilisation  not  having  taken  place,  ovum  and  mucous 
membrane  are  cast  out  together  in  the  menstrual  flow.  Unfortunately 
almost  equally  definite  chnical  evidence  has  been  adduced  for  the  view  that 
ovulation  occurs  during  or  after  the  menstrual  period.  Light  is  thrown 
upon  the  question  by  the  study  of  the  phenomena  of  '  rut '  or  '  heat '  in  the 
lower  animals.  In  most  mammals  impregnation  and  conception  can  only 
occur  at  certain  definite  periods  of  the  year.  At  these  seasons  the  female 
presents  a  swelhng  of  the  mucous  membrane  of  the  external  genitals,  and 
often  a  flow  of  blood  or  mucus.  As  a  rule  it  is  only  when  in  this  condition 
that  it  wiU  permit  the  approach  of  the  male.  Thus  the  bitch  '  comes  on 
heat '  as  a  rule  twice  in  the  year  ;  the  cat  three  or  four  times  ;  most  car- 
nivora  only  once  a  year.  At  these  periods  the  uterus  shows  well-marked 
histological  changes,  which  may  be  divided  into  the  following  periods  : 

(1)  The  period  of  rest.  During  this  time,  which  extends  over  the  greater 
part  of  the  year,  the  mucous  membrane  is  thin  and  pale.  The  period  of 
heat  being  known  as  the  oestrus,  this  first  period  is  denoted  by  Heape  the 
ancestrum. 

(2)  The  peilod  of  growth  or  congestion.  This  corresponds  to  the  pre- 
menstrual thickening  of  the  mucous  membrane  of  the  human  female. 

(3)  Period  of  destruction,  associated  with  haemorrhages  into  the  mucous 
membrane,  desquamation  of  the  superficial  epithehal  cells,  and  occasionally 
discharge  of  blood  and  mucus  from  the  vagina.  These  two  periods  are 
grouped  together  as  the  pro-oestrum. 

(4)  Period  of  recuperation  corresponding  to  the  post- menstrual  regenera- 
tion of  the  mucous  membrane.  It  is  during  the  first  part  of  this  period  or  at 
the  very  end  of  the  last  period  that  ovulation  occurs  in  those  animals  where 
ovulation  is  independent  of  coitus.  It  is  at  this  time,  too,  that  the  animal 
exhibits  sexual  desire  and  permits  the  approaches  of  the  male.  If  fertilisa- 
tion occurs,  the  mucous  membrane  undergoes  rapid  hypertrophy,  much 
more  marked  than  that  occurring  during  the  pro- oestrum.  In  the  absence 
of  impregnation  the  mucous  membrane  returns  to  the  condition  of  rest,  the 
stage  of  return  being  known  as  the  metoestrum. 

These  results  have  been  found  by  Heape  and  Marshall  to  apply  to  a 
large  number  of  difierent  mammals.  We  are  therefore  justified  in  con- 
cluding that  menstruation  is  the  physiological  homologue  of  the  pro-oestrum 
in  the  lower  mammals,  and  that  ovulation  occurs,  or  at  any  rate  that  the 
ova  attains  maturity,  after  or  at  the  very  end  of  the  menstrual  flow.  If  we 
consider  that  the  ovum  may  take  some  days  to  pass  down  the  Fallopian 
tube  to  the  uterus,  and  that  the  spermatozoa  may  retain  their  vitahty  for 
ten  days  or  more  in  the  Fallopian  tubes  or  uterus,  it  is  evident  that  in  man 
impregnation  may  take  place  at  any  time  between  two  menstrual  periods. 


REPRODUCTION  IN  MAN  1227 

Sexual  desire  is  thus  not  limited  to  certain  seasons,  as  is  the  case  with  most 
of  the  lower  animals. 

FERTILISATION 

The  act  of  impregnation  consists  in  the  introduction  of  spermatozoa 
into  the  female  genital  tract,  where  they  may  come  in  contact  with  and 
fertihse  the  ovum,  which  is  discharged  from  the  ovary  by  bursting  of  a 
Graafian  folUcle.  This  is  effected  in  the  act  of  coitus  or  sexual  congress  by 
the  insertion  of  the  penis  into  the  vagina  of  the  female.  Before  this  can 
occur  erection  of  the  male  organ  must  take  place.  The  mechanism  of 
erection  is  twofold.  The  most  important  factor,  as  was  shown  by  Eckhard 
and  Loven,  is  an  active  dilatation  of  the  vessels  of  the  penis,  especially  of  the 
medium-sized  and  smaller  arteries.  If  the  penis  be  cut  across  while  in  the 
flaccid  condition,  venous  blood  merely  trickles  away  from  the  cut  surface, 
whereas,  if  erection  be  excited,  the  flow  of  blood  from  the  cut  surface  is 
increased  eight  to  ten  times,  and  the  blood  becomes  bright  arterial  in  colour. 
It  is  thus  possible  to  excite  erection  in  an  animal,  in  whom  the  second  factor 
has  been  aboUshed  by  paralysing  the  muscles  by  means  of  curare.  This 
second  factor  is  the  contraction  of  the  iscliio-cavernosus  or  erector  fenis 
muscle,  certain  fibres  of  which  pass  over  the  dorsal  vein  of  the  penis 
and  compress  this  vessel  when  they  contract.  Since  hgature  of  the 
veins  coming  from  the  penis  does  not  produce  erection,  the  contraction 
of  this  muscle  must  be  regarded  as  simply  aiding  the  effects  of  the 
arterial  dilatation. 

Before  or  at  the  beginning  of  coitus  analogous  changes  occur  in  the 
female  organs,  leading  to  erection  of  the  chtoris  and  of  the  erectile  structures 
of  the  vulva.  The  glands  of  the  vulva,  especially  the  glands  of  Barthohni, 
secrete  a  mucous  fluid,  thus  lubricating  the  passage  into  the  vagina.  The 
friction  between  the  glans  penis  and  the  wall  of  the  vagina  causes  a  reflex 
aischarge  of  motor  impulses  in  both  male  and  female.  In  the  former  the 
muscular  walls  of  the  vasa  deferentia  and  seminal  vesicles  enter  into  rh}'th- 
mic  contractions,  thus  forcing  the  spermatozoa  they  contain  into  the 
urethra.  The  spermatozoa,  mixed  with  the  secretions  of  the  epididyim's,  the 
seminal  vesicles,  the  prostatic  glands,  and  the  glands  of  Cowper,  form  the 
semen,  which  is  pressed  along  the  urethra  by  rhythmical  contractions, 
from  behind  forwards,  of  the  bulbo-  and  ischio-cavernosi  muscles.  It  has 
been  stated  that  movements  take  place  coincidently  in  the  uterus,  so  that 
its  axis  more  nearly  corresponds  to  that  of  the  vagina.  The  movement  of 
the  semen  along  the  uterus  and  Fallopian  tubes  is  ascribed  by  certain 
observers  to  an  antiperistaltic  contraction  of  these  organs.  A  more  im- 
portant factor  is  probably  the  movement  of  the  spermatozoa  themselves. 
As  we  have  already  seen,  these  are  introduced  into  the  female  passage  in 
countless  numbers.  They  will  be  chemiotactically  attracted  by  the  alkahne 
mucus,  secreted  by  and  filling  the  cervix  of  the  uterus.  When  they  have 
entered  this  organ  they  will  meet  the  downward  stream  of  mucus  impelled 
by  the  action  of  the  cilia  fining  the  uterus  and  Fallopian  tubes.     It  seems 


1228  PHYSIOLOGY 

probable  that  their  reaction  to  this  current  is  to  swim  *  against  it  {'positive 
rheotaxis),  so  that  they  reach  the  upper  part  of  the  Fallopian  tubes  or  the 
surface  of  the  ovary  itself.  FertiUsation  of  the  ovum  occurs  in  most  cases 
in  the  Fallopian  tube,  and  the  fertihsed  ovum  is  then  carried  slowly  down 
the  tube  into  the  uterus. 

NERVOUS  MECHANISM  OF  IMPREGNATION.  Although,  in  both 
sexes,  coitus  is  attended  by  a  high  degree  of  psychical  excitement,  yet  it  is 
essentially  a  spinal  reflex,  and  can  be  carried  out  when  all  impulses  from  the 
higher  centres  are  cut  off  by  section  of  the  cord  in  the  dorsal  region.  The 
centre  presiding  over  the  act  is  situated  in  the  lumbar  spinal  cord.  The 
external  generative  organs,  hke  the  bladder,  are  suppHed  from  two  sets  of 
nerve  fibres — from  the  lumbar  nerves  through  the  sympathetic,  and  from 
the  sacral  nerves.  The  fibres  from  the  lumbar  nerves  arise  in  the  cat  from 
the  second,  third,  and  fourth,  or  the  third,  fourth,  and  fifth  lumbar  nerve- 
roots,  and  in  the  dog  from  the  thirteenth  thoracic,  and  the  first  to  the  fourth 
lumbar  roots.  They  run  in  the  white  rami  communicantes  to  the  sympathetic 
chain,  whence  they  may  take  two  paths. 

{a)  The  great  majority  of  the  fibres  run  down  the  sympathetic  chain  to 
the  sacral  gangha,  whence  fibres  are  given  off  in  the  grey  rami  communicantes 
to  the  sacral  nerves ;  their  further  course  is  by  the  pudic  nerves,  none 
running  in  the  nervi  erigentes. 

(6)  A  few  fibres  go  by  the  hypogastric  nerves  to  the  pelvic  plexus. 

Excitation  of  these  fibres  causes  contraction  of  the  arteries  of  the  penis, 
nad  of  the  unstriated  muscles  of  the  tunica  dartos  of  the  scrotum.  In  animals 
which  possess  a  retractor  penis  muscle,  excitation  of  the  lumbar  nerves 
causes  strong  contraction  of  the  muscle. 

The  fibres  from  the  sacral  nerves  can  be  divided  into  two  classes — 
visceral  and  somatic.  The  visceral  branches  run  in  the  pelvic  nerves,  or 
nervi  erigentes.  Stimulation  of  these  fibres  produces  active  dilatation  of  the 
arteries  of  the  penis  or  vulva,  and  also  inhibition  of  the  unstriated  muscle  of 
the  penis,  the  retractor  muscle  of  the  penis,  when  present,  and  of  the  vulva 
muscles.  The  somatic  branches  supply  motor  nerves  to  the  ischio-  and 
bulbo-cavernosi,  as  well  as  the  constrictor  urethrge.  In  the  female  they 
supply  the  analogous  muscles,  namely,  the  erector  clitoridis  (ischio-caver- 
nosus)  and  the  sphincter  vaginae  (bulbo-cavernosus).  Both  these  sets  of 
fibres  are  therefore  involved  in  the  erection  of  the  generative  organs  which 
accompanies  coitus. 

The  internal  organs,  i.e.  the  uterus  and  vagina  in  the  female,  and  vasa 
deferentia,  seminal  vesicles,  and  uterus  mascuHnus  in  the  male,  difier  from 
the  external  organs  in  receiving  no  efferent  nerve  fibres  from  the  sacral  nerves, 
as  has  been  pointed  out  by  Langley  and  Anderson.     They  are  supplied  with 

*  Spermatozoa  move  in  a  straight  line,  at  the  rate  of  2-3  mm.  per  minute.  Thus 
they  might  traverse  the  distance  of  16-20  cm.  between  the  os  uteri  and  the  trumpet- 
Khaped  orifice  of  the  Fallopian  tubes  in  three-quarters  of  an  hour.  In  animals  sper- 
matozoa have  been  found  at  the  peritoneal  end  of  the  Fallopian  tubes  within  an  hour 
or  two  after  coitus. 


REPRODUCTION  IN  MAN  1229 

fibres,  which  pass  out  through  the  anterior  roots  of  the  third,  fourth,  aud 
fifth  lumbar  nerves  (in  the  rabbit  and  cat),  and  run  through  the  sympathetic 
to  the  inferior  mesenteric  ganglia,  whence  they  proceed  by  the  hypogastric 
nerves.  On  stimulating  these  fibres,  two  effects  are  produced  on  the  uterus 
and  vagina,  namely,  a  contraction  of  the  small  arteries,  leading  to  pallor 
of  the  organs,  and  a  strong  contraction  of  the  muscular  coats*  In  the 
vagina  the  contraction  can  usually  be  seen  to  start  from  one  end  and  spread 
to  the  other.  The  whole  then  remains  for  a  time  in  a  state  of  powerful 
tonic  contraction,  which  affects  both  longitudinal  as  well  as  circular  nmscles. 
In  the  male  stimulation  of  these  nerves  excites  contraction  of  the  whole 
musculature  of  the  vasa  deferentia  and  seminal  vesicles,  which  may  be 
strong  enough  to  cause  emission  of  semen  from  the  penis.  These  effects  on 
the  uterus  and  seminal  vesicles  are  not  abolished  by  injection  of  atropine. 

The  course  of  the  sensory  fibres  from  the  generative  organs  to  the 
lumbo-sacral  cord  has  not  yet  been  fully  made  out,  but  it  seems  probable 
that  it  corresponds  to  the  course  taken  by  the  efferent  fibres. 

An  accessory  genital  muscle,  the  retractor  penis,  which  is  found  in  the  dog,  cat,  horse, 
donkey,  hedgehog  (not  in  the  rabbit  or  man),  presents  considerable  physiological 
interest.  It  was  first  described  by  Eckhard  as  the  Afterruthenhand ,  and  consists  of  a 
thin  band  of  longitudinally  arranged  unstriated  muscle  (15  to  20  cm.  long  in  a  spaniel 
weighing  about  15  kilos),  which  is  inserted  at  the  attachment  of  the  jirepuce,  and  is 
continued  backwards  in  a  sheath  of  connective-tissue  to  the  bulb,  when  it  divides  into 
two  slips  which  pass  on  either  side  of  the  anus.  A  few  striated  fibres  are  found  in  the 
back  part  of  this  muscle,  derived  from  the  external  sphincter  of  the  anus  and  the  bulbo- 
cavernosus  muscles.  This  muscle  is  extremely  sensitive  to  changes  of  temperature, 
and  is  at  the  same  time  very  tenacious  of  life.  Thus  it  maybe  cut  out  of  the  body  and 
kept  in  serum  or  blood,  in  a  cool  place,  for  two  days.  At  the  end  of  this  time  it  will, 
on  warming,  relax,  and  enter  into  spontaneous  rhythmic  contractions.  At  about  40°  C. 
the  muscle  is  quite  flaccid.  On  cooling  slightly  (to  35°)  it  wU  shorten,  and  at  the  same 
time  may  enter  into  slow  rhythmic  contractions.  If  cooled  to  15°  C.  the  muscle  will 
contract  to  about  a  quarter  of  its  previous  length.  The  same  shortening  may  be 
produced  on  exciting  the  muscle  with  strong  interrupted  currents. 

The  muscle  is  innervated  from  two  sources,  the  two  nerves  having  antagonistic 
actions  (cp.  p.  247).  The  motor  fibres  to  the  muscle  are  derived  from  the  lumbar  sympa- 
thetic {i.e.  the  upper  .set  of  nerve-roots),  and  run  to  the  muscle  in  the  internal  pudic 
nerve.  The  pelvic  nerves,  on  the  other  hand,  carry  inhibilori/  impulses  to  the  muscle, 
thus  enabling  the  concomitant  vascular  dilatation  to  take  effect  in  producing  erection 
of  the  penis. 

*  Under  some  circumstances  stimulation  of  the  sympathetic  nerves  may  cause 
relaxation  of  the  uterus. 


SECTION  IV 
PREGNANCY  AND  PARTURITION 

PREGNANCY 

Fertilisation  of  the  ovum  takes  place,  as  a  rule,  in  the  Fallopian  tube. 
Directly  one  spermatozoon  has  penetrated  into  the  ovum,  a  membrane  is 
formed  round  the  yolk,  which  prevents  the  entrance  of  any  other  sperma- 
tozoa. The  fusion  of  the  male  and  female  pronuclei  is  followed  immediately 
by  division  of  the  fertilised  ovum,  so  that,  by  the  time  it  arrives  in  the  uterus 
(about  eight  days  after  fertilisation),  it  consists  of  a  mass  of  cells  known  as 
the  morula.  At  this  time  the  ovum  has  a  diameter  of  about  0-2  mm. 
Pregnancy  in  the  human  being  lasts  about  nine  months,  birth  generally 
taking  place  280  days,  i.e.  ten  periods  after  the  last  menstrual  period.  During 
pregnancy  menstruation  is  absent. 

With  the  arrival  of  the  fertihsed  ovum  in  the  uterus,  extensive  changes 
begin  in  this  and  the  neighbouring  organs  of  generation.  The  virgin  uterus 
is  pear-shaped,  and  its  cavity  amounts  to  about  2-5  c.c.  Just  before  birth 
the  volume  of  the  uterus  is  about  5000-7000  c.c,  and  the  walls  of  the  organ 
are  thickened  in  proportion.  In  the  hypertrophy  of  the  uterine  wall  all 
its  elements  are  involved,  but  especially  the  muscle-cells.  It  is  doubtful 
whether  there  is  an  actual  new  formation  of  muscle-fibres,  but  each  fibre 
grows  in  length  and  thickness,  becoming  finally  between  seven  and  eleven 
times  as  long  and  three  to  five  times  as  thick  as  in  the  unimpregnated 
uterus  (Fig.  563).  There  is  at  the  same  time  a  great  growth  of  the  blood- 
vessels, which  have  to  supply  not  only  the  growing  wall  of  the  uterus  but  also, 
by  means  of  a  special  organ — the  placenta — the  nutritional  needs  of  the 
developing  foetus. 

CHANGES  IN  THE  UTERINE  MUCOUS  MEMBRANE.  At  the  moment 
of  conception  the  uterine  mucous  membrane  begins  to  undergo  hyper- 
trophy. Within  fourteen  days  it  has  attained  a  thickness  of  |  cm.,  and  by 
the  end  of  the  second  month,  f  cm.  On  section  it  shows  a  compact  layer, 
lining  the  cavity  of  the  uterus,  and  beneath  this,  abutting  on  the  muscular 
tissue,  is  a  spongy  layer  three  times  as  thick  as  the  compact  layer.  The 
superficial  epithelium  becomes  flattenecl,  loses  its  cilia,  and  degenerates.  In 
the  spongy  layer  the  uterine  glands  proHferate,  the  stroma  cells  are  enlarged, 
and  the  blood-capillaries  are  widely  dilated.  The  stroma  cells  become  con- 
verted into  the  large  decidual  cells.  By  the  time  the  fertilised  ovum  arrives 
in  the  uterus  the  process  of  hypertrophy  and  loosening  of  the  layers  of  the 

1230 


PREGNANCY  AND  PARTURITION 


1231 


mucous   membrane  has   already  made  some  progress.     As  it  lies  on  the 

mucous  membrane,  the  outermost  cells  of  the  developing  ovum  exercise 

a  destructive  influence  on  the  adjacent  cells  of  the  mucous  membrane, 

apparently  through  some  sort  of  digestion,  so  that 

the  ovum  sinks  in  the  membrane  and  reaches  the  sub- 

epitheUal  connective  tissue.     Round  the  margins  of 

the  depression,  which  the  ovum  has  made  for  itself, 

the  mucous  membrane  grows  over  the  protruding 

part  of  the  ovum  (Fig.  564).     When  this  has  taken 

place,  the  different  parts  of  the  mucous  membrane 

receive  different  names.     Since  (in  man)  they  are  all 

to  be  cast  off  with  the  foetus  at  birth,  each  part  is 

spoken  of  as  the  decidua,  that  hning  the  main  body 

of  the  uterus  being  known  as  the  decidua  vera,  that 

covering  the  protruding  part  of  the  egg  as  the  decidua 

rejlexa,  while  that  to  which  the  egg  is  immediately 

attached  is  the  decidua  serotina  or  hasalis.     It  is  from 

the  latter  that  the  placenta  is  formed.     By  the  end 

of  the  second  week  the  blood-vessels  in  this  situa- 
tion are  considerably  enlarged.  This  enlargement 
proceeds,  affecting  especially  the  capillaries  and 
veins,  until  these  form  venous  sinuses  at  the  junc- 
tion between  the  mucous  membrane  and  the  muscular 
coat.  Changes  take  place  at  the  same  time  in  the 
embryo.  When  it  sinks  into  the  mucous  membrane 
it  has  a  diameter  of  1  mm.  The  blastoderm  is  fully 
formed  with  its  three  layers ;  the  yolk-sac,  the 
body  cavity,  and  the  amnion  are  present.  The 
outermost  layer  of  the  epiblast  becomes  specially 
modified  to  serve  for  the  nutrition  of  the  embryo, 
and  gives  rise  to  the  production  of  numerous  villi,  the 
chorionic  villi,  so  that  the  whole  ovum  has  a  shaggy 
appearance.  Since  this  tissue  takes  no  part  in  the 
further  development  of  the  embryo,  but  serves  simply 
for  its  nutrition,  it  is  often  spoken  of  as  the  tropJio- 
hlast.  With  the  formation  of  foetal  blood-vessels, 
these  penetrate  into  the  villi,  together  vnth.  mesoblast. 
The  villi  grow  into  the  venous  spaces,  especially  in 
the  basal  part  of  the  decidua,  so  that,  at  this  period,  the  foetal  \'illi  are 
immersed  in  maternal  blood,  the  foetal  blood-vessels  being  separated  from  the 
maternal  blood  by  a  double  layer  of  epithehum,  one  layer  of  which  is  maternal 
and  the  other  foetal  in  origin.  Later  these  cells  become  reduced  to  a  single 
layer. 

NUTRITION  OF  THE  EMBRYO.  At  the  earliest  period  of  its  develop- 
ment the  fertilised  oxiim  is  dependent  for  its  nourishment  on  the  remains  of 
the  cells  of  the  discus  proligerus  adhering  to  it.  or  on  the  fluid  of  the  Fallopian 


Fig.  563.  Isolated  mus- 
clo  -  cells    from   the 
uterus,  showing  tho 
hypertrophy  during 
pregnancy. 
a,  fibre  from  uterus 
in  ninth  month  of  preg- 
nancy ;  6,  fibre  from  a 
non-gravid  uterus. 
(After  Botim.) 


1232 


PHYSIOLOGY 


tube  in  which  it  is  immersed.  The  first  blood-vessels  which  are  formed 
serve  to  take  up  nourishment  from  the  yolk-sac.  In  man,  however,  this 
source  of  supply  is  insignificant,  and  from  the  second  week  onwards  blood- 
vessels traversing  the  chorionic  vilh  come  into  close  relation  with  the 
maternal  blood,  from  which,  henceforth,  the  whole  growth  of  the  foetus  is  to 
be  maintained  by  a  special  development  of  these  connections  in  the  placenta. 
In  the  fully  formed  foetus  blood  passes  from  the  foetus  to  the  placenta 
by  the  umbihcal  artery,  and  is  returned  by  the  umbihcal  veins.  There  is 
no  communication  between  foetal  and  maternal  circulations.  The  placenta 
represents  the  foetal  organ  for  respiration,  nutrition,  and  excretion.     Thus 


Fig.  564.  Diagram  to  illustrate  the  imbedding  of  the  ovum  in  the  decidua,  and  the 
first  formation  of  the  foetal  villi  in  the  form  of  a  syncytial  troflwhlast  (derived 
from  the  outer  layer  of  the  ovum)  which  is  invading  sinus-like  blood-spaces  in  the 
decidua.     (After  T.  H.  Bryce.) 

the  umbihcal  artery  carries  to  the  placenta  a  dark  venous  blood,  which  in 
this  organ  loses  carbonic  acid  and  takes  up  oxygen,  so  that  the  blood  of  the 
umbilical  vein  is  arterial  in  colour.  The  oxygen  requirements  of  the  foetus 
are,  however,  but  small.  It  is  protected  from  all  loss  of  heat,  movements  are 
sluggish  or  for  the  most  part  absent,  and  the  only  oxidative  processes  are 
those  required  in  the  building  up  of  the  developing  tissues.  On  the  other 
hand,  the  foetus  has  need  of  a  rich  supply  of  food-stu£Es,  which  it  must 
obtain  through  the  placental  circulation.  It  is  imagined  that  the  epithehum 
covering  the  villi  serves  as  an  organ  for  passing  on  the  necessary  food-stuffs 
from  the  maternal  to  the  foetal  blood  in  the  form  best  adapted  for  the 
requirements  of  the  foetus.  We  know,  however,  practically  nothing  as  to  the 
changes  or  mechanism  involved  in  this  transference.  Although  most  of  the 
organs  of  the  foetus  are  fully  formed  some  time  before  birth,  they  are  for  the 
most  part  in  a  state  of  suspended  activity.     The  nitrogenous  excreta  are 


PREGNANCY  AND  PARTURITION  1233 

turned  out  by  the  placenta,  so  that  the  foetal  secretion  of  urine  is  minimal 
or  absent.  The  alimentary  apparatus  is  for  the  most  part  ready.  Thus 
pepsin  can  be  extracted  from  the  foetal  gastric  mucous  membrane.  The 
pancreas  contains  trypsinogen  and  the  intestinal  mucous  membrane  pro- 
secretin. Amylolytic  ferments  seem,  however,  to  be  absent  both  from 
the  sahvary  glands  and  the  pancreas.  The  liver  stores  up  glycogen  and 
secretes  bile,  which  accumulates  in  the  small  intestine,  forming  the  '  meco- 
nium.'    This  is  generally  voided  by  the  child  shortly  after  birth. 

THE  FCETAL  CIRCULATION.  In  the  foetus,  from  the  middle  of  intra- 
uterine life,  wc  find  certain  arrangements  of  the  circulation  which  are 
directed  to  providing  the  forepart  of  the  body,  especially  the  rapidly  growing 
brain,  with  oxygenated  blood,  while  the  less  important  tissues  of  the  limbs 
and  trunk  receive  venous  blood  (Fig.  5G5).  The  arterial  blood  coming  from 
the  placenta  along  the  umbihcal  vein  can  pass  directly  into  the  Uver.  The 
greater  part  of  it,  however,  traverses  the  ductus  venosus  to  enter  the  inferior 
vena  cava,  by  which  it  is  carried  to  the  right  auricle.  Here  it  impinges  on 
the  Eustachian  valve,  and  is  directed  thereby  through  the  foramen  ovale  into 
the  left  auricle,  whence  it  passes  into  the  left  ventricle  to  be  driven  into  the 
aorta.  As  this  arterial  blood  passes  into  the  inferior  cava,  it  is  of  course 
mixed  with  the  venous  blood,  returning  from  the  lower  limbs  and  lower  part 
of  the  trunk.  By  the  aorta  this  mixture,  containing  chiefly  arterial  blood, 
is  carried  to  the  head  and  fore  Umbs.  The  venous  blood  from  these  parts  is 
carried  by  the  superior  vena  cava  to  the  right  auricle,  and  thence  to  the 
right  ventricle,  by  which  it  is  driven  into  the  pulmonary  artery.  Only  a 
small  part  of  the  blood,  however,  passes  through  the  lungs,  the  greater  part 
traversing  the  patent  ductus  arteriosus  to  be  discharged  into  the  aorta 
below  the  arch,  whence  it  flows  partly  to  the  lower  limbs  and  trunk,  but 
chiefly  to  the  placenta  by  the  umbihcal  arteries.  In  the  foetus  therefore 
the  work  of  the  circulation  is  largely  carried  out  by  the  right  ventricle.  The 
greater  thickness  of  the  left  ventricular  walls,  which  is  so  characteristic  of 
the  adult,  does  not  become  evident  until  shortly  before  birth. 

With  the  first  breath  taken  by  the  new-born  child  all  the  mechanical 
conditions  of  the  circulation  are  modified.  The  resistance  to  the  blood-flow 
through  the  lungs  being  diminished,  the  blood  passes  from  the  pulmonary 
arteries  through  the  lungs  into  the  left  auricle.  The  pressure  in  the  left 
auricle  is  thus  raised,  while  that  in  the  right  auricle  falls,  so  that  the  foramen 
ovale  is  maintained  closed.  Even  before  birth  proliferation  of  the  Hning 
membrane  may  be  seen  both  in  the  ductus  arteriosus  and  in  the  ductus 
venosus  ;  and  with  the  mechanical  relief  of  the  vessels  afforded  by  respira- 
tion and  the  changed  conditions  of  the  foetus,  this  proliferation  goes  on  to 
complete  obliteration  of  the  vessels. 

PARTURITION 
As  the  uterus  increases  in  size  and  becomes  more  distended,  its  irritability 
becomes  greater,  so  that  it  is  easily  excited  to  contract.     The  stimulus  may 
be  supplied  from  adjacent  abdominal  organs,  from  the  brain,  as  by  emotions. 


1234 


PHYSIOLOGY 


or  by  direct  excitation  of  the  internal  surface  of  the  uterus,  in  consequence 
of  movements  of  the  foetus.     In  many  cases  no  antecedent  stimulus  can  be 


Fig.  565.  Diagrammatic  outline  of  the  organs  of  circulation  in  the 
foetus  of  six  months.  (After  Allen  Thomson.  ■» 
EA,  right  auricle  of  the  heart ;  EV,  right  ventricle  ;  la,  left  auricle  ;  EV,  Eustachian 
valve  ;  lv,  left  ventricle ;  L,  liver ;  k,  left  kidney  ;  i,  portion  of  small  intestine ;  a,  arch 
of  the  aorta  ;  a',  its  dorsal  part ;  a",  lower  end  ;  vcs,  superior  vena  cava  ;  vci,  inferior 
vena  where  it  joins  the  right  auricle  ;  vci,  its  lower  end ;  s,  subclavian  vessels ; 
j,  right  jugular  vein  ;  c,  common  carotid  arteries  ;  four  curved  dotted  arrow-lines  are 
carried  through  the  aortic  and  pulmonary  opening  and  the  auriculo-ventricular  ori- 
fices ;  da,  opposite  to  the  one  passing  through  the  pulmonary  artery  marks  the  place 
of  the  ductus  arteriosus  ;  a  similar  arrow-line  is  shown  passing  from  the  inferior  vena 
cava  through  the  fossa  ovalis  of  the  right  auricle  and  the  foramen  ovale  into  the  left 
auricle  ;  hv,  the  hepatic  veins  ;  vp,  vena  portaj  ;  x  to  vci,  the  ductus  venosus  ;  uv, 
the  umbilical  vein ;  ua,  umbilical  arteries  ;  uc,  umbilical  cord  cut  short ;  ii',  iliac 
vessels. 


discovered,  and  the  automatic  contraction  of  the  uterus  seems  to  be  analo- 
gous to  that  which  occurs  in  the  distended  bladder.     These  contractions 


PREGNANCY  AND  PARTURITION  1235 

ordinarily  give  rise  to  no  sensations,  and  are  only  felt  when  they  are  aug- 
mented in  consequence  of  reflex  stimulation.  During  the  greater  part  of 
pregnancy  they  have  little  or  no  effect  on  the  contents  of  the  uterus.  During 
the  last  weeks  or  days  of  pregnancy,  however,  these  contractions,  which  have 
now  become  more  marked,  have  a  distinct  physiological  effect.  Not  only 
do  they,  by  pressing  on  the  foetus,  cause  it,  in  most  instances,  to  assume  a 
suitable  position  for  its  subsequent  expulsion,  but,  affecting  the  whole  body 
of  the  uterus,  including  the  longitudinal  muscular  fibres  surrounding 
its  neck,  they  assist  the  general  enlargement  of  the  organ  in  dilating 
the  internal  os  uteri,  so  that  the  upper  part  of  the  cervix  is  obliterated 
and  drawn  up  into  the  body  of  the  uterus  some  httle  time  before  labour 
has  commenced. 

With  these  changes  in  the  uterus  are  associated  changes  in  the  round 
ligaments  and  in  the  vagina  and  vulva.  The  muscular  fibres  of  the  round 
ligaments  become  much  hypertrophied  and  lengthened,  and  these  structures 
can  therefore  aid  appreciably  the  uterine  contractions  in  the  subsequent 
expulsion  of  the  foetus.  The  vaginal  walls  become  thickened  and  of  looser 
texture,  so  as  to  afford  less  resistance  to  distension  during  the  passage  of  the 
foetal  head. 

Considerable  discussion  has  taken  place  as  to  the  cause  for  the  onset  of 
the  processes  comprised  under  the  heading  of  labour  or  parturition  at  a  nearly 
constant  period  of  two  hundred  and  seventy-two  days  after  conception. 
Most  of  the  explanations  which  have  been  suggested,  such  as  the  great  irri- 
tability of  the  uterus  at  the  termination  of  pregnancy,  the  loosening  of  the 
foetal  membranes,  the  return  of  the  menstrual  congestion  after  ten  months, 
thrombosis  of  the  placental  sinuses,  simply  replace  one  question  by  another. 
According  to  Spiegelberg  the  phenomena  accompanying  the  birth  of  twins, 
which  are  often  born  at  a  considerable  interval  from  each  other,  the  onset  of 
contractions  of  the  uterus  at  the  right  time  in  normal  as  well  as  in  extra- 
uterine foetation,  the  fact  that  the  extra-uterine  foetus  dies  when  it  has 
become  mature,  all  go  to  show  that  the  reason  why  labour  occurs  at  a 
definite  time  must  be  sought  for  in  foetal  rather  than  in  uterine  changes. 
This  author  suggests  that  some  substances  which  had  pre\nously  been  used 
up  by  the  foetus  gradually  accumulate  in  the  maternal  blood  as  the  foetus 
becomes  mature,  and  provoke,  by  their  direct  action  on  the  uterus  or  spinal 
cord,  the  uterine  contractions  which  give  rise  to  labour. 

Actual  parturition  is  in  man  generally  divided  into  two  stages.  In  the 
first  stage  the  contractions  are  confined  to  the  uterus,  and  chiefly  act  in  dila- 
ting the  OS  uteri.  In  this  dilatation  two  factors  arc  involved,  namely,  the 
active  dilatation  brought  about  by  the  contraction  of  the  longitudinal 
muscular  fibres  which  form  the  chief  constituent  of  the  lower  part  of  the 
uterine  wall ;  and  in  the  second  place,  a  passive  dilatation  by  the  pressure 
of  the  foetal  bag  of  membranes,  which  is  filled  with  amniotic  fluid,  and  forced 
down  as  a  fluid  wedge  into  the  os  by  the  contractions  of  the  uterine  fundus. 
The  uterine  contractions  are  essentially  rhythmical,  being  feeble  at  first,  and 
increasing  gradually  in  intensity  to  a  maximum  which  endures  a  certain 


1236  PHYSIOLOGY 

time,  and  then  gradually  subsides.  The  frequency  and  duration  of  the 
contractions  increase  as  labour  advances. 

As  soon  as  the  os  is  fully  dilated  and  the  foetal  head  has  entered  the 
pelvis,  the  contractions  change  in  character,  being  much  more  prolonged 
and  frequent,  and  attended  by  more  or  less  voluntary  contractions  of  the 
abdominal  muscles.  This  action  of  the  abdominal  muscles  is  associated 
with  fixation  of  the  diaphragm  and  closure  of  the  glottis,  so  that  pressure  is 
brought  to  bear  on  the  whole  contents  of  the  abdomen,  including  the  uterus. 
No  expelhng  force  can  be  ascribed  to  the  vagina,  since  it  is  too  greatly 
stretched  by  the  advancing  foetus.  In  this  way  the  foetus  is  gradually 
thrust  through  the  pelvic  canal,  dilating  the  soft  parts  which  impede  its 
progress,  and  is  finally  expelled  through  the  vulva,  the  head  being  born  first. 
The  membranes  generally  rupture  towards  the  end  of  the  first  stage  of  partu- 
rition. 

A  third  stage  of  labour  is  generally  described.  This  consists  in  a  renewal 
of  uterine  contractions  about  twenty  to  thirty  minutes  after  the  birth  of  the 
child,  and  results  in  the  expulsion  of  the  placenta  and  decidual  membranes. 

NERVOUS  MECHANISM.  We  possess  httle  experimental  knowledge 
of  the  nervous  mechanism  of  parturition.  The  most  important  observation 
on  this  point  is  the  already  quoted  experiment  by  Goltz,  in  which  this 
physiologist  observed  the  normal  performance  of  menstruation  (heat), 
impregnation,  and  parturition  in  a  bitch  whose  spinal  cord  had  been  com- 
pletely divided  in  the  dorsal  region  during  the  previous  year.  On  the  other 
hand,  destruction  of  the  lumbo-sacral  cord  completely  abohshes  the  normal 
uterine  contractions  of  parturition,  so  that  this  act  must  be  regarded  as 
essentially  reflex,  presided  over  by  a  controlHng  '  centre  '  in  the  grey  matter 
of  the  cord.  The  activity  of  the  centre  can  be  inhibited  or  augmented  by 
impulses  arriving  at  it  from  the  peripheral  parts  of  the  body,  as  by  the 
stimulation  of  sensory  nerves,  or  from  the  brain,  as  under  the  influence  of 
emotions.  The  nerve-paths  from  the  centre  to  the  uterus  have  been  already 
described. 


SECTION   V 
THE   SECRETION    AND   PROPERTIES   OF   MILK 

LACTATION 
During  pregnancy  the  foetus  obtains  the  whole  of  its  nourishment  from  the 
mother  by  means  of  the  placenta.  After  birth  the  quahty  of  the  nutriment 
supplied  to  the  young  child  depends  on  the  acti\'ity  of  the  cells  of  the 
mammary  glands.  Now,  however,  nutrition  involves  further  acti\Tity  on  the 
part  of  the  young  animal,  the  ahmentary  canal  being  concerned  in  the  diges- 
tion of  the  milk  supplied  by  the  mother,  and  the  excretory  organs,  especially 
the  kidneys,  being  made  use  of  for  getting  rid  of  waste  material.  The 
preparation  of  the  mammary  glands  for  the  subsequent  nourishment  of  the 
new-born  child  begins  in  the  first  month  of  pregnancy,  and  is  marked  by 
swelling  of  the  glands,  rapid  prohferation  of  the  duct  epithehum,  and 
production  of  many  new  secreting  alveoh.  The  developing  of  these 
glands  in  the  rabbit  has  been  already  described,  and  there  is  no  doubt 
that  in  the  human  species  the  process  follows  very  much  the  same 
course,  being,  however,  spread  over  nine  months  instead  of  four  weeks, 
as  is  the  case  with  the  rabbit.  During  the  latter  half  of  pregnancy 
a  watery  fluid  can  generally  be  expressed  from  the  nipple.  In  certain 
mammals  this  watery  secretion  gives  place  to  a  secretion  of  true  milk  at  the 
end  of  gestation  or  during  the  process  of  parturition  itself.  In  the  woman 
the  secretion  does  not  begin  as  a  rule  until  the  second  or  third  day  after 
birth,  though  the  formation  of  milk  may  be  anticipated  if  a  child  has  been 
put  to  the  breasts  during  the  latter  part  of  pregnancy.  Secretion  begins  on 
the  second  or  third  day,  even  if  the  child  has  been  born  dead  and  no  attempt 
at  suckUng  has  taken  place.  For  the  maintenance  of  the  secretion  the 
process  of  suckling  is  absolutely  necessary.  If  the  woman  does  not  nurse 
her  child,  the  swelling  of  the  breasts  gradually  passes  off,  the  milk  disappears, 
and  the  glands  undergo  a  process  of  involution.  Under  normal  conditions 
the  secretion  of  milk  lasts  for  six  to  nine  n\onths  and  may  in  rare  cases  extend 
over  more  than  a  year.  The  amount  secreted  increases  at  first  ^^^th  the 
growth  and  size  of  the  child.  The  Table  on  p.  1238  represents  the  average 
amoinit  of  milk  secreted  during  the  thirty-seven  weeks  after  birth.  It  will,  of 
course,  bo  greater  with  strong,  big  children,  and  smaller  with  weakly  children. 

COLOSTRUM.  Before  the  secretion  of  true  milk  begins,  the  fluid  which 
is  obtained  from  the  breast  is  known  as  colostrum.  It  may  be  expressed 
from  the  breasts  immediately  after  birth  and  is  ingested  by  the  child  during 

1237 


1238 


PHYSIOLOGY 


the  first  two  days  after  birth.  The  colostrum  is  formed  only  in  slight 
quantities.  It  is  an  opalescent  fluid,  often  somewhat  yellowish,  containing 
fat  globules,  which,  if  the  fluid  be  allowed  to  stand,  form  a  yellowish  layer 
on  the  top.  Under  the  microscope,  in  addition  to  the  fat  globules,  may  be 
seen  the  so-called  colostrum  corpuscles,  which  consist  of  multinucleated  cells 
loaded  with  particles  of  fat.  They  are  probably  leucocytes  or  phagocytes 
which  have  wandered  into  the  alveoh  and  have  taken  up  fat  globules.  Some 
of  the  corpuscles  may  be  desquamated  secretory  cells.  Colostrum  is  distin- 
guished from  true  milk  by  containing  httle  or  no  caseinogen.  It  contains 
about  3  per  cent,  of  proteins,  namely,  lactalbumen  and  lactoglobuhn,  which 
coagulate  on  boiling.  Lactose  and  salts  are  present  in  the  same  proportions 
as  in  ordinary  milk.  It  is  popularly  supposed  to  have  a  laxative  eflect  on 
the  child. 

Table   Showing  Amoitnt   of  Mii:k  Secketed  by  a  Nursing  Woman. 

increase 


Time 

Milk  secreted 

1st  day         ........         20  grm. 

2nd,, 

97  „ 

3rd  „ 

211    „ 

4th  „ 

326   „ 

5th  „ 

364  „ 

6th  „ 

402   „ 

7th  „ 

478  „ 

2nd  week 

502  „ 

3rd-4th  week 

572  „ 

5th-8th      „ 

736  „ 

9th-12th    „ 

797  „ 

13th-16th  „• 

836  „ 

17th-20th  „ 

867  „ 

21st-24th  „ 

.       944  „ 

25th-28th  „ 

.       963  „ 

DECREASE 

29th-32nd  week 916  grm. 

33rd-36th    „ 909  „ 

37th  week 

.       885   „ 

PROPERTIES  OF  MILK 
Fully  formed  milk  presents  certain  features  which  are  common  to  all 
mammals.  These  have  been  cjiiefly  studied  in  the  case  of  cows'  milk.  We 
may  therefore  deal  with  the  composition  of  cows'  milk  and  point  out  later 
in  what  respects  human  milk  difiers  therefrom.  Milk  forms  an  opaque 
white  fluid  with  characteristic  odour  and  sweetish  taste.  Its  specific  gravity 
varies  between  1028  and  1034.  Its  reaction  to  litmus  is  neutral,  to  lacmoid 
it  reacts  alkaline,  and  to  phenolphthalein,  acid.  One  hundred  cubic  centi- 
metres of  fresh  milk,  when  treated  with  lacmoid,  requires  41  c.c.  w/10  acid 
for  neutralisation.  When  treated  with  phenolphthalein  the  same  amount 
requires  19-5  w/10  alkaH  for  neutralisation.  When  exposed  to  the  air  milk 
rapidly  undergoes  changes  in  consequence  of  infection  by  micro-organisms. 
The  most  common  of  these  changes  is  the  formation  of  lactic  acid  by  the 


THE  SECRETION  AND  PROPERTIES  OF  MILK  1239 

bacillus  lacticus.  In  some  cases  the  milk  may  undergo  a  species  of  alcoholic 
fermentation,  as  in  the  formation  of  kephir,  which  is  made  by  the  fermenta- 
tion of  mares'  milk. 

The  opaque  appearance  of  milk  is  due  chiefly  to  the  presence  of  multitudes 
of  fine  fatty  particles.  On  allowing  the  milk  to  stand  the  particles  rise  to 
the  surface,  forming, cream,  and  by  mechanical  agitation,  especially  if  the 
milk  is  sUghtly  sour,  they  may  be  caused  to  run  together  with  the  formation 
of  butter.  Much  discussion  has  arisen  as  to  the  reason  why  the  fat  globules 
do  not  run  together  naturally.  By  many  authors  it  has  been  imagined  that 
they  are  clothed  with  a  special  protein  membrane  {haptogen  membrane) 
originating  from  the  protoplasm  of  the  cell  in  which  the  fat  globules  were 
originally  formed.  It  must  be  remembered  that  in  any  protein  solution, 
such  as  that  in  which  the  globules  are  suspended,  the  protein  tends  to  aggre- 
gate, with  the  formation  of  a  pelhcle,  at  the  surface,  so  that  an  emulsion 
once  produced  in  such  a  fluid  will  tend  to  be  more  or  less  permanent.  There 
seems  therefore  no  reason  to  assume  the  presence  of  a  distinct  membrane 
differing  in  composition  from  the  proteins  present  in  the  surrounding  fluid. 
The  fats  of  milk  consist  for  the  greater  part  of  the  neutral  glycerides,  tripal- 
mitin,  tristearin,  and  triolein.  In  smaller  quantities  it  contains  the  tri- 
glycerides of  myristic  acid,  butyric  acid  (?),  and  capronic  acid,  with  traces 
of  capryhc,  capric,  and  lauric  acids. 

The  milk  plasma,  the  fluid  in  which  the  fat  globules  are  suspended, 
contains  various  proteins,  a  carbohydrate,  lactose,  and  inorganic  salts, 
with  a  small  amount  of  lecithin  and  nitrogenous  extractives. 

THE  PROTEINS  OF  MILK.  The  chief  protein  of  milk  is  caseinogen, 
belonging  to  the  class  of  phosphoproteins.  Like  other  bodies  of  this  class 
it  presents  distinct  acid  characteristics,  being  precipitated  by  acids  and 
soluble  in  dilute  alkalies.  It  may  be  prepared  from  separated  milk  by  the 
addition  of  weak  acids.  A  convenient  method  is  to  dilute  one  litre  of  milk 
with  ten  Utres  of  distilled  water  and  add  to  the  mixture  10  c.c.  of  glacial 
acetic  acid.  The  precipitate  which  is  formed  rapidly  sinks  to  the  bottom 
and  may  be  washed  two  or  three  times  by  decantation.  It  may  be  purified 
by  solution  in  dilute  ammonia  and  precipitation  by  acetic  acid  two  or  three 
times.  The  precipitate  finally  obtained  is  extracted  with  alcohol  and 
ether,  and  the  dried  caseinogen  prepared  in  this  way  forms  a  snow-white 
powder  which  is  practically  insoluble  in  water  and  dilute  salt  solutions.  It 
is  easily  dissolved  on  the  addition  of  a  little  alkah,  when  it  yields  solutions 
which  are  acid  to  htmus.  When  rubbed  up  with  chalk  it  dissolves,  displacing 
the  carbonic  acid  and  forming  a  calcium  caseinogenate.  A  solution  of  case- 
inogen in  soda  or  potash  is  transparent  and  passes  easily  through  a  clay  cell. 
The  calcium  caseinogenate  forms  only  opalescent  solutions.  Apparently 
the  compound  is  dissociated  by  water  with  the  formation  of  caseinogen  acid 
which  is  in  a  state  of  partial  solution  as  swollen-up  aggregates.  It  is 
impossible  therefore  to  filter  calcium  caseinogenate  through  a  clay  cell.  It  is 
mainly  in  this  form  that  caseinogen  is  contained  in  milk,  hence  the  opalescent 
appearance  of  the  milk-plasma.     When  calcium  caseinogenate  solution  is 


1240  PHYSIOLOGY 

boiled  it  forms  a  pellicle  on  the  surface  in  the  same  way  as  milk  does.  On 
treating  the  caseinogen  with  rennet  ferment  it  is  converted  into  a  modifica- 
tion known  as  paracasein,  which  in  the  presence  of  Hme  salts  is  thrown  out 
as  insoluble  casein.  To  this  process  is  due  the  clotting  of  whole  milk  by 
rennet,  which  is  made  use  of  in  the  preparation  of  cheese,  the  curd  consisting 
of  a  network  of  casein  enclosing  fat  globules  in  its  meshes.  On  allowing 
the  clot  to  stand  it  shrinks,  pressing  out  a  milk-serum. 

From  the  milk-serum  or  whey  may  be  obtained  two  other  proteins, 
known  as  lactalhumen  and  lactoglobulin.  These  resemble  very  nearly  the 
albumen  and  globuhn  of  blood-serum.  They  are  coagulated  on  heating. 
According  to  some  authors  a  third  protein  is  present  in  the  whey,  to  which 
the  name  whey-protein  has  been  given,  and  which  is  supposed  to  be  split  off 
from  the  caseinogen  under  the  action  of  the  rennet  ferment. 

Milk  can  be  boiled  without  undergoing  any  coagulation.  If  it  be 
allowed  to  stand  and  become  sour  by  the  formation  of  lactic  acid,  at  a  certain 
period  boihng  the  milk  causes  its  complete  coagulation.  Later  on  the  acid 
produced  is  sufficient  in  itself  to  precipitate  the  caseinogen.  Both  these 
processes,  namely,  coagulation  of  half-sour  milk  by  heating,  and  spon- 
taneous clotting  of  milk  by  the  production  of  acid,  are  made  use  of  in 
different  countries  for  the  manufacture  of  cheese. 

MILK  SUGAR.  The  sugar  of  milk,  or  lactose,  is  most  easily  obtained 
from  whey,  which,  after  separation  of  the  clot,  is  boiled  to  precipitate  the 
remaining  proteins.  On  filtering  and  evaporating  slowly,  the  milk  sugar 
crystallises  out.  Lactose  is  a  disaccharide  and  has  the  formula  CiJl22^n' 
It  is  only  known  to  occur  in  milk.  It  may  be  found  in  the  urine  of  nursing 
women  when  the  breasts  are  not  kept  empty,  so  that  there  is  reabsorption 
of  the  lactose  formed  in  the  mammary  glands.  It  is  unaltered  by  ordinary 
yeast,  so  that  the  yeast  test  is  the  best  means  of  distinguishing  lactose  from 
dextrose  in  the  urine.  It  gives  the  ordinary  tests  for  reducing  sugar.  The 
salts  of  milk  include  insoluble  salts,  soluble  calcium  salts,  sodium  and' 
potassium,  phosphates  and  chlorides. 

Mere  enumeration  of  the  constituents  of  milk  presents  but  httle  interest 
unless  we  realise  how  closely  the  composition  of  this  fluid  is  adapted  to  the 
needs  of  the  growing  animal.  In  the  first  place,  we  find  a  proportionahty 
between  the  total  solids  of  the  milk  and  the  rate  at  which  the  young  animal 
grows.  It  must  be  remembered  that  the  milk  taken  by  the  animal  serves 
only  in  part  for  the  production  of  energy  in  its  body,  a  great  proportion  of 
it  being  required  for  the  building  up  of  new  tissue.  In  no  respect  is  this 
correspondence  seen  better  than  in  the  comparative  analyses  of  the  ash  of 
milk  and  of  the  young  animal  of  the  same  species  which  were  made  by 
Bunge.  The  following  Table  shows  the  composition  of  the  ash  of  a 
rabbit  fourteen  days  old,  of  the  milk  which  it  was  receiving  from  its 
mother,  of  the  ash  of  rabbit's  blood  and  blood-serum.  Nothing  could  be 
more  striking  than  the  marvellous  way  in  which  the  cells  of  the  mammary 
gland  have  picked  out  from  the  salts  of  the  circulating  plasma  exactly  those 
salts  which  are  needed  for  the  growing  animal  and  in  the  same  proportion  : 


THE  SECRETION  AND  PROPERTIES  OF  MILK 


1241 


Rabbit 

Rabbit'3 

Rabbit's 

Rabbit's 

14  aays  old 

milk 

blood 

blood-serum 

Potash   .          .          .          • 

10-8 

101 

23-8 

3-2 

Soda       .          .          .          ■ 

60 

7-9 

31-4 

54-7 

Lime      .          .          .          • 

350 

35-7 

0-8 

1-4 

Magnesia 

2-2 

2-2 

0-6 

0-6 

Iron  oxide 

0-23 

008 

6-9 

0 

Phosphoric  acid 

41-9 

39-9 

111 

30 

Chlorine 

4-9 

5-4 

32-7 

47-8 

This  close  correspondence  is  only  necessary  where  growth  is  very  rapid, 
so  that  the  greater  part  of  the  constituents  of  the  milk  have  to  be  utihsed 
in  the  building  up  of  the  animal  tissues.  As  Bunge  has  showm,  the  slower 
tlie  growth  of  the  animal  the  greater  the  divergence  between  the  composition 
of  the  milk  and  that  of  the  new-born  animal.  We  may  compare,  for  instance, 
the  rabbit,  which  doubles  its  weight  in  six  days,  with  the  dog,  which  doubles 
its  weight  in  ninety-six  days,  and  the  human  infant,  which  takes  one  hundred 
and  eighty  days  to  double  its  weight  at  birth. 

The  last  column  of  the  following  Table  represents  the  composition  of  the 
ash  of  cow's  milk,  and  shows  how  very  inefficiently  this  milk  can  be  regarded 
as  replacing  human  milk,  the  natural  food  of  the  infant. 


Rabbit  14 
days  old 

Rabbit's 
millv 

Puppy  few 
hours  old 

Bitch's 
milk 

Infant 

some 

minutes 

afterbirth 

Human 
milk 

Cow's 
milk 

Potash      . 

10-S 

101 

11-4 

15  0 

8-9 

35-2 

22  1 

Soda 

6-0 

7-9 

10-6 

8-8 

10-0 

10-4 

13-9 

Lime 

35-0 

35-7 

29-5 

27-2 

33-5 

14-8 

20  0 

Magnesia . 

2-2 

2-2 

1-8 

1-5 

1-3 

2-9 

2G 

Lon  oxide 

0-23 

0-08 

0-72 

0-12 

10 

0-18 

0  04 

Phosphoric  acid 

41-9 

39-9 

39-4 

34-2 

37-7 

21-3 

24-8 

Chlorine  . 

4-9 

5-4 

8-4 

16-9 

8-8 

19-7 

21-3 

The  fitness  of  caseinogen  for  buildingup  the  tissues  of  the  body  is  evident 
when  we  compare  as  in  the  Table  on  page  1242  the  products  of  its  hydrolysis 
with  those  of  all  the  proteins  in  other  food-stuft's.  It  will  be  seen  that 
practically  every  amino-acid  and  alhed  substance  employed  in  the  building 
up  of  the  various  proteins  is  represented  in  caseinogen.  The  only  exception 
is  glycine,  which  can  be  easily  formed  from  other  amino-acids. 

In  another  point  we  find  an  adaptation  of  the  milk  to  the  growth  of  the 
young  animal,  and  that  is  in  its  lecithin  content.  Lecithin  is  probably 
employed  to  the  largest  extent  in  the  building  up  of  the  central  nervous 
system,  where  it  forms  the  most  important  constituent  of  the  medullary 
sheaths  of  the  nerve  fibres.  There  is  a  corresponding  proportionality  between 
the  lecithin  content  of  milk  and  the  relative  brain  weight  of  the  young 


1242 


PHYSIOLOGY 

CHEivncAL  Constitution  of  Different  Proteins 


c 

a 

S3 

C3 

;§ 

3 

J2 
O 

e 

^ 
^ 

1 

a 

a 
1 

o 

a 

w 

a 

M 
CO 

S3 
'53 

S3 

■■B 
.2 
3 

S3 

S 
> 
< 

.9 

s 

a 

o 

Glycine  . 

0 

3-5 

0-4 

0-1 

10 

16-5 

36-0 

2-0 

Alanine . 

4-19 

2-7 

2-2 

0-9 

2-0 

2-0 

2-5 

0-8 

21-0 

3-7 

Valine    . 

4-3 

+ 

1-0 

o-:5 

1-0 

1-0 

0-9 

Leucine . 

29-04 

20-0 

18-7 

10-5 

8-0 

5-6 

15-0 

21 

1-5 

11-1 

Isoleucine 

Phenylalanine 

4-24 

31 

3-8 

3-2 

3-7 

2-4 

3-2 

0-4 

1-5 

3-1 

Tyrosine 

1-33 

2-1 

2-5 

4-5 

1-5 

1-2 

1-5 

10-5 

2-2 

Serine    . 

7-8 

0-56 

0-6 

0-2 

0-5 

0-2 

0-4 

1-0 

Cystine  . 

0-31 

2-5 

0-7 

0-6 

0-5 

0 

Proline  . 

11-0 

2-34 

1-0 

2-8 

3-1 

3-2 

7-0 

5-4 

5-2 

+ 

5-1 

Oxyproline 

1-04 

0-2 

3-0 

Aspartic  acid  . 

4-43 

3-1 

2-5 

1-2 

5-3 

0-6 

4-0 

0-6 

+ 

4-1 

Glutamic  acid 

1-73 

7-7 

8-5 

11-0 

13-8 

37-4 

18-4 

0-9 

15-1 

Tryptophane  . 

+ 

+ 

+ 

1-5 

+ 

+ 

0 

+ 

Arginine 

87-4 

5-42 

4-8 

10-1 

3-2 

7-6 

1-0 

7-1 

Lysine   . 

0 

4-28 

5-8 

4-3 

0-0 

2-8 

+ 

7-1 

Histidine 

0 

10-96 

2-5 

2-5 

1-0 

0-4 

+ 

1.1 

Ammonia 

1-6 

2-0 

5-1 

0-4 

1-0 

animal.  Thus,  in  the  calf  the  brain  is  only  -y^^  of  the  whole  animal.  In 
cow's  milk  lecithin  is  present  in  the  proportion  of  1*4:  per  cent,  of  the  total 
protein.  In  the  puppy  the  brain  is  J^  of  the  whole  body  and  the  proportion 
of  lecithin  to  protein  in  the  milk  is  2-11  per  cent.  In  the  infant,  the  brain 
forms  -^  of  the  body  weight,  while  the  lecithin  is  3-05  per  cent,  of  the  protein 
of  human  milk. 


Calf 


Puppy 


Infant 


Relative  brain  weight  .... 

Lecithin   content  of  milk  in  percentage 

of  protein         ..... 


1  :  370 
1-40 


1  :  30 
211 


1  :7 
305 


We  thus  see  that  under  normal  conditions  the  young  animal  is  supphed 
through  its  natural  food  with  all  the  food-stufis  in  the  proportions  which  it 
requires  for  its  normal  nourishment  and  growth.  It  is  impossible  therefore 
satisfactorily  to  replace  the  natural  milk  of  an  animal  by  that  of  another 
species.  In  civilised  communities  it  is  becoming  more  and  more  the  custom 
to  endeavour  to  feed  the  child  with  cow's  milk,  more  or  less  modified,  in  the 
vain  endeavour  to  reproduce  the  properties  of  human  milk.  Among  all 
classes  this  involves  the  administering  of  a  milk  differing  in  its  qualities 
and  in  the  relative  proportions  of  its  proteins,  its  fats,  carbohydrates,  and 
salts,  from  human  milk.  So-called  '  humanised  '  milk  is  only  a  rough  imita- 
tion of  the  natural  mother's  milk.  Among  the  poorer  classes  this  artificial 
feeding  means  the  replacement  of  a  natural  sterile  food,  throwing  very  little 
work  on  the  digestive  organs  of  the  child,  by  a  foreign  milk,  very  difficult 


THE  SECRETION  AND  PROPERTIES  OF  MILK 


1243 


to  digest,  and  often  teeming  with  micro-organisms.  There  is  no  doubt  that 
of  the  children  dying  during  the  first  year  of  hfe  four-fifths  are  murdered  by 
this  unnatural  method  of  feeding.  In  some  cases  it  is  necessary  to  adopt 
artificial  feeding  because  the  mother  is  abnormal,  and  there  is  an  insufiicient 
secretion  of  milk.  It  is  therefore  important  to  know  what  are  the  main  dift'er- 
ences  in  composition  between  human  and  cow's  milk.  In  human  milk  the 
caseinogen  is  not  only  absolutely  but  also  relatively  less  than  in  cow's  milk, 
while  the  latter  is  relatively  poorer  in  milk  sugar.  Human  milk  is  poorer 
in  salts,  especially  in  lime,  containing  only  one-sixth  of  the  amount  present  in 
cow's  milk.  Human  milk  is  also  said  to  be  poorer  in  citric  acid.  The  main 
differences  may  be  summarised  as  follows  : 


Water 

Proteins 

Fat 

Milk  sugar 

Salts 

Caseinogen 

Albumin 

Human  milk 
Cow's  milk    . 

88-5 
87-1 

1-2 

302 

0-5 
0-53 

3-3 
3-7 

6-0 
4-8 

0-2 
0-7 

The  caseinogen  of  human  milk  presents  several  points  of  difference  from 
the  caseinogen  of  cow's  milk.  It  is  less  easly  precipitated  by  acids.  When 
coagulated  by  rennet  it  does  not  form  a  firm  clot,  but  is  thrown  out  in  a 
flocculent  form.  It  is  thus  much  more  susceptible  to  the  action  of  gastric 
juice.  Whereas  the  caseinogen  of  cow's  milk  generally  gives  a  precipitate 
of  '  pseudonuclein  '  on  digestion  with  pepsin  and  hydrochloric  acid,  a  smaller 
or  no  precipitate  is  formed  with  human  caseinogen. 

Another  important  advantage  of  human  milk  for  the  infant  lies  in  the 
presence  of  antitoxins.  It  has  been  shown  by  Ehi'lich  that  when  a  female 
animal  has  been  immunised  against  any  toxin  and  has  produced  in  conse- 
quence antitoxins  in  its  blood,  these  antitoxins  will,  if  it  has  young,  pass  over 
into  the  milk.  The  same  passage  of  anti-bodies  into  the  milk  has  been 
proved  in  the  case  of  various  infective  disorders.  The  ingestion  of  human 
milk  will  therefore  not  only  nourish  the  infant,  but  will  provide  it  with  a 
certain  measure  of  passive  immunity  against  possible  infection  by  diseases  to 
which  its  species  is  liable. 

THE  SECRETION  OF  MILK.  When  fully  formed,  each  mammary  gland 
consists  of  fifteen  to  twenty  lobes  connected  by  connective  tissue.  Each 
lobe  is  made  up  of  a  mass  of  secreting  alveoli  which  lead  by  narrow  ducts  into 
one  large  lactiferous  duct.  These  lactiferous  ducts,  one  from  each  lobe,  open 
on  the  nipple,  undergoing  in  the  nipple  itself  an  oval  enlargement.  Before 
secretion  begins,  the  alveoli  as  well  as  ducts  are  lined  with  a  cubical  epithe- 
lium. When  secretion  commences  a  marked  difference  develops  between  the 
epithelium  of  the  alveoli  and  that  of  the  ducts.  While  the  latter  retains  its 
previous  character,  the  cells  of  the  secreting  epithelium  grow  in  length  and 
project  into  the  lumen  of  the  gland.  In  the  innermost  part  of  the  protoplasm 
numerous  fat  globules  make  their  appearance.     If  sections  be  made  of  the 


1244 


PHYSIOLOGY 


gland  diuing  the  vaiious  stages  of  its  activity  and  stained  by  Altmann's 
method  (acid  fuchsin  and  picric  acid)^  it  will  be  seen  that  the  commencement 
of  acti\dty  is  marked  by  the  growth  of  the  innermost  part  of  the  cells  and  the 
development  in  these  of  a  number  of  grannies  (Fig.  566).  These  granules 
finally  lengthen  into  shapes  hke  spirilla,  while  others  of  them  form  fat  and 
become  metamorphosed  into  fat  granules.  The  nuclei  of  the  cells  also  divide, 
apparently  in  preparation  for  the  replacement  of  some  cells  which  undergo 
complete  degeneration  and  are  cast  off  into  the  secretion. 

We  know  very  httle  about  the  mechanism  of  milk  secretion.     It  seems 
impossible  at  present  to  explain  the  very  close  adaptation  between  the 


'^Oi'gi) 


'\) 


W,  n 


Fig.  566.  Sections  of  mammary  gland  of  guinea-j)ig  (fat  granules 
stained  black  with  osmic  acid). 
A,  during  rest,  b,  during  active  secretion.  It  will  be  noticed  that  in  this  case 
the  active  formation  of  j)roducts  of  cell-metabolism  (granules,  &c.)  begins  with 
the  commencement  of  secretion,  and  does  not  occur  almost  exclusively  during  rest, 
as  in  the  salivary  glands.  In  the  mammary  gland,  the  active  growth  of  protoplasm, 
the  formation  of  granules  from  the  protoplasm,  and  the  discharge  of  these  granules 
in  the  secretion  appear  to  go  on  at  one  and  the  same  time. 

activity  of  the  secretory  cells  and  the  needs  of  the  infant  or  young  animal. 
Two  at  least  of  the  constituents  of  milk,  caseinogen  and  lactose,  are  peculiar 
to  this  secretion.  It  has  been  assumed  that  the  caseinogen  is  produced  by 
some  sort  of  alteration  in  the  nucleo-proteins  of  the  gland-cells,  and  that  the 
lactose  is  derived  in  the  same  way  from  some  sort  of  gluco-protein  or  gluco- 
nucleoprotein,  but  the  evidence  for  either  of  these  assumptions  is  very  scanty. 
The  growth  of  the  mammary  glands  during  pregnancy  is  largely  determined 
by  some  form  of  chemical  stimulation,  the  specific  hormone  being  produced  in 
the  corpus  luteum  of  the  ovary  and  possibly  also  in  the  growing  foetus.  It  has 
been  suggested  by  Hildebrandt  that  this  stimulus  is  inhibitory  in  character — 
inhibitory,  that  is  to  say,  of  secretion — and  therefore  tending  to  the  con- 
tinuous growth  of  the  gland-cells.  With  the  removal  of  the  foetus  at  birth  the 


THE  SECRETION  AND  PROPERTIES  OF  MILK  1245 

source  of  the  inhibitory  stimulus  is  removed  and  the  overgrown  gland-cells 
enter  into  a  condition  of  spontaneous  activity.  However  this  may  be,  there 
is  no  doubt  that  the  secretion  of  the  gland,  once  formed,  is  continued  inde- 
pendently of  the  foetus,  or  indeed  of  any  of  the  pelvic  organs.  The  onset  of  a 
new  pregnancy  brings  the  secretion  to  a  close.  Removal  of  the  ovaries  in  a 
cow  is  sometimes  employed  as  a  means  of  prolonging  the  secretion  of  milk. 
The  only  condition  which  is  necessary  for  secretion  to  continue  during  six  to 
nine  months  after  birth  is  the  repeated  emptying  of  the  gland,  i.e.  the  removal 
of  the  secreted  milk.  The  process  of  suckling  not  only  removes  the  milk 
already  secreted  but  excites  the  secretion  of  more  milk.  The  secretion  is 
certainly  subject  to  nervous  influences,  but  physiologists  have  not  succeeded 
in  either  producing  secretion  by  stimulation  of  the  nerves  going  to  the  glands, 
or  in  stopping  secretion  by  section  of  these  nerves.  Moreover  the  food  of  the 
animal  may  be  varied  \\dthin  very  wide  limits  without  altering  the  composition 
or  amount  of  the  milk  secreted,  provided  only  that  the  food  is  sufficient  in 
amount.  The  only  constituent  of  the  milk  for  which  we  have  direct  e%'idence 
of  alteration  by  changes  in  the  food-supply  of  the  mother  is  the  fat.  It  is 
well  known  that  the  composition  of  butter  may  be  affected  according  to  the 
food  supplied  to  the  cow.  A  large  supply  of  oilcake,  for  instance,  may  result 
in  the  production  of  a  butter  which  is  deficient  in  the  higher  fatty  acids  and 
is  therefore  oily  at  ordinary  temperatures.  Abnormal  fats  and  fatty  acids, 
such  as  iodised  fats  or  erucic  acid,  when  administered  to  an  animal  in 
lactation  may  appear  among  the  fats  of  the  milk.  .  Not  only  can  the  secretion 
and  composition  of  the  milk  be  afiected  reflexly  through  the  nervous  system, 
as,  e.fj.  under  the  influence  of  emotions,  but  the  influence  may  be  reciprocal. 
This  is  especially  marked  in  the  case  of  the  pelvic  organs.  The  act  of 
suckhng  excites  tonic  contractions  of  the  uterus.  Putting  the  child  to  the 
breast  shortly  after  birth  is  therefore  an  important  means  of  causing  con- 
traction of  the  uterus  and  stopping  any  tendency  to  haemorrhage  from  the 
venous  siniLses  opened  by  the  separation  of  the  placenta  and  foetal  mem- 
branes. The  nursing  of  the  child  is  therefore  an  important  means  of  pro- 
curing a  proper  involution  of  the  uterus  after  labour.  Many  uterine  troubles 
among  women  may  be  ascribed  to  the  previous  neglect  of  this  elementary 
duty. 


INDEX 


Absentiie.  action  of,  440 

Absorption  from  connective  tissues,  1019 

in  largo  intestine,  723 

of  amino-acids,  749 

of  carbohydrates,  743 

of  fats,  738 

of  food-stuffs,  731-753 

of  lymph,  1019 

of  proteins,  744 

of  water  and  salts,  731 

significance  of  lipoids  in,  735 
Absorption-coefficient  of  gases,  1057 
Acapnia,  1101 

Accelerator  nerves  of  heart,  975 
Accessory  olive,  367,  382 
Accommodation,  539-549 

comparative  physiology  of,  547-549 

range  of,  546 
Acetamide,  49 
Acetic  acid,  48 
Aceto-acetic  acid,  detection  of,  1123 

production  from  fats,  793 
from  amino-acids,  802 
Acetone.  49 

bodies  in  urine,  1123 

in  diabetes,  804 
Aclu-omatic  spindle,  1205 
Aehroodcxtrin,  68,  662 
Acid  albumin.  98 

amides,  49 

hydrolysis  of  proteins,  76 

number  of  fats,  56 
Acidosis.  793 

in  diabetes,  804 
Acromegaly,  1191 
Acrose,  62 

synthesis  of,  153 
Action-current,  226 

E.M.F.  of,  233 
Adaptation,  4 

sensory.  482 

visual,  572 
Addisan^s  disease,  1185 
Adenine,  103.  778 
Adipose  tissue.  53 

action  of  gastric  juice  on,  688 
Adrenaline,  51.  1182 

action  on  blood-pressure.  1183 
on  blood-vessels.  1003 
on  heart,  977 
on  nerve  terminations,  278 

and  sympathetic  sj'stem,  1183 

glycosuria.  SOI 

instability  of.  1185 

isomers,  action  of,  1183 
Adsorption,  by  colloids,  141 


Adsorption,  in  ferment  action,  168 

law  of,  148 

of  toxins,  1033 
Adventitia  of  artery,  870 
Aerotonometers,  1058.  1068 

specific  surface  of.  1069 
Afferent  autonomic  fibres,  476 

impulses  from  muscles,  345 

nerves,  255 

path,  328 

tracts,  cerebellum.  402 
cerebrum,  422 
After-images,  571 

coloured,  576,  581 
After-load,  207 
Air,  composition  of,  1052 

expired,  1052 
Alanine.  48,  77,  81 

deamination  of,  154 
Albuminates,  99 
Albuminoids,  106 
Albvimins,  characters,  97 
Albuminuria,  1121 
Albumoscs,  100.  686 
Alcaptonuria.  770.  1124 
Alco-gels,  139 
Alcohol,  food- value  of,  646 
Alcohols,  46 

polyatomic,  47 
Aldehyde.  47 

reactions  of,  47 

resin,  48 
Aldol,  120,  785 

condensation,  120 
Aldoses,  60 
Alexia,  456 

Alkaline  htematin,  98,  830 
Allantoin,  779 

'  All  or  none  '  phenomenon,  205 
Altitude,  effect  of,  on  red  corpuscles 
1102 
on  respiration.  1082 
A  Itinann's  granules.  1 7 
Aluminium.  44 
Alveolar  air.  carbon  dioxide  in,  1081 

composition  of,  1053 

sampling  of.  1052 
Amacrine  cells.  560 
Amboceptors,  1036 
Amide  nitrogen  of  proteins.  91 
Amines.  49 

action  of.  1185 

formed  in  putrefaction,  I.")5,  1185 
Amino-acids.  48,  77 

absorption  of,  745—749 
aromatic,  84 
1247 


1248 


INDEX 


Amino-acids,  esters  of,  80 

fate  after  absorjition,  750 

food- value  of,  645 

heat  equivalents  of,  763 

in  digestion,  659 

interconvertibility  of,  765 

separation  of,  80 

sulphur  in,  86 

synthesis  of,  115,  154 
Amino-isobutyl  acetic  acid,  82 
a-amino-glutaric  acid,  82 
a-amino-succinic  acid,  82 
a-amino-thiopropionic  acid,  86 
Ammonia,  estimation  in  urine,  1127 

production  from  amino-acids,  761 
in  acidosis,  766 
Ammonia-nitrogen  of  proteins,  92 
Amoeba,  14 

Amoeboid  movement,  248 
Amphoteric  electrolytes,  80,  149 
Amylase,  68 

of  pancreatic  juice,  706 
Amyloid  substance,  106 
Amyloplasts,  68 
Amylopsin,  706 
Anacrotic  pulse,  926 
Anaemia,  1011 
Anaerobic  organisms,  26 
Analgesia,  495 
Anal  sphincter,  732 
Anaphase  of  mitosis,  1206 
Anarthria,  454 
Anelectrotonus,  265 
Anisotropous  substance,  182 
Ankle  clonus,  335 
Anodal  contraction,  263 
Anode,  187 
Anoestrum,  1226 
Anterior  cerebellar  tract,  354,  371 

commissure,  426 
Antidromic  fibres,  323,  999 
Antigens,  1036 
Antilysins,  1033 

Anti-peristalsis  in  large  intestine,  730 
Antithrombin,  846 
Antitoxins,  150,  847,  1032 
Antipeptone,  704 
Apex-beat,  903 
Aphasia,  454 
Apnoea,  1080,  1095 

spuria,  1096 

vagi,  1096 

vera,  1096 
Aqueduct  of  Sylvius,  363,  373 
Arabinose,  61 
Arachidic  acid,  54 
Archipallium,  417 
Arcuate  fibres,  367 
Arginase,  767 
Arginine,  83,  84,  91 
Aristotle's  experiment,  493 
Aromatic  compounds,  49 

substances,  fate  of,  770-773 
'  Arrest '  curves,  200,  208 
Arterial  pressure,  872,  874 

and  cardiac  output,    884 

in  man,  875 
Arteries,  distensibility  of,  871 

flow  in,  918-931 

structure  of,  870 
Arterioles,  structure  of,  870 


Arytenoid  cartilage,  520 

muscle,  521 
Ascending  tracts,  387 
Ash,  estimation  in  food,  614 
Asparagine,  83 

food- value  of,  646 
Aspartic  acid,  82,  91 
Aspergillus  oryzse,  168 
Asphyxia,  blood-pressure  changes  in, 
984 

factors  in,  984-987 

in  decerebrate  animal,  985 

stages  of,  1079 
Assimilation,  425 
Association  areas,  452 

ceUs  of  cortex,  427 

centres,  433 

fibres  of  cerebrum,  427 

sensory,  451 
Astasia,  404 
Asthenia,  404 
Asthma,  1048 
Astigmatism,  538 
Asymmetric  carbon  atoms,  51 
Ataxy,  346,  598 
Atonia,  404 
Attraction  sphere,  16 
Atwater- Benedict  calorimeter,  622 
Auditory  area,  447 

fatigue,  518 

localisation,  518 

nerve,  nucleus  of,  379,  380 

ossicles,  513 

mechanics  of,  514 

projection,  518 

radiation,  423 

sensations,  603 

analysis  of,  517 
Audito-sensory  area,  433 
Auerbach's  plexus,  469,  474 

in  intestine,  functions  of,  726,  727 

in  stomach,  699 
Aurse  in  epilepsy,  439,  446 
Auricle,  pressure-changes  in,  901 
Auriculo-ventricular  bundle,  893,  952 

node,  952 
Autonomic  fibres,  afferent,  476 

cranial,  472 

of  vagus,  473 

sacral,  473 

system,  classification  of,  470 
Autonomic  nervous  system,  466—477 
Autoxidisable  substances,  1106 
Average  error  method,  484 
Avogadro's  hypothesis,  126 
Axis  cylinder,  251 
Axon,  251 

reflexes,  474 

in  vaso-dilator  fibres,  999 

Bacteria,  action  on  amino-acids,  76 

of  putrefaction,  155 
Bacterium  nitromonas,  40 
BaJmung,  305 

in  cortex,  441 
Balanced  reactions,  166 
Balance-sheets  of  body,  613 
Barcroffs  blood-gas  apparatus,  1055 
Burger's  method,  129 

Barometric  pressure,   influence   on  alveolar 
COo,  1082 


INDEX 


1249 


Basal  ganglia,  detinitioii  of,  377 

developuieut,  3t>3 
liadopliilo  leucocytus,  813 
iiasilar  mouabraue,  funotioos  of,  olU 
iiatliinotropic    etfeot   of    vagus    exuitatiou, 

973 
liay  i.-i'^i  ou  doprusdor  roiluxes,  97;^,  lUUl 
BayLina   and    Slarlmy   ou   intesLinal    movo- 
uionts,  7zt3 
ou  dcuretin,  7uy 
Beats,  50S 

Beckterews  nucleus,  381,  4Mz 
Btckmann's    apparatus    for    treezing-poiut, 

1219,  13U 
iiuhuuic  acid,  Ji 

Bell  and  Jlaytndie's  law,  'AHo,  323 
Benedict' t>  respiration  appaiutos,  611 1 
Beiisley  on  islots  of  Laugeruans,  807 
JtJeazeno  ring,  ^19 

origin  oi,  118 
Benzyl  alanine,  155 

pyrotartarie  acid,  155 
Bernard  d  experiment  on  vaso-motor  uerves, 

98:^ 
Betz  cells,  -iZS 
Biciu:omate  cell,  187 
Bidder's  ganglion,  9iU 
Biederinann's  lluid,  2iO 
Bile,  713-717 
acids,  715 

composition  of,  714 
flow  of,  715 
functions  of,  71t» 
pigment,  origin  of,  834 
salts,  714,  716 

cii'culation  of,  717 
effects  of,  ou  lipase  action,  707 
functions  of,  717 
secretion  of,  715 
Biliary  tistula,  715 
Bimolecular  reaction,  l(i3 
Binocular  vision,  587,  592^ 
Biogen,  20^ 
Biopiior,  20 
Biuret,  1115 
base,  88 

reaction,  93,  100 
Bladder,  afferent  impulses  from,  lioo 
central  control  of,  1159 
evacuation  of,  1157 
filling  of,  1155 
innervation  of,  1154,  1157 
musculature,  1152 
rhythmic  contractions  of,  115(5 
spiiincters  of,  1153,  1159 
Blind  spot,  502 
Blix  apparatus,  197 

on     energy     of     muscular    ooutraction 
201 
Blood,  810-807 

alkalinity  ol,  1007 
amount  in  body,  854 
carbon  dioxide  in,  1004,  1071 
coagulation,  812,  839-853 
effect  of  calcium  on,  852 
Historical  account,  849-853 
negative  phase,  847 
positive  phase,  847 
corpuscles,  relative  amount.  857 
electrical  ooaductivity,  801 
fraeziug-poiut  of,  8t>l 


Blood,  gases  of,  1U54 

gas   detorminatiou.    ',111,^11-11    m. mua-. 
1055 
pumps,  10.>4 
general  composition  of,  802 
hiemolysis,  23,  127,  820,  834,  loll,  103(1 
hydiogeu  ion  coucuatration  of,  1087 
ialcing  of,  820 

life-history  ot  rod  corpuaclea,  831-835 
methods  of  pi-e venting  coagulation,  839 
osmotic  pressure  of,  801 
oxygen  capacity  of,  806,  858 
pigments,  829 

syutliesis  of,  829 
plasma,  coagulation  of,  840 
composition  of,  804 
pi'oteins  ot,  i>4() 
relative  amount,  857 
platelets,  830-838 
pi"essuiv,  alterations  of,  884 
apparatus,  872 
in  capillaries,  930 
in  man,  875 

in  vascular-  system,  873,  874r-885 
reaction  of,  800,  1007,  1087 
red  corpuscles,  811,  818-835 
chemistry  of,  820 
destruction  of,  832 
effect  of  altitude  on  number, 

1102 
enmueration  of,  868 
life  of,  834 

osmotic  properties  of,  819 
regeneration  of,  833 
stroma,  821 
reducing  substances  in,  1U87 
serum,  proteins  of,  805 
specitic  gravity  of,  860 
variations  in  amount  of,  l(X»9-l0ll 
velocity  of,  880-«9(.i 
vessels,   nervous  control  of,  982-1005 
volume,  carbon  monoxide  method,  855 
white  corpuscles,  8 13-*)  17 
Body  as  a  machine,  3 

temperature,  diurnal  variations,   1170 
regulation  of,  1107-1177 
Bone-marrow,  structure  of,  815,  831 
Boundary  layer,  1131 
Bmoiiuin  ti  capsule,  1 132 

glands,  502 
Boyle  s  law,  124 
Brachium,  superior,  377 
Brain,  301-390 

development  of,  302 
evolution  of,  305,  385 
stem,  ascending  tract-*,  387 
association  areivj  of.  452 
cortical  areas,  430 
descending  tracts,  3S9 
evolution  of,  301 
functions  of,  383-;i87,  392-390 
long  paths  in,  383 
structure  of,  301-391 
lireak  contraction,  192 
excitation,  204 
induction  shook,  189 
Broca's  aphasia,  454 
convolution.  435 
Brodie'is  perfusion  apparatus.  9(>4 
Bromine,  44 
BroQohi,  1039 

40 


1250  INDEX 


Bronchial  murmur,  1045 
Bronchioles,  1039 

innervation  of,  1047 
Brownian  movement,  145,  146 
Bruits,  cardiac,  907 
Bulbo-spinal  animal,  393 
Bulbo-spiral  fibres  of  heart,  892 
Bundle  of  His,  893,  952 
Burch's  capillary  electrometer,  227 
Burdon-Sanderson' s  electrodes,  224 
Burdach's  column,  324,  352,  354 
Biitschli's  emulsion  theory,  19 
Butyric  acid,  48,  54 

Cadaverine,  155 
Caffeine,  103.  775 

diuretic  action  of,  1141 
Calcium  salts,  43 

Calcium  salts,  in  milk  coagulation,  t)88 
eii'ect  on  heart,  963,  975 
excretion  of,  724 

function  in  blood  coagulation,  841 
phosphate  in  urine,  1125 
in  starvation,  626 
Calculi,  biliary,  47 
Callender  recorder,  221 
Calorific  value  of  diet,  650 

food-stuffs,  620 
Calorimeter,  3 

Atwater-Benedicfs,  622 
Canal  of  Schlemm,  543 

functions  of,  597 
Cane-sugar,  67 

inversion  of,  in  stomach,  685,  689 
Cannon's  shadow  methods  for  movements  of 

alimentary  canal,  677,  697,  725 
Capillary  circulation,  928-931 
electrometer,  174,  226 

tracings,  analysis  of,  230 
pressure,  930 

wall,  permeability  of,  1014 
Capric  acid,  54 
Caprylic  acid,  54 
Caproic  acid,  54 
Caput  cornu  posterioris,  316 
Carbamide,  see  Urea 
Carbamino-acids,  80 
Carbohydrate  metabolism,  796-809 

in  starvation,  628 
radical  in  proteins,  94 
Carbohydrates,   action  of  gastric  juice   on. 
689 
influence  of,  on  metabolism,  636 
Carbohydrates,  59-70 
absorption  of,  743 
imbibition  by,  151 
synthesis  of,  37,  110 
Carbon  assimilation,  109 

importance  of,  36 
Carbon  dioxide,  assimilation  of,  109 
in  atmosphere,  37 
condition  of,  in  blood,  1064 
constancy  of,  in  alveolar  air,  1081 
excretion  of,  1051 
tension  in  alveoli,  1071 
tension  in  blood,  1065,  1071 
tensions  in  tissues,  1064 
Carbonic  oxide  hseraochromogen,  827 
hsemoglobin,  823,  824 
Cardiac  cycle,  sequence  of  events,  894 
time  relations,  908 


Cardiac  impulse,  903 

murmurs,  906 

muscle,   factors   modifying  activity   of, 
958-966 
influence  of  tension  on,  958 
physiological    properties    of,    955- 
958 

nerves,  969 

output,  910-915 

sound,  896 
Cardinal  points  in  schematic  eye,  532 
Cardiogram,  904 
Cardiograph,  904 
Cardio-inhibitory  centre,  978 
Cardiometer,  914 

Cardio-pneumatic  movements,  910 
Carlson  on  heart  of  limulus,  946 
Carotid  gland,  1194 
Casein,  formation  of,  688 

hydi'olysis  of,  80 
Caseinogen,  91,  100 

action  of  gastric  juice  on,  688 

preparation  of,  1239 
Catacrotic  pulse,  926 
Catalase,  1108 
Catalysers,  159 
Catalysis,  159 

as  a  surface  phenomenon,  161 

by  formation  of  intermediate  products. 
161 

of  methyl  acetate,  166 

theories  of,  160 

velocity  of,  162,  163 
Catechol,  50 
Catelectrotonus,  265 

Catlicart  on  carbohydrate  metabolism,  803 
Cathodal  contraction,  263 
Cathode,  187 
Cell,  13-17 

sap,  14 

structure  of,  16 

wall,  14,  22 

composition  of,  22 

electrical  phenomena  in,  173 
permeability  of,  22,  23,  127 
Cells,  chemical  changes  in,  153 

galvanic,  see  Galvanic  cells 

growth  of,  1199 

histological  differentiation  of,  7,  31 

synthesis  in,  168 

vital  phenomena  of,  25 
Cellulose.  70,  646 

digestion  of,  722 

food-value  of,  646 

hydrolysis  of,  70 
Central  nervous  system,  288^77 
Centres  in  medulla,  394 
Centro-acinar  cells,  711 
Centrosome,  16,  19,  33 
Cephalin,  57 
Cetyl  alcohol,  47,  56 
Cerebellar  ataxy,  405 

gait,  405 

path,  388 
Cerebello-olivary  fibres,  369 
Cerebellum,  ablation  of,  404 

afferent  tracts,  402 

corpus  dentatum,  373 
Cerebellum,  efferent  tracts,  402 

functions  of,  397 

Golgi  cell,  401 


INDEX 


1251 


Cerebellum,  inferior  peduncles,  369.  370,  402 
middle  peduncle,  402 
nucleus  cmbolifonuis.  378.  389 
fastigii.  373,  389 
globosus,  373,  389 
Purkinje  cells,  400 
roof  nuclei,  373,  383,  389,  402 
stimulation  of.  403 
structure  of.  400 

superior  jicduncles.  371,  389.  402,  423 
vermis,  373.  400 
Cerebral  axis,  intermediate  grey  matter,  382 
cortex,  associative  functions,  451 
excitability  of,  435 
function  of  layers.  431 
lamination  of,  427.  430 
motor  areas  in,  436 
sensory  areas  in,  444 
structure  of.  416^27 
thickness  of,  431 
hemispheres,  416-^65 
development  of.  416 
functions  of,  434^60 
tracts  in.  422 
localisation,  historical,  435 
vesicles,  297 
Cerebrum,  afferent  tracts  of,  422 
association  fibres,  425 
commissural  fibres  in,  422 
development  of.  362 
fissures  of,  417 
lateral  ventricles.  420 
lobes  of.  419 
l)rojcction  fibres,  423 
structure  of,  416-133 
Cerumen,  512 

'  Characteristic  '  of  excitability,  263,  271 
Chemical  changes  in  cells.  153  " 

in  living  matter,  153-169 
in  muscle.  212-218 
correlation  of  functions.  1 1 78 
stimulation  of  muscle.  186 
Chilli iotaxis.  6.  27.  498 
in  leucocytes.  1026 
Cheyne-Stokp-1  breathing.  1096 
Chitin.  65 
Chlorides,  estimation  of.  in  urine.  1  129 

resorption  of.  in  kidney,  1149 
Chlorine.  43 

Chlorophvll.  6.  17,  37.  109,  829 
f'hl()r()i)lasts.  17.  33 
( 'iiolesterol.  47.  56 
( 'lioliue.  57 
Ciioiidroitin.  106 
('liniidroitiii-suiphurie  acid.  106 
( 'liondronnicoid.  106 
Chorda  tym])ani.  472.  665 

vaso-dilator  fibres  of,  096 
(!horoid  coat,  542 

plexus.  375 
Chromaftine  sul)stanee.  11  SI 
Clu'omatie  aberration.  537 
Cliromatin.  17.  31 
filaments.  31 
granules.  15 
Chromatolysis.  320 
Chroiuopliile  substance.  1181 
Cliromoproteins.  101 
Chroiuosoiues.  17.  31 

number  of.  in  somatic  colls.   1206 
(Chronograph,  194,  195 


Chronotropic  effect  of  vagus  excitation.  973 
Chvle.  1013 

fat  in.  739 
Ciliary  ganglion.  552 
movement.  248 
muscle,  545 
nerves,  552 
processes,  542 
Ciliated  epithelium.  249. 
r'ilio-s|)irial  centre.  553 
Cingulum.  417,  426 
Circulating  proteins.  642 
Circulation,  general  features  of.  868-873 
in  amphibia.  868 
in  fishes.  868 
f<etal,  1233 

influence  of  gravity  on,  883 
in  lungs,  935-938  " 
in  mammals  and  birds.  869 
physiology  of.  868-917 
effect  of  respiration  on,  936 
schema,  881 
time,  912 
Clarke's  column.  318.  353.  354.  357,  3SS 
Climacteric,  1217 
Climate,  influence  of.  on  diet,  653 
Clonus,  241 
Closing  tetanus,  273 
Clostridium  pfistcnrianum,  40 
Coagulation  of  blood,  812.  839-853 
of  colloids.  72.  150 
of  milk,  688 
of  proteins.  72.  95 
reversible,  72 
Coccvgeal  ganglion.  4()fi 

gland.  1194 
Cochlea.  515 

development  of,  603 
Cochlear  canal.  516 

nerve,  nucleus  of.  380 
Coefficient  of  partage.  24 
Ccelom.  34 
Coitus.  1227 
Cold,  actions  of.  on  muscle,  208 

sensjitions.  conduction  in  cord.  359 
spots.  487 
Collagen.  106 

action  of  gastric  juice  on.  (i87 
food-value  of.  ()45 
Collateral  sym])athetic  ganglia.  468 
CollatL-rals  in  cord.  351.  3.57 
Collecting  tubules  of  kidncv,  I  I  .S2 
Colloidal  niel '.Is,  140 

particles,  movements  of.  145.  146 

size  of.  144 
solution,  grades  of.  151 
solutions.  ])hases  in.  151 
Colloids.  22.  72.  139-1. 52 
adsor])tion  by,  141.  147 
aggregation  of.  147 
charge  of.  145.  147 
coagulation  of.  150.  151 
eoml)ination  between.  149 
electrical  pi-o]>erties  of.  145-149 
heat  coagulation  of.  72.  ]'tO 
imbibition  by.  151 
of  serum.  1 .")() 
Coil   ids.  optical  properties  of.  144 
osmotic  pressure  of.  142 
preeipitatiim  of.  147 
.surface  phenomena  of.  141.  147 


1252 


INDEX 


Colon,  movements  of,  729-732 
Colostrum.  1237 
Colour-blindness,  578 
Colour,  contrast  phenomena,  581 

mixers,  576 

saturation,  575 

vision,  574-584 

Edridge-Ch-een's  classification.  580 
Bering's  theory,  579 
Toung-Helmlioltz'  theory,  577 
Combination  tones.  510 
Comma  tract,  353 
Commissural  cells  of  cord.  318 

fibres  of  cerebrum,  426 
Commissure  of  Gitdden.  388 
Commutator,  sec  Reverser 
Compasses  test,  492 
Complement,  1036 
Complemental  air,  1046 
Complementary  colours,  576 
Compressor  urethrse,  1153 
Concentration  cell.  171 
Conchiolin,  108 
Condenser,  191 

discharges,      use     of.      in     excita^tion, 
263 
Conduction,  irreciprocal,  275.  302 
Cone  cells,  559 

function  of.  574 
Congo  red,  adsorption  of.  148 

colloidal  properties  of,  137,  143 
Conjugate  deviation.  438,  587 

foci,  529 
Conjugated  proteins,  101 
Conjunctival  reflex,  594 
Cormective  tissues,  action  of  gastric  juice  on. 

688 
Consciousness,  9 
Conservation  of  energy  in  body,  3,  621 

of  mass.  3 
Consonance,  509 
Consonants,  525 
Constant  current,  186 

flow  in  capillaries.  879 
Constrictor  fibres  to  limbs.  995 
Contractile  stress,  200.  207 

tissues,  177-249 

vacuole,  15,  33 
Contraction,  paradoxical,   283 

remainder,  208 

secondary,  233 

voluntary,  239 

wave  in  muscle,  204 
Contrast  in  sensation,  483 
Conus  arteriosus,  892 
Convection,  loss  of  heat  by.  1175 
Convoluted  tubules,  1132 ' 

secretion  by,  1144 
structure  of,  1133 
Co-ordinated    movements,     mechanism     of, 

338-348 
Copper,  44 

ferrocyanide  cell,  125 
Cornea,  542 

Corpora  mammillaria,  374,  375 
Corpora  quadiigeniina,  363,  373 
Corpus  Arantii.  894 

callosum,  426 

dentatum  of  corcbelhim,  373 

hitoura,  formation  of.  J  222 
function  of,  1218 


Corpus  luteum,  spurium.  1224 

subthalamicum,  377 

striatum.  363,  421 

trapezoides,  371,  381,  387 
Corresponding  points,  587 
Cortex,  histological  localisation  in,  430 

reciprocal  innervation  from,  437 

thickness  of,  430 
GmWs  organ,  517 
Cortical  areas,  sensory,  444 
motor,  436 

epilepsy,  438 

excitation,  latent  period  of,  436,  444 

inhibition.  438,  441 

motor  functions,  characters  of,  449 
Crampton's  muscle,  547 
Cranial  autonomic  fibres,  472 

nerves,  functions  of,  410-415 
nuclei  of,  378,  410-415 
Cra3rfish,  central  nervous  svstem,  293 
Creatine,  84,  213,  766         " 
Creatinine,  767 

estimation  of,  1128 

in  urine,  1116 

tests  for.  1117 
Crescents  of  Gianuzzi.  664 
Cretinism.  1187 
Crico-arytenoid  joint,  520 
Cricoid  cartilage,  520 
Crico-thjrroid  muscle.  521 
Crista  acustica,  605 
Crossed  pyramidal  tract,  352 

reflexes,  304 
Crura  cerebri.  373 

development  of,  363 
Crusta,  374 
Crystallin,  98 
Crystalline  lens,  543 
Crystallisation  of  egg  albumin,  73 

of  serum  albumin,  73 
Crvstalloids,  139 

diffusibility  of.  136 
Crystals,  mixed,  73 
Cuorine,  57 

Curare,  action  of,  186,  259 
Current,  demarcation,  233 

minimal  gradient  of,  272 

of  action.  E.M.P.  of,  233 

of  injury,  170.  225,  233 

of  rest.  225 
Cushny  on  renal  resorption,  1147 
Cutaneous  end-organs,  497 

sensation.  486-^-97 

sensibility,  classification,  495 
Cutis  vera,  1161 
Cyanuric  acid,  1115 
Cysteine,  86 
Cystine,  86,  91.  1124 
Cytase,  70,  646 
Cytolvsins,  1036 
Cytoplasm,  14,  17 
Cytosine,  104,  776 

b  :  N  RATIO  in  diabetes,  795.  803.  805.  809 
Daniellce]].  171,  186 
Dark-adapted  eye,  482,  572 
JQ'/lr,sowvrtZ  galvanometer,  228 
Dead  space  (in  lungs),  1047 
Deamination,  76,  154,  762 

energy  changes  in,  763 

reversibility  of,  762 


INDEX 


1253 


Decapitate  animal,  329 
Decarboxylation,  155 
Decerebrate  dog,  396 

frog,  395 

pigeon,  306 

rigidity,  394,  398,  449 
Decidua,  formation  of,  1231 
Decussation  of  fillet,  368 

of  pyramids,  352,  366 
Deep  sensibility,  345,  495 
Defects  of  ej'c,  535 
Defsecation,  731 
Defence,  chemical,  against  infection,  1030- 

1038 
Deglutition,  676-682 

movements  of  lar\'nx,  678 

muscles  of,  678 

nervous  mechanism  of,  681 

effect  of,  on  respiration,  677,  682 

sounds,  677 

studj'  of,  by  Rontgen  rays,  676,  677 

stages  of.  677 

time-relations,  679 
Deiters'  cells,  516 

nucleus,  381,  383,  402 
connections,  404 
Delirium  cordis,  968 
Demarcation  current,  170,  225,  233 

compensation  of,  226 
E.M.F.  of,  226,  233 
Demilune  cells,  664 
Dendrites,  301 
Dental  consonants,  527 
Depressor  reflexes,  997,  1001 
DescemeCs  membrane,  543 
Descending  tracts,  389 
Detrusor  urinje,  1152 
Deutero-albumosc,  686 
Development,  1212-1216 
Dex-trins,  68 
Dextrose,  63 
Diabetes,  800-809 

in  fasting  animals,  802 

in  man,  807 

pancreatic,  804 

sugar  consumption  in,  805 
Diabetic  puncture,  800 
Dialysis,  136 
Diamino-acids,  83,  91,  97 

precipitation  of,  93 
Diamino-caproic  acid,  155 
Diamino-nitrogen  of  proteias,  93 
Diamino-trioxydodecoic  acid,  S3,  84,  88 
a-5-diamino-valerianic  acid,  79 
Diaphragm,  movements  of,  1041 

muscles  of,  1041 
Diastase,  68 

Diastolic  arterial  pressure,  874 
Dichromatic  vision,  578 
Dienccphalon,  363,  392 
Diet,  normal,  of  man,  040-657 
Dietaries,  649 
Difference  tones,  511 
Differential  blood-gas  apparatus,  1050 
Diffusion,  124,  131 

coefHcient,  131 

of  solutes,  131 
Digestion.  658-755 

course  of,  751-753 

in  duodenum,  752 

in  intestine,  702-724 


Digestion,  in  stomach,  683-696 

gastric,  685 

pancreatic,  702 

salivary,  661-675 
Dihydroxybcnzcnes,  50 
Dilatator  pupilla;,  550 
Dilemma,  459 
Dimethylamine,  49 
Dioptre,  definition  of,  530 
Dipeptides,  89 
Diphasic  variation,  228 
Direct  cerebellar  tract,  354 

vision,  563 
Disaccharides,  61,  67 
Discus  proligerus,  1223 
Dissimilation,  4,  25,  26 
Dissociated  colloids,  138 
Dissonance,  508 
Distearyl-lecithin,  57 
Diuretics,  action  of,  1140 
Divers'  palsy,  1103 
Dominant  characters,  1215 
Dorsal  cerebellar  tract,  354 
Dromotropic    effect    of    vagus    excitation, 

973 
Dry  cell,  187 

Du  Bois  Reymond's  key,  187 
Ductless  glands,  1178-1196 
Ductus  arteriosus,  1233 
Dudgeon's  sphygmograph,  922 
Dulcite,  62 
Dyne,  definition,  262 
Dysoxidisable  substances,  1105 

Ear,  analysis  of  sounds  by.  511 

external,  512 

internal,  515 

phj-siologj'  of,  511-519 
Eck's  fistula,  760 
Edestin,  98 

composition  of,  91,  92 
Edkins  on  gastric  secretion,  694 
Edridge-Green,  classification  of  colour-vision 

580 
Efferent  nerves,  255 
path,  327 

projection  fibres,  423 
tracts,  cerebellum,  402 
Efficiency  of  machines,  234 
Egg  albumin,  97 

composition  of,  01 
crystallisation  of,  73 
EkrlicKs  side-chain  theory,  1034 

methylene  blue  experiment,  1063 
Eighth  nerve,  nucleus  of,  380,  412 
Einthorcn  galvanometer,  227 
Elasticity  of  muscle,  203 
Elastin,  108 

action  of  gastric  juice  on,  688 
Elastose,  100 
Electrical  capillarity,  174 

changes  in  living  tissues,    170-174 
Electrical  changes  in  muscle,  224 

properties  of  colloids,  14;')— 149 

stimulation,  nature  of.  270 

variations,  effect  of  temperature  on,  230 

variation,  time-relations  of,  228 
Electrocardiograms,  232.  953 
Electrodes,  non-polarisable,  224 
Electrolytes,  conductivity  of,  129 
Elcctroh'tic  dissociation,  170 

40* 


1254 


INDEX 


Electrolytic  solution  tension,  171 
Electrotonic  current,  280 
Electrotonus,  264 

influence  of  intrapolar  length,  268 
Electro-vagogram,  1093 
Eleidin,  1161 

Embryo,  nutrition  of,  1231 
Emmetropic  eye,  535 
Emulsion,  56 

theory  of  protoplasm,  18 
Endocardiac  pressure,  896-902 

negative  phase,  902 
Endolymph,  515 
End-plate  delay,  276 
End-plates,  183,  275 

effect  of  nicotine  on,  277 

fatigue  of,  260 
End-products,  effect  of,   on  ferments,   166, 

167 
Enemata,  nutrient,  va,lue  of,  723 
Energy  balance-sheet  of  body,  620 

exchange,  3,  26 

exchanges  of,  in  body,  620-623 

sources  of,  25 

total  daily  output  of.  650 

transformations  of,  123 
Engelmanri' s  contractile  strings,  234 
Enterokinase,  703,  705 
Enteroceptive  nervous  system,  479 
Enterograph,  817 
Entoptic  phenomena,  536 
Enzymes,  see  Ferments 
Eosinophile  leucocytes,  813 
Ependyma,  362,  375 
Epiblast,  33 

Epicritic  sensibility,  495 
Epididymis,  function  of,  1220 

structure  of,  1220 
Epilepsy,  438,  446 
Epithelium,  ciliated,  277-249 
Equilibration,  399 

djTiamic,  606 

functions  of  labyrinth  in,  605 

static,  608 
Erectile  tissue.  1221 
Erection,  1221 
Erepsin,  720 
Erg,  definition,  262 
Ergastoplasm,  672 

Ergotoxin,  action  of,  1184  ' 

Erlanger's  sphygmomanometer,  876 
Erythroblasts,  832 
Erythrodextrin,  68.  662 
Esbacli's  reaction,  95 
Ester  method  for  separation  of  amino-acids, 

80 
Esters,  46,  47,  53 

mixed,  54 

glyceryl,  54 
Ethereal  sulphates,  excretion  of,  769 
EthylamJne,  49 
Euglobulin,  866 
Eustachian  tube,  513 

valve,  1233 
Excitability,  26 
Excitation,  duration  of  current,  271 

effect  of  intrapolar  length,  268 

minimal  gradient,  272 

Nernst's  theory,  286 

rate  of  change,  270 

strength  of  current,  271 


Excitation,  time,  272 

without  contraction,  231 
Excitatory  process,  nature  of,  284 

response,  nature  of,  271 
Exophthalmic  goitre,  1189 
Extensibility  of  muscle,  203 
Extensor  reflex,  332 
External  auditory  meatus,  512 
Exteroceptive  nervous  system,  479 
Ej^e,  angle  between  axes  in,  537 

centring  of,  537 

constants  of,  in  man,  533 

dark-adapted,  482 

filtration  angle  of,  597 

movements,  centres  for,  407,  438 

o^Jtical  defects  in,  535 
Eyeball,  dioptric  mechanism  of,  528   530 

electrical  changes  in,  566 

nutrition  of,  594-597 

rotation  of,  586 
Eyeballs,  movements  of,  585-588 
Eye-muscles,  extrinsic,  585 
intrinsic,  552 

innervation  of,  552 

Eacial  nerve,  nucleus  of,  379,  381,  413 
Eacilitation  of  reflexes,  305 
Eseces,  composition  of,  755 

examination  of,  in  metabolism  experi- 
ments, 648 
Faraday-Tyndcdl  phenomenon,  144 
Ear  point  of  vision,  546 
Fasciculus  retroflexus,  421 

solitarius,  368,  378 
Fasting,  metabolism  in,  618,  624-630 
Fatigue,  muscular,  208 
Fat,  45,  53,  55,  784 

absorption  of,  738 

acid  number  of,  56 

composition  of,  784 

depots,  783 

estimation  in  faeces,  649 
in  food,  614 

formation  from  food,  785 

from  carbohydrates,  785 
from  proteins,  788 

functions  of,  784 

history  of,  in  body,  783-795 

in  intestinal  epithelium.  740 

iodine  number  of,  56,  784 

metabolism  in  starvation,  630 

oxidation  of,  792 

saponification  number  of,  56 

solubility  of,  742 

stains  for,  739 

synthesis  of,  119,  169 

utilisation  of,  in  body,  790 
Fats,  action  of  gastric  juice  on,  689 

action  of  pancreatic  juice  on,  707 

chemistry  of,  53-58 

influence  of,  on  metabolism,  636 
Fatty  acids,  54 

heat  equivalents,  763 
volatile,  56 
Fatty  degeneration,  nature  of,  739 
Fechner's  law,  485 
Fehliwfs  test,  64,  1123 
Fenestra  ovalis,  515 
Fenton's  reaction,  1 109 
Ferment  action,  adsorption  in,  168 

reversibility  of,  167,  169 


INDEX 


125i) 


Ferment  action,  velocity  of.  103.  104 
Fermentation  in  stomach,  684 
Fermentation  test,  1123 
Ferments,  1.57-1 09 

action  on  optical  isomers,  1 07 

adenase,  778 

amylase,  158 

arginase,  158,  767 

as  catalyse rs,  159 

catalase,  1108 

characters,  157 

classification,  158 

(leaminising,  154,  158 

definition,  157 

effect  of  end-products  on,  IGG 

enterokinase,  158 

erepsin,  158 

inverting,  158 

isolation  of.  158 

laccase,  1109 

lactase,  158 

lactic,  158 

lipase,  158,  109 

maltase,  158,  108 

nuclease,  776 

optimum  temperature  for.  100 

oxidases,  1108 

pepsin.  158,  1G9,  085 

peroxidase,  1108 

properties  of,  159 

rennin,  088 

specificity  of,  100,  107 

as  synthetic  agents,  108 

sucrase,  158 

trypsin,  158 

urease,  158 

uricolytic,  779 

zymase,  158 
Fertilisation,  1209-1211,  1227 

artificial,  1211 
Fibre  layers  in  cortex,  430 
Fibrillar  of  muscle,  179 
Fibrin,  805 

composition  of,  92 

ferment,  842 
fate  of,  847 
Fibrinogen,  98,  841,  864 
Fibroin,  107 

Fick  and  Wislicenus's  experiment,  038 
Field  of  vision,  503 
Fifth  nerve,  nucleus  of,  380 
Fillet,  368,  387,  423 

decussation  of,  368 

lateral,  372,  389 
Final  common  path.  343 
First  focal  plane,  531 
point,  531 
Fischer's  method  for  separating  amino-acids, 

80 
Flechsig's  myelination  method,  319 
Flexion  reflex,  332,  340 
Flicker  phenomena,  571 
Fluoride  plasma,  clotting  of,  848 
Fluorine,  44 
Foci  in  ej'e,  533 

of  lenses,  529 
Foetal  circulation,  1233 
Folin's  method  for    ammonia    estimation, 
1127 
for  urea  estimation.  1127 
for  uric  acid  estimation,  1 128 


Fontana.  spaces  of,  .'US 

Food,  amount  necessary,  649 

analysis  of,  in  raetabolLsm  expcriment.s, 

614 
materials,  utilisation  of,  6 

Food-stuffs,  digestibility  of,  649 

changes    in    alimentar}-    canal, 

658-600 
heat-values  of,  620 
history  of,  750-809 
proportioas  necessary,  652 
significance  of,  642—647 

Foramen  of  Monro,  376 

Foramen  ovale,  514,  1233 
rotundum,  515 

Fore-brain,  362,  375 

Formic  acid,  48,  54 

Fornix.  420 

pillars  of,  370 

Fourth  nerve,  nucleus  of,' 379,  382,  41 1 

Fovea  centralis,  501 

Frank's  manometer,  897 

Frank  on  pulse,  926 

Fraunhofer''s  lines,  569 

V.  Frey,  testing  hairs,  490 

Frontal  lobe,  417 

Frog,  muscles  of.  1 84 

Frog's  heart,  anatomy  of,  939 

Fronto-pontine  fibres,  424 

Fructose,  61.  64 

Fundamental  tone,  507 

Fungiform  papilla,  499 

Galactolitcves,  57 
Galactosamine,  105 
Galactose,  64.  67 
Gall-bladder.  713 

innervation  of,  715 
Galvanic  cells,  bichromate,  187 

concentration.  171,  172 
Daniell,  171,  186 
drv,  187 
E.'M.F.  of,  173 
Leclanche,  187 
positive  element,  186 
positive  pole,  186 
source  of  energy,  171 
Galvanic  excitation,  law  of,  264 
Galvanometer,  D' Arsonval,  227 

Eintkoven's,  227 
Ganglia,  evolution  of,  1293 

sympathetic,  468 
Ganglion  habenulse,  375 

Gasserian,  380,  382 
Gaseous  diffusion,  134 

exchange  in  lungs,  1068-1075 
secretory  theory,  1073 
Gaseous  metabolism  of  s^^livary  glands,  674 
Gases,  tension  of,  in  liquids,  1058 
Gas  laws,  123 
Gastric  digestion,  685 
fistula,  683.  690 
hormone,  695 
juice,  083 

acid  of,  684 

action  of,  on  carbohydrates,  089 

action  of,  on  fats.  689 

action  of.  on  proteins.  685 

action  on  food-stutls,  685 

'  appetite  '  secretion,  691,  696 

composition  of,  684 


1256 


INDEX 


Gastric  juice,  chemical  excitants,  694 

determination  of  hvdi'ochloric  acid 

in,  685 
inverting  power  of,  685 
rate  of  secretion  of.  690 
variations  in,  690-693,  696 
psychical  secretion  of,  691 
secretion  of,  690 

secretin,  695 
Gastrocnemius  of  frog,  183 
Gelatin,  107 

composition  of,  91,  92 

food  value  of,  645 
Gels,  139 
Gemmules,  20 
General  physiology,  13-174 
Geniculate  "bodies,  375.  376,  383,  388 
Genital  hormones,  1218 
Geotasis.  27 
Germ  cells,  1202 

chromosomes  in,  1208 
division  of,  1205 
Germinal  spot,  1222 

vesicle,  1222 
Gierke,  respiratory  bundle  of,  1077 
Glaucoma,  597 

Gliadin,  composition  of,  91,  92 
Gliadins,  98 
Globin,  825 

composition  of,  91 
Globulin,  adsorption  bj^  149 

salts  of.  866 
Globulins,  98 
Glomerulus,  filtration  in,  1136 

of  kidney,  1131 

pressure  of  blood  in,  1 1 37 
Glossopharyngeal  nerve,  nucleus  of,  414 
Glottis,  521,  524 
Gluconic  acid,  62 
Glucosamine,  64,  87,  105 
Glucosazone,  63 
Glucosazone  crystals,  1122 
Glucose,  61,  63 

in  blood,  796 

identification  of,  63,  1123 

lactonic  structure,  66,  67 
Glucosides,  65 
Glutamic  acid,  80,  82,  91 
Glutelins,  98 
Gluten  peptone,  100 
Glycerides,  53 
Glycerophosphoric  acid,  57 
Glycerol,  47,  53 
Glyceryl  aldehyde,  59,  122 
Glyceryl  esters,  53 
Glycine,  78,  81,  91 

ring  formula  of,  79 

salts  of,  79 

ester,  polymerisation  of,  89 
Glycogen,  69,  213,  796 

preparation  of,  797 

formation  of,  797-798 
Glycoproteins.  105 
Glycosuria,  800-809,  1122 

alimentary,  800 
Glycuronic  acid,  65,  1123 
Glycyl-glycine,  88 
Glyoxylic  acid,  94 
Goitre,  1187 
Golgi  cells,  318,  401 

corpuscles,  497 


Go'gl  network,  301,  309 

GolW  column,  324,  352 

Gonads,  1204 

Gotch's  heart  apparatus,  964 

Goiuefs  tract,  356,  371,  388 

Graafian  follicles,  structure  of,  1223 

Gracilis  experiment,  254 

of  frog,  184 
Grahain  on  colloids,  139 
Grape-sugar,  see  Glucose 
Graphic  method,  194 
Gravity,  effect  of,  on  circulation,  933 
Green-blindness,  581 
Grey  matter  of  cortex,  minute  structure  of,  427 

rami,  468 
Growth,  4 

of  cells,  1199 

food  requirements  in,  656 
Guanine,  103,  105,  778 
Guanylic  acid,  105 
Gudden's  commissure,  388 
Gunzherg's  reagent,  684 
Gustatory  area,  449 

sensations,  499 
Guttm'al  consonants,  527 
Gyrnnema  sylvestre,  effect  on  taste,  500 

Haib  follicles,  1162 

Hairs,  sensibility  of,  490 

Haldane-Pembrey  respiration  ax^paratus,  616 

Hales'  experiment,  872 

Haploscope,  588 

Haptogen,  1239 

Haptophore  group,  1034 

Harmonic  intervals,  509 

Harmonics,  507 

Hausmami' s    method    for    distribution    of 

nitrogen,  91 
Hayem's  fluid,  836 
H^matin,  97,  101,  826 

chemical  relationships,  828 

synthesis  of,  829 
Hsematinic  acids,  828 
Hsematoporphyrin,  825,  827 

combination  with  iron,  830 

in  urine,  1121 
Htemin,  825 

structure  of,  829 
Hsemochromogen,  827,  830 
Hsemocyanin,  44,  93 
Hsemocytometer,  858 
Hsemodiomograph,  888 
Haemoglobin,  43 

absorption  spectrum,  823 

composition  of,  91,  101 

crystallisation  of,  73 

derivatives  of,  825 

dissociation  curve,  1060 

iron  in,  822 

molecular  weight  of,  75,  144 

oxygen  capacity  of,  822,  1059 

preparation  of,  820 

reduction  of,  822 

union  with  oxj'gen,  1059 
Hsemoglobin-crystals,  821 
Hsemoglobinometer,  855,  858 
Hsemolysins,  1036 

Haemolysis,  23,  127,  820,  834,  1011,  1036 
Hsemolytic  sera,  1030 
Hsemopyrrol,  829 
Ha;morrhage,  1011 


INDEX 


1257 


Head  on  cutaneous  sensibility',  495 
Head's  diaphragm  slip,  1089 
Hearing,  end-organ  of,  514 

Helmholtz's  theory,  517 

physiology  of,  511 

Rutherford's  theory,  518 

telephone  theory,  518 

Waller's  theory,  519 
Heart,  action  of  sympathetic  nerves  on,  975 

action  of  vagus,  971 

changes  in  form,  902 

diastolic  filling,  909 

effect  of  calcium  on,  963,  975 
muscarine  on,  974 
nicotine  on,  974 
potassium  on,  903,  975 

electrical  variations,  230 

frog's,  automatic  contraction,  940 

human,  electrocardiogram  of,  953 

influence  of  temperature  on  rate  of,  962 

inhibition  of,  972 

mammalian,  ganglion-cells  in,  949 

mechanism  of,  891-917 

nerve  fibres  in,  946 

nutrition  of,  966 

l^rimitive  vertebrate,  950 

rate  in  exercise,  1007 

reflexes,  978 

sounds,  905 

graphic  record  of,  907 

systolic  output,  910-915 

theories  of  inhibition  of,  974 

work  of,  915-917 
Heart-beat,  causation  of,  939-968 

contraction  wave,  947-949 

electrometer  records  of,  948 

in  mammals,  949-955 

myogenic  hypothesis,  942 

neurogenic  hypothesis,  941 

propagation  of  contraction  in,  943 

significance  of  carbon  dioxide  for,  905 
Heart-^ltlock.  955 
Heart-fibrillation,  968 
Heart-lung  preparation.  Starling's  method, 

911 
Heart-muscle,  '  all  or  none  '   phenomenon, 
955 
excitation  of,  955 
influence  of  tension  on,  958 

of  chemical  substances  on,  962 
physiological  properties  of,  955-958 
refractory  period  of,  950 
summation  of  stimuli  in,  956 
Heart-musculature,  891 
Heat-coagulation,  1 50 
'Heat-engines,  efficionoj'  of.  234 
Heat-loss,  regulation  of,  1174 
Heat,  production  in  body.  1171 
in  muscle,  219 

regulation,  nervous  mechanism  of,  1176 
in  new-born,  1177 

rigor.  208,  214 

sensations,  conduction  in  cord,  359 

sexual,  in  animals,  1226 

spots,  487 

values  of  food-stuffs,  619 
Heats  of  conibustion.  156 
Heller's  test,  95,  1122 
Helmholtz  resonators,  508 

side  wire.  189 
Helweg's  bundle,  353 


Hemiansesthesia.  446 
Hemianopia,  407,  447 
Hemiplegia,  446 
Henle's  loop,  1132 
Hensen's  disc,  lh2 
Heredity,  1212-1216 

basis  of,  20 
Hering's  theory  of  colour- vision,  579 
Herpes  zoster,  causation  of,  999 
Heteroalbumose,  100 
Heterocyclic  amino-acids,  85 
Heterotj'pe  mitosis,  1207 
Hexachromie  vision,  580 
Hexone  bases,  83 
Hexoses,  61 

classification  of,  61 

derivatives  of,  64 

reactions  of,  62 
Hind-brain,  362,  366-373 
Hippocampal  commissure,  427 
Hippocampus,  419 
Hippuric  acid.  770,  1119 
Hirudinised  blood,  840,  849 
His'  bundle,  893,  952 
Histidine,  86,  91,  104 

fate  of,  772 
Histological  difterentiation,  7,  31 

localisation  in  cortex,  431 
Histones,  92,  97,  101 
Hoffmann's  test,  85 
Hoinans  on  islets  of  Langerhans,  807 
Homogentisic  acid,  51,  770,  1124 
Homoiothermic  animals,  1169 
Hopkins'  test  for  lactic  acid,  215 
for  tryptophane,  94 
Hopkins- Adamkieioicz  reaction,  94 
Hormones,  genital,  1218 

mammary,  1218 

nature  of,  1180 

pancreatic,  709 
Horopter,  588 

HUfner's  method  for  urea  estimation,  1126 
Human  stomach,  form  and  movements,  698 
Hiirthle's  manometer,  897 
Hyaline  corpuscles,  813 
Hyaloid  membrane,  543 
Hyaloplasm,  18 
Hydraemic  plethora,  1009 

effect     on     volume     of 
urine,  1140 
Hydrated  proteins,  99 
Hydrazones,  62 
Hydrocarbons,  45 

unsaturated.  46 
Hydrocele  fluid,  849 

Hydrochloric  acid  in  gastric  juice.  684,  685 
Hydiogels,  72,  140 
Hydrogen,  39 
Hj-diogen  ion  concentration,  determination 

of,  1067 
Hydrolysis.  154 

of  casein,  80 
of  proteins,  70,  80.  99 
Hydroquinone.  50 
Hydrosols.  139 

osmotic  pressure  of,  14  2 

properties  of.  142,1 44 
Hyperglycajmia,  805 
Hypcrmotropia.  535 
Hyperpncpa.  1079 
Hypoblast.  33 


1258 


INDEX 


Hypogastric  nerves,  action  on  bladder,  1159 
Hypogastric  reflex,  475 
Hypoglossal  nucleus,  379,  415 
Hypoxanthine,  103,  778 

Identical  points  in  retina,  587 
Idiopathic  epilepsy,  439 
Ileocolic  sphincter,  729 
Illusions  of  size,  591 
Image,  size  of,  530 
Imbibition  by  coUoids,  151 

pressure,  152 

relation  to  constitution,  152 
Iminazol,  104 

ring,  86 

sjTithesis  of,  117 
Iminazol-alanine,  86 
Immunity,  1030-1038 

Impregnation,  nervous  mechanism  of,  1228 
Incisura  angularis,  698 
Incus,  513 

Indican,  of  urine,  1120 
Indicators,  1067 
Indigo  as  catalyser,  161 
Indigo-carmine,  excretion  by  kidney,  1146 
Indirect  vision,  563 
Indol,  fate  of,  770 
Induced  currents,  188 
Inductorium,  188,  189 
Infection,  cellular  defence  against,  1021-1029 

chemical  defence  against,   1030-1038 
Inferior  cervical  ganglion,  466 

mesenteric  ganglion,  466 

oblique  muscle,  585 

peduncles  of  cerebellum,  368,  369,  370 
Inflammation,  816,  1024 
Infundibula,  1039 
Infundibulum  in  brain,  375 
Inhibition,  26,  306,  339 

Gaskell's  theory  of,  974 

of  heart,  nature  of,  974 

in  peripheral  ganglia,  475 
Injury,  effect  of,  on  nerve,  274 
Injury-current,  170,  225 
Inner  cell-lamina  of  cortex,  428 

fibre-lamina  of  cortex,  428 

line  of  Baillarger,  430 
Inorganic  food-stuffs,  647 
Inosinic  acid,  774,  776 
Inosit,  214 

Inotropic  effect  of  vagus  excitation,  973 
Instrumental  inertia,  196,  927 
Insular  lobe,  417 

Intercostal  muscles,  action  of,  1044 
Internal  capsule,  364,  376,  421,  423 
Internal  ear,  515 

respiration,  1039 

restiform  body,  370 

secretions,  1178-1196 
Intestine,  absorption  in,  733 

law  of,  727 

movements  of,  725-732 

pendular  movements  of,  725 
Intestinal  fistula,  718 

juice,  718 

characters  of,  720 
secretion  of,  719 
Tntima  of  artery,  870 
Intra-auricular  pressure,  901 
Tntra-molecular  oxygen,  25 
Intra-ocular  fluid,  596 


Intra-ocular  pressure,  543,  595 

pressure  and  blood  pressure,  597 
Intra -thoracic  pressure,  1045 
Intra-ventricular  pressure  curve,  898 
Intra-vesical  pressure,  1156 
Intra-vitam  staining,  23 
Inulin,  69 
Inversion,  67,  160 
Invertase,  67 

of  intestinal  juice,  721 
Invert  sugar,  67 
Iodine,  44 

in  thyroid  gland,  1189 

number  of  fats,  56 
lodothyrin,  1189 
lonisation,  128 
Ions,  170 

velocity  of  transport,  173 
Iris,  542 

as  diaphragm,  537 

functions  of,  550 

local  stimulation  of,  554 

nerve-supply,  553 
Irradiation,  339 

Irreciprocal  conduction,  275,  302 
Iron,  42,  74 

excretion  of,  43 

in  large  intestine,  724 

in  haemoglobin,  74 

in  liver,  835 
Island  of  Reil,  420,  423 
Isoamylamine,  156 
Isodynamic  food-stuffs,  632 
Isoleucine,  82 
Isomaltose,  167,  168 
Isometric  contraction,  heat  of,  221 

lever,  197 
Isosmotic  solutions,  132 
Isotonic  lever,  197 

solutions,  819 
Isotropous  substance,  182 

Jacksonian  epilepsy,  435,  439 
Jafte's  test,  1117 
Joints,  sensibility  of,  600 
Jugular  ganglion,  473 

Kakyokinesis,  see  Mitosis 

Karyosome,  16 

Keratin,  composition  of,  91,  107 

Keratins,  86,  107 

'  Kernleiter  '  model,  281,  284 

Keto-acids,  49,  154 

origin  of,  762 
Ketoses,  60 
Key,  kick-over,  195 
Keys,  187 
Kidney,  adaptability  of,  1149 

cells,  structure  of,  1145 

functions  of  glomeruli,  1135-1142 

nerves  of,  1134 

secretion  in  frog,  1145 

of  water  and  salts,  1135-1142 

structure  of,  1131-1134 

tubules,  functions  of,  1144 
absorption  in,  1147 

work  of,  1135 
Kinaesthetic  areas,  442 
Knee-clonus,  335 
Knee-jerk,  333 

abolition  of,  334 


INDEX 


1259 


Knee-jerk,  exaggerated,  451 

latent  period,  3.34 
Knoop  on  deamination,  762 
Kiau-.e's  membrane,  179 
Krogh's  microtonometer,  1070 
Kiihne's  gracilis  experiment,  254 
Kymograph,  872 

Labial  consonants,  527 

Labour,  1235 

Labyrinth,  evohition  of,  603 

functions  of,  398 
Labyrinthine  sensation,  603 
Laccase,  1109 
Laerymal  gland,  594 
Lactalbumcn,  1240 
Lactase,  action  of,  158,  165 

in  intestinal  juice,  721 
Lactation,  1237-1245 
Lacteals,  734,  1013 
Lactic  acid,  49 

Hopkins'  test,  215 
in  blood,  1085 
in  gastric  juice,  684 
in  muscle,  215 
in  urine,  216,  1085 
Lactoglobulin,  1240 
Lactosazone  crystals,  1122 
Lactose,  67    1240 
LcEvorotation,  52 
Lajvulinic  acid,  104 
Lagena,  603 
Lamina  cinerea,  375 
Langerlians'  islets  in  pancreas,  807 
Lanoline,  56 
Lardacein,  106 
Large  intestine,  absorption  in,  723 

excretion  in,  724 

functions  of,  722 

movements  of,  725-732 
Laryngoscope,  523 
Larynx,  anatomy  of,  521 

movements  of,  in  deglutition,  678 
Latent  period,  198.  207 
Lateral  columns  of  cord,  354 

crico-arytenoid  muscle,  522 

fillet,  372,  387 

nucleus  in  medulla,  366 
in  pons,  370 

sympathetic  ganglia,  468 
Lateritious  deposit,  1118 
J^auric  acid,  54 
Law  of  forward  direction,  310 

of  the  intestines,  727 
I^aw  of  specific  irrital)ilit\-.  480 
Jjccithin,  57 
Leclanchi.  cell.  187 
Lemniscus,  368,  387 
Lens,  543 

elasticity  of,  546 

variation  with  age,  546 
Lenses,  formation  of  images  by,  528 
Lenticular  ganglion,  552 
Legumin,  98 
Leguminous  nodules,  41 
Leucine,  82,  91 

cones,  82 
Leucines,  oxidisability  of,  1106 
Leucocytes,  chemiotaxis  in,  1026 

classification  of,  813 

origin  of,  815 


Leucopla.sts,  17 
Leucosin,  98 

Lever,  momentum  of,  197 
Levulose,  64 

Liebermann's  reaction,  94 
Life,  evolution  of,  5,  6,  33 

laws  of,  7 

without  oxygen,  25 
Ligamentum  pectinatumiridis,  543 
Light,  nature  of,  568 

reflex,  550 
Lignin,  106 
Lignoceric  acid.  ;54 
Limbic  lobe,  417 

Liminal  intensity  of  stimulus,  482 
Limulus  heart,  946 
Line  of  Gennari,  430 
Lines  of  direction,  531 
Linin,  17 
Linoleic  acid,  54 
Linolinic  acid,  54 

series,  54 
Lipase  of  pancreatic  juice,  707 

in  gastric  juice,  689 

reversibility  of  action  of,  169 
Lipines,  57 
Lipoids,  23,  57 
Liquor  folliculi,  1223 
Lissauer's  tract,  324,  353,  357 
Liver,  bile  formation  in,  713 

formation  of  urea  in.  759 

of  uric  acid  in,  778 

glycogen  of,  797 

haemolysis  in,  835 

lymph  production  in,  1015 
Living  matter,  chemical  changes  in,  153-169 
liOad.  effect  of  a  contraction,  203 
Local  reflexes,  474 

sign  of  tactile  sensation,  493 
Locke's  fluid,  963 

Localisation  of  function  in  brain,  435 
Locomotion,  co-ordination  of,  346 
Locomotor  ataxia,  346 
Locus  perforatus  posticus,  375 
Long  ciliary  nerves,  552 

sight,  536 
Longitudinal  inferior  fasciculus,  426 

superior  fasciculus,  426 
Loudness  of  sound,  506 
Ludwig's  Slromi(hr.  888 

manometer,  872 
Luminosity  of  spectral  colours,  569,  575 
Lungs,  circulation  in,  935 

distensibility  of,  1044 

exchange  of  gases  in,  1068-1075 
Lungs,  vaso-motor  fibres  of.  935 
Lutein.  1224 
Lmj's  nucleus.  377 
Lymph,  absorption  of.  1019 

movements  of.  1017 

production,  1013 

effect  of  capillary  ]ii-es.sure  on,  1015 
in  small  intestine,  735 
osmotic  phenomena  in,  1015 

properties  of,  1013 

role  of,  in  nutrition.  1020 

and  tissue  fluids,  1012-1020 
Lymphagogues,  1016 
Lymphatic  glands.  1013 

tissue,  struetvire  of.  815 
Lymphatics,  course  of,  1012 


1260  INDEX 


Lymphocyte,  813 
Lysine,  83,  91 

decarboxylation  of,  155 
Lysins,  1034 

MacdonaliVs  theory,  287 

MacdougalV s  theory,  muscular  contraction, 

235 
Macro-nucleus  of  paramoecium,  1200 
Macrophages,  1028 
Macula  acustica,  399,  605 

lutea,  561 
Magnesium,  43 

excretion  in  large  intestine,  724 
Major  chord,  509 
Make  contraction,  192 
excitation,  263 
induction  shock,  189 
Mall  on  heart  musculature,  891 
Malleus,  513 
Malpighian  follicles  of  spleen,  1194 

pyramids,  1131 
Maltase,  167 

of  intestinal  juice,  721 
reversibility  of  action,  167 
Malto-dextrin,  69 
Maltose,  66,  67,  69 
Mammary  gland,  structure  of,  1243 

hormones,  1218 
Mannite,  62 
Mannose,  61,  64 
Manometer,  Hiirthle's,  897 
Ludtvig's,  872 
Piper's,  897 
MarcM's  method,  320 
Marey's  law  of  blood-pressure,  980 

sphygmograph,  922 
Marginal  lobe,  417 
Marie's  tract,  354 
Mark-time  reflex,  343 
Marrow,  53 
Martinotti  cells,  428 
Material  basis  of  body,  36-122 
Matter,  exchanges  of,  in  body,  613-657 
Maximal  stimulus,  193,  205 
Mayer  curves,  988 

Mechanical  changes  in  muscular  contraction, 
194-204 
coagulation  of  colloids,  150 
efficiency  of  muscle,  222 
response  of  muscle,  205-211 
Mechanism,  8 
Meconium,  1233 
Media  of  artery,  870 
Medulla  oblongata,  366-370 

functions  of,  392 
Medullary  sheath,  251 
Medusa,  nervous  system  of,  290 
Meibomian  glands,  594 
Mciosis,  1207 
Meissner's  corpuscles,  497 
plexus,  469,  474,  720 
Mcmbrana  granulosa,  1223 
reticularis,  517 
tectoria,  517 
tympani,  512 
Membranes,  electrical  phenomena  at  surface 
of,  173 
permeability  of,  22,  131 
semi-pcrmcablc,  132 
Membranous  labyrinth,  515,  603 


MendeVs  law,  1215 
Menstruation,  1224 

relation  of  ovulation  to,  1225 
Mercurial  manometer,  872 
Mesencephalon,  363,  392,  394 
Mesial  fillet,  368,  387 
Mesotartaric  acid,  52 
Metabolism,  effect  of  foods  on,  631-636 
during  starvation,  624-630 
experiments,  analysis  of  excreta,  615 
general,  613-647 
influence  of  age  on,  656 

of  carbohydrates  on,  636 
of  fats  on,  636 
of  muscular  work  on,  637 
of  protein  on,  631 
of  temperature  on,  1168,  1172 
methods,  614-623 
of  muscle,  216 
of  nucleo -proteins,  774-782 
of  proteins,  756-773 
relation  to  body  weight,  627 

to  surface  of  body,  628 
Metakinesis,  9 
Metal '  sols,'  140,  160 
Metaphase  of  mitosis,  1205 
Metaplasm,  16 
Metaplasmic  products,  18 
Meta  position,  50 
Metaproteins,  98 
Metencephalon,  362,  392,  394 
Methsemoglobin,  824 
Methyl-acetate,  catalysis  of,  166 
Methylamine,  49 
Methyl  glucosides,  66 
glycine,  84 

guanidin  acetic  acid,  84 
purines,  103,  775 
Micellje,  20 

Micro-nucleus  of  paramcecium,  1201 
Microphages,  1028 
Microsome,  16 
Microtonometer,  1070 
Micturition,  1152-1160 
nerves  of,  1157 
reflex,  1159 
Mid-brain,  362,  373 
crusta,  374 
functions  of,  394 
pes,  374 

tegmentum,  374 
Middle  cell-lamina  of  cortex,  428 
Milk,  coagulation  by  pancreatic  juice,  706 
fats  of,  119,  1239 

origin  of,  1245 
human,  composition  of,  657 
properties  of,  1238 
proteins  of,  1239 

in  relation  to  growth,  657 
quantity  secreted,  1238 
salts  of,  1241 
secretion  of,  1237-1245 
Milk-sugar,  1240 
Millon's  reaction,  85,  94,  100 
Mineral  salts,  importance  of,  647 
Minimal  difference  method,  484 
effective  stimuli,  483 
gradient,  272 
stimulus,  193,  205,  482 
Mitosis.  1207 

heterotypc,  1207 


INDEX 


1261 


Mitral  cells,  421 

valve,  893 
Modality  of  sensation,  479 
Molecular  layer  of  cortex,  428 
Molecules,  energy  in  solution,  123 

size  of,  140,  143 
MoliscJi's  test,  64,  94 
Molybdic  acid  as  catalyser,  162,  163 
Monakow's  bundle,  353,  389 
Mono-amino-dibasic  acids,  82 
Mono-amino-monobasic  acids,  81 
Mono-araino-nitrogen  in  ])roteins,  93 
Monochromatic  patches,  575 

vision,  579 
Monomolecular  reaction,  163 
Monophasic  variation,  230 
Monosaccharides,  61 
Moore's  test,  63 
Morphotic  proteins,  642 
Moss  fibres,  401 
Motor  aphasia,  454 

area,  lamination.  431 

cells  of  cord,  318 

centres,  ablation  of,  440 

end-plates,  183 

sensibilit}'^,  446 
'  Motor  points,'  269 

somatic  nuclei,  378 
Mountain  sickness.  1099 
Jlovcmcnt,  co-ordinated,  338 

and  sensation,  177—609 

sensation?  of,  598-602 
Movements  of  alimentary  canal,  676,  697,  725 

of  deglutition.  676 

of  large  intestine,  729 

of  small  intestine,  725 

of  stomach,  697 
Mucin,  action  of  gastric  juice  on,  688 
Mucins,  105 
Mucoids,  105 
Mucous  glands,  663 

Midler's  law  of  specific  irritability,  255,  480 
Multirotation.  05 
Murexidc  test,  1118 
Muscao  volitantcs,  537 
Muscarine,  action  on  heart.  974 
Muscle,  afferent  nerves,  336 

anistropic  substance.  182 

action  of  vcratrin.  211 

arrested  contraction.  200 

break  contraction.  192 

chemical  changes  in,  212-218 

chemical  stimulation  of.  186 

clotting  of.  213 

composition.  212 

contractile  stress.  200 

contract  ion-remainder.  208 

demarcation  current.  170,  225,  233 

efficiency  of,  222,  639 

elasticity  of.  203 

electrical  variation,  effect   of  tcmi)era- 
ture.  230 

excitation  of.  185-193 

excitation  without  contraction,  231 

extcnsihilitv  of.  203 

heat -production  in.  219-223 

independent  excitability.  185 

injurv-cmrent,  170,  225.  233 

involuntary,  180,  243 

of  invertebrates.  248 

isotropous  substance,  182 


Muscle,  longitudinal  striat ion.  180 
make  contraction,  192 
mechanical  response  of,  205-211 
metabolism  of,  216 
production  of  carbon-dioxide,  217 
products  of  activity,  216-218 
reciprocal  innervation  of,  355 
red,  180 
reflex  tone,  398 
respiratory  cjuotient,  217 
stimulation   by  constant   current,    186, 

192 
thickening  of,  199 
utilisation  of  energy,  221 
voluntary,  177 

structure  of,  179 
white,  181 
Muscle-current,  170,  225,  228.  229 
Muscle-curve,  correction  of,  197,  208 
Muscle  fibre,  179 

reversal  of  stripes,  182 
Muscle-fibrillK,  179 
Muscle-plasma,  212 
Muscle-sound.  240 
Muscle-spindle,  601 
Muscle-twitch,  192,  194.  198 
Muscle-wave,  204 

Musical  notes,  vibration  frequencies,  510 
Muscular  aft'erents,  600 

contraction,  '  all  or  none  '  phenomenon. 
255 
Engehnann' s  theorj',  234 
effect  of  drugs,  211        :,i 
of  fatigue,  208 
of  load,  203 
of  salts,  210 
of  temperature,  207 
of  tension,  222 
latent  period  of,  198 
MacdouqalVs  theory,  235 
mechanical  changes  in,  194-204 
nature  of.  234-238 
optical  method,  1 98 
osmotic  theory,  235 
point  of  stimulation,  194 
Schdfer's  theory,  182 
strength  of  stimtilus,  205 
time-relations  of,  198 
voluntary,  239 

electrical  changes  in,  242 
record  of.  241 
contractions,  summation  of,  206 
energy,  source  of.  637 
exercise,  effect  on  circulation.  1006-1008 
movements,  co-ordination  of,  345 
relaxation,  198 
sense,  600 

psychology  of,  601 
sensibiiitv,  paths,  446 
tone,  333",  449 

relation  to  labyrinthine  sens;itions, 
606 
work,  energy  exchanges  in,  639 
effect  on  metabolism,  637 
Muscularis  mucosa^  of  small  intestine.  735 
^lusculi  papillares.  894 
Musculns  vocalis.  522 
Mj'elencephalon.  362.  392 
Myelin  sheath,  251-252 
Myclination,  252 
method,  319 


1262  INDEX 

Myelocytes,  816 
Mylohyoid  of  frog,  184 
Myogen.  213 

fibrin,  213 
Myogenic  movements  of  intestine,  726 
Myolisematin,  213 
Myopia,  535 
Myosin,  98,  213 
Myosin  fibrin,  213 
Myosinogen,  212 
Myristic  acid,  54 
Myxcedema,  1187 

Nasal  consonants,  527 
Near  point,  539,  546 
Nectocysts,  33 
Negative  after-image,  572 

polarisation  of  nerve,  280 
variation,  233 
ventilation,  1091 
Negativity,  229 
Neopallium,  417 

evolution  of,  419 
Nerve,  core  model,  281 

double  conduction,  250 
electrotonic  current,  280 
electrotonus,  265 
endoneurium,  252 

excitability,    'characteristic'     of,    263, 
271 
effect  of  temperature  on,  273 
fatigue  in,  259,  285 
galvanic  excitation,  262 
human,  stimulation,  268 
law  of  forward  direction  in,  310 
negative  polarisation,  282 
neurilemma,  252 
nodes  of  Ranvier,  252 
non-meduUated,  252 
polarisation  in,  280 
positive  polarisation,  282 
primitive  sheath,  251 
unipolar  excitation,  268 
Nerve-axon,  251 
Nerve-block,  266 
Nerve-cell,  automaticity  of,  314 
functions  of,  312 
Golgi  net,  301,  309 
Nissl's  granules,  300 
pericellular  network,  308 
structure  of,  300 
Nerve-centres  in  medulla,  393 
Nerve-current,  MacdonaWs  theory,  173 
Nerve  fibres,  250-287 

excitation  of,  262 
size  of,  252 
Nerve  fibres,  structure,  250 
Nerve-impulse,  253 

conditions  affecting,  258 
effect  of  temperature  on,  258 
electrical    changes    accompanying, 

256 
influence  of  drugs  on,  260 
velocity  of,  253 
Nerve-injury,  effect  of,  274 
Nerve-trunk,  composition  of,  327 
Nerves,  cranial,  410 

nuclei  of,  378,  410^15 
grafting  of,  255 
Nervi  erigentes,  functions  of,  473,  996,  1154, 
1158,  1228 


Nervous  system,  evolution  of,  288-296 
ganglia,  293 
of  medusa,  290 
of  vertebrates,  297 
Neural  canal,  297 
Neurilemma,  251 
Neurine,  57 
Neuroblasts,  298 
Neuro-fibrillar  network,  428 
Neuro-fibrils,  296 

continuity  of,  307 
Neuroglia,  297 
Neurokeratins,  107,  251 
Neuro-muscular  junction,  183,  275 

spindles,  601 
Neuron,  definition  of,  295,  301 
Neurons,  continuity  of,  296 

structure,  296 
Neuropilem,  296 
Neutrophile  leucocytes,  813 
Nicol's  prism,  51 

Nicotine,  effect  on  end-plates,  277 
on  heart,  974 

method,  472 
Ninth  nerve,  nucleus  of,  379,  414 
Nissl's  granules,  301 
Nitrates,  40 

Nitrification  of  sewage,  40 
Nitrifying  organisms,  40 
Nitrogen,  39 

endogenous,  in  urine,  758 

estimation    of    by   KjeldahVs    method, 
1126 

excretion  in  starvation,  629,  633 

exogenous,  in  urine,  758 

in  food,  614 

output,  756 

requirements  of  body,  633 

source  of,  39 
Nitrogenous  constituents  of  urine,  757 

equilibrium,  616,  631,  653 
Nociceptive  stimuli,  341 
Nodal  point,  531,  533 
Nceud  vital,  1077 
Non-polarisable  electrodes,  224 
Normoblasts,  834 
Nuclear  sap,  17 
Nucleic  acid,  101 
Nuclein,  97,  101 

hydrolysis  of,  774 

metabolism  of,  774-782 
Nucleins,  fate  of,  777 

formation  in  body,  777 
Nucleolus,  16 
Nucleoplasm,  17 

Nucleoprotein,  decomposition  of,  102 
Nucleoprotein.  digestion  of,  104 
Nucleus,  14,  27,  31 

ambiguus,  379 

oi  Bechterew,  381,  402 

branched,  31 

caudatus,  363 

cuneatus,  367 

emboliformis,  373 

effect  of  removal,  28 

fastigii,  373 

function  of,  27 

globosus,  373 

gracilis,  367 

lenticularis,  363 

necessity  for  growth,  30 


INDEX 


1263 


Nucleus  of  Luys,  377 

of  Rolando,  3(57 

relation  to  cytoplasm,  27 
Nutrition,  mechanisms  of,  (313,  809 

Occipital  lobe,  417 
Occipito-frontal  fasciculus,  426 
Oculo-motor  nucleus,  379,  407,  410 
Occoid,  818 

(Esophagus,  inhibition  of,  in  swallowing,  080 
(Estrus,  1226 

Ohm's  law  of  auditory  analysis,  51 1 
Oleic  acid,  55,  56 
Oleyl-lecithin,  57 
Olfactie,  504 
Olfactometer,  503 
Olfactory  ajiparatus,  421 
area,  448 
bulb,  421 
glomcrali,  421 
lobe,  417,  448 
mucous  membrane,  502 
sensations,  498,  502 
tract,  421 
tubercle,  421 
Olivary  body,  367,  382 
Olive,  3G8,  382 
Olivo-cerebellar  fibres,  389 
Olivo-spinal  tract,  353,  391 
Oncometer,  992 
Optic  axis,  531 

chiasma,  388,  406 

disc,  561 

nerve,  decussation,  387,  406 

efferent  fibres  in,  500 
radiation,  423 
thalamus,  363,  375,  383,  395,  420 

nuclei  of,  377 
tracts,  387,  406,  447 
Optical  activity,  51 
axis  of  lens,  528 
centre  of  lens,  529 
defects  in  eye,  535 
isomers,  action  of  ferments  on,  167 
Optimum  temperature  for  ferments,  160 
Opsonic  index,  1038 
Opsonins,  1037 
Ophthalmometer,  541 
Ophthalmoscope,  554-557 
Optograms,  565 
Ora  serrata.  561 

Orcin  reaction  for  pentoses,  61,  94 
Organ  of  Corli,  517 
Organic  compounds  in  body,  45 
Organic  sensations,  598-609 
Organic  synthesis,  mechanism  of,   109 
Organisation.  6 
Ornithine.  79,  83 

decarboxylation  of,  156 
Ortho  position,  50 
Osamines,  63 
Osazones,  47,  62,  1123 
Osmometer,  143 
Osmotic  pressure,  123,  133 

Bargcr's  method,  129 
Beckvmniis  methotl,  129,  130 
and  boiling-point,  129 
of  colloids,  143 
of  electrolytes.  1 28 
freezing-point  method,  129 
by  htcmolysis,  127 


Osmotic  pressure,  Hamburger'' s  method,  127 
measurement  of,  125-130 
Ijy  plasmolysis,  127 
of  proteins,  75,  142 
of  serum  proteins,  142 
and  transport  of  water,  133 
and  vapour  teasion,  129 
Osseous  labyrinth,  515,  604 
Osteoporosis,  626 
Otic  ganglion,  473 
Otolith  organ,  399,  605,  608 
Otoliths,  function  of,  608 
Outer  cell  lamina  of  cortex,  427 
Outer  fibre-lamina  of  cortex,  427 
Outer  line  of  BuiUargrr,  430 
Overtones,  507 
Overton's  theory,  23 
Ovulation,  1222 
Ovum,  1205 

maturation  of,  1209 
Oxalate  crj^stals,  1125 
Oxidases  in  tissues,  1108 
Oxidation.  157,  1063,  1105-1109 
by  indigo,  161 
mechanisms  of,  1105-1109 
seat  of,  in  body,  1063 
Oxyacids,  49 

origin  of,  761 
Oxygen,  39 

absorption  of,  in  lungs,  1062 

'  active,'  1107 

avidity  of  tissues  for,  1063 

capacity  of  blood.  1056 

effect  of  changes  in  tension  of,  1099 

lack,  in  asphj^xia,  985 

production  of  lactic  acid  in,  1085 
tension  in  alveoli.  1062,  1070 
in  blood,  1071 

in  blood  by  CO  method,  1074 
Oxyhaemoglobin,  821 

absorption  spectrum  of,  823 
crystals,  821 
dissociation  of,  1060 
influence  of  acids  on  reduction  of,  1064 
])-uxyphen}'l  alanine,  84 
Oxyproliue,  85 

Pacinian  corpuscles,  497 

Pain  impulses,  path  of  in  cord,  359 

sense,  494 
Palmitic  acid.  54 
Pancreas,  extii^pation  of.  804 
internal  secretion  of,  806 
structural  changes  accompanying  secre- 
tion. 711 
Pancreatic  diabetes,  804 
fistula.  707 
juice.  702 

action  on  carbohydrates,  706 
fats.  707 
milk,  706 
proteins,  703 
activation  of,  705 

by  calcium  salts,  706 
composition.  702 
secretion  of,  707 
variations  in,  710 
secretion.effect  of  acids  in  duodenum,  708 

regvdation  of,  710 
secretin,  709 
Pangene,  20 


1264 


INDEX 


Para  position,  50 

Paracasein,  1240 

Paracentral  lobe,  417 

Parados  cold,  488 

Paradoxical  contraction,  283 

Paraffins,  45 

Paragiobulin,  98 

Paramoecium,  conjugation  of,  1201 

Paramucin,  105 

Paramyosinogen,  98,  213 

Paranuclein,  100,  688 

Paraplasm,  16 

ParathjToids,  functions  of,  1189 

Parietal  lobe,  417 

Parotid  gland,  663 

innervation  of,  666 
Parthenogenesis,  1211 
Partition  coefficient.  24 
Parturition,  1233-1236 

nervous  mechanism  of,  1236 
Passive  movement,  600 
Pawlow's  gastric  fistula,  690 
Pelvic  visceral  nerve,  473 

action  on  bladder,  1157 
Pendular  movements  of  intestine,  725 
Pendulum  myograph,  195,  196 
Pentachromic  vision,  580 
Pentamethylene  diamine,  155 
Pentosanes,  61,  106 
Pentoses,  61,  105 
Pentosuria,  61 
Pepsin,  action  of,  685 
Peptone,  food  value  of,  645 
Peptones,  100 

fractionation  of,  685 
Peptonised  blood,  840,  849 
Pericardium,  use  of,  894,  910 
Perilymph,  515 
Perimeter,  563 
Peripheral  ganglia,  inhibition  in,  475 

nerve  nets,  469 

reflexes,  474 
Peripolar  zone,  268 
Peristalsis,  727 

Permeability  of  membranes,  22,  125,  131 
Peroxidases,  1108 
Pes,  374 

Pette7iJcofer's  respiration  apjmratus,  618 
Pfeffer's  cell,  125 
Pfiicger's  law,  267 
Phagocytes,  1022 
Phagocytosis,  816,  1022 
Phakoscope,  540 
Phenylalanine,  85,  91 
Phenylethylamine,  156 
Phenylglucosazone,  63 
Phenylhydrazine  test,  123,  162 
Phenyllactosazone,  68 
Phenylmaltosazone,  67 
Phloridzin  diabetes,  801 
Phloroglucin  reaction  for  pentoses,  01 
Phonation,  pressure,  523 
Phosphates,  estimation  of,  1129 

excretion  in  large  intestine,  724 
by  kidney,  ]  147 

in  urine,  1]  13 
Phosjihatides,  57 
Phospholipincs,  57 
Phosphoprotein,  100 ' 

Phosphoprotcins.  action  ofgastric  juice  on,  68 
Phosphorus,  43,  57 


Photochemical  substances  in  retina,  567 

Photo-hajmatachometer,  889 

Phototaxis,  27 

Phrenic  nerve,  electrical  variations  in,  242 

Phrenology,  434 

Physiology,  definition  of,  1,  7 

general,  13 
Physiological  heat- values,  621 
Pick  on  fractionation  of  proteoses,  085 
Picric  acid,  51 
Pilomotor  nerves,  469 
Pineal  gland,  1193 
Pinna,  function  of,  511 
Piqure  diabetes,  800 
Pituitary  body,  extirpation  of,  1191 
structure  of,  1190 

extract,  effect  of,  1192 
Placenta,  functions  of,  1232 
Plain  muscle,  180,  243 

chemical  stimulation  of,  246 
contraction,  time-relations  of,  243 
double  innervation  of,  247 
influence  of  temperature  on,  247 
mechanical  stimulation  of,  246 
stimulation  of,  244 
Plasma,  muscle-,  212 

blood,  811,  857 
Plasmalmut,  21 
Plasmolysis,  22,  23,  127 
Plasmosome,  16 
Plasome,  20 
Plasteins,  169 
Plastids,  17,  33 
Plethora,  1009 

Plethysmograph  for  kidney,  993 
Pleura,  1040 

permeability  of,  136 
Pleural  cavity,  negative  pressure  in,  1045 
Pneumogastric  nerve,  see  Vagus 
PoliVs  reverser,  188 
Poikilothermic  animals,  1169 
Polar  bodies,  1209 
Polar  zone,  268 
Polarimeter,  51 
Polarisation,  51,  173,  224 

by  colloids,  145 

in  nerve,  280 
Polarised  light,  51 
Polarising  current,  265 
Polymorphonuclear  leucocytes,  813 
Polymorijhous  layer  of  cortex,  428 
Polypeptides,  89,  90,  99,  704 

action  of  trypsin  on,  89 

reactions  of,  89 

synthesis  of,  88 
Polysaccharides,  62,  68 
Pons  Varolii,  371 

antero-lateral  tract,  372 

functions  of,  394 

pedal  portion,  372 

structure,  370 

tegmentum,  372 
Portal  system  in  birds,  761 
Position,  sensations  of,  603-609 
Positive  after-images,  571 

polarisation  of  nerve,  282 

ventilation,  1091 
Posterior  columns  of  cord,  354 

crico-arytenoid  muscle,  521 

longitudinal  bundle,  369,  370,  372,  381, 
389,  408 


INDEX 


1265 


Posterior  root-ganglion,  development,  298 
Postganglionic  fibres,  472 
Postural  reflexes,  449 

tonus,  449 
Potassium,  43 

Potential  energy  of  compounds,  156 
Precipitins,  10o6 
Precuneus,  417 
Preganglionic  fibre,  471 
Pregnancy,  1230-1230 
Pre-pyramidal  tract,  353 
Presbyopia,  546 
Pressor  reflexes,  1001 
Pressure  impulses  in  cord,  359 

sense.  489 

slope  in  vascular  S3'stem,  877 
Primary  coil,  189 
Primitive  sheath  of  nerve,  251 
Primordial  follicles,  1222 

utricle,  14,  127 
Principal  focus  of  lens,  531 

plane,  531 

point,  531,  533 
Projection  fibres  of  cerebnim,  422 
Projicient  sense  organs,  293,  384 
Proline,  85,  91 

fate  of,  772 
Pro-nuclei,  1209 
Proojstrum,  1226 
Prophase  of  mitosis,  1205 
Propionic  acid,  48,  54 
Proprioceptive  system,  397,  479,  598 
Propriospinal  fibres,  351 
Pro-sccretin,  709 
Prostate,  1221 
Prosthetic  group,  101 
Protamines,  92,  97,  101 
Proteins,  45.  71 

absorption  of,  744 

amide  nitrogen  in,  93 

ammonia  nitrogen  in,  93 

amount  of  nitrogen  in,  616 

biuret  reaction,  93 

carbohydrate  radicle  in,  94 

classification  of,  97-108 

colour  reactions  of,  93 

composition  of,  71,  90 

conjugated,  101 

constitution  of,  90 

copper  compounds,  75 

crystallisation  of.  72 

derivatives  of,  98 

diamino-nitrogen,  93 

disintegration  products  of,  81 

distribution  of  nitrogen  in  molecule.  91 

effect  of.  on  metabolism,  631,  653 

halogen  derivatives,  98 

heat  coagulation  of,  72,  95 

hj^dratcd,  98 

hycbolysis,  76,  99 

hydrolysis  by  enzymes,  76 

in  urine,  1121 

metabolism  of,  756-773 

effects  of  variation  in  diet,  ()33 
endogenous,  767 
Foliiis  theorv.  644 
in  starvation^  630,  633 
Pflugcr's  theory,  642 
Voit-s  theory,  642 

minimum  requirement,  654 

molecule,  structure  of,  76,  88 


Proteins,  synthesis  of,  88 

molecular  weight  of,  74 

osmotic  pressure  of,  75 

oxidation  of,  764 

physical  characters,  72 

precipitation  bj'  metallic  salts,  94 

putrefaction  of,  76 

salting  out,  96 

salts  of,  72 

separation  of,  95 

specific  dynamic  effect  of,  636 

sulphur  in,  74 

synthesis  of  in  body,  113-119 

tests  for,  93 
Proteose,  food  value  of,  645 
Proteoses,  100 

fractionation  of,  687 

hydrolytic  products,  687 
Prothrombin,  843 
Protocercbrom,  294 
Protopathic  sensibilitj-,  495 
Protoplasm,  15 

constituents  of,  36 

ph5'sical  condition  of,  20 

salts  of,  43 

surface  tension  in,  21,  24 

theories  of  structure,  17 

ultra-microscopic  structure.  20 
Proximate  constituents  of  the  bod}\  45 
Psalterium,  427 
Pseudo-globulin,  866 
Pseudo-ious,  149 
Pseudomucin,  105 
Pseudo-nucleiu,  100.  088 
Pseudopodia,  14 
Pseudo-reflexes,  474 
Psychical  secretion  of  gastric  juice.  691 
Ptyalin,  601 

Puberty,  changes  at,  1217 
Pulmonary  circulation,  935-938 

ventilation,  1046 
Pulse,  918-928 

anacrotic  wave,  926 

catacrotic,  926 

clinical  features  of,  928 

dicrotic  wave,  921,  923,  925 

in  veins,  933 

percussion  wave,  923 

pre-dicrotic  wave,  923 

primarj'-  wave,  923 
Pulse-pressure,  875 
Pulse-rate,  in  man,  981 
Pulse-wave,  velocity  of,  923 

nature  of,  918 
Pulvinar,  376 
Pupil,  543 

contraction  of.  550 

dilatation  of.  551 
Purine  bases,  102 

in  fa?ces,  754 
in  urine,  780 

metabolism,  774-7S2 

ring,  102,  775 
Purkinje  cells  of  cerebellum,  400 

fibres  of  heart,  952 

figures,  562 
Putreseine,  156 
Pyloric  canal,  698 

sphincter,  699 

vestibule,  698 
Pylorus,  nervous  mechanism  for  opening,  CO') 


1266  INDEX 


Pylorus,  opening  of,  697 
Pyramidal  cells  of  cortex,  427 

decussation,  352,  366 

tracts,  352,  366,  423 
Pyi'imidine,  103 

bases,  775 
Pyrogallol,  50 
Pyrrol  ring,  85 

synthesis  of,  118 
apyrrolidin  carboxylic  acid,  85 
Pyruvic  acid,  49,  762 
origin  of,  762 

Qtjadki-tjbates,  1118 
Quellung,  151 

Racemic  compounds,  52 
Rami  communicantes,  468 
Reaction,  velocity  of,  162,  163 
of  blood,  987,  1087 
of  degeneration,  269 
time,  457 
Reactions,  balanced,  166 
reversible,  166,  169 
Recapitulation,  Law  of,  13 
'  Receptor  '  substance,  276 

action  of  adrenaline  on,  278,  1184 
Recessive  characters,  1215 
Reciprocal  innervation  from  cortex,  437 

of    antagonistic    muscles, 
335 
Recti  muscles,  585 
Red-blindness,  578 

corpuscles,  see  Blood 
marrow,  834 
nucleus,  377,  383 
'  Red  reflex,'  555 
Reduced  eye,  533 
Referred  pain,  476 
Reflex  action,  Bahnung,  305 
block  in,  305 
delay  in,  303 
facilitation  of,  305 
fatigue  of,  304,  343 
general  characters  of,  303 
inhibition  of,  306,  339 
in  spinal  animal,  329,  332 
localisation,  303 
reinforcement,  341 
successive  spinal  induction,  344 
summation,  304 
arc,  178,  295 
movements,  177 

scratch-,  332,  343 
time,  304 
tone,  398 
Refractive  indices  in  eye,  533 
Refractory  period,  273 
Eegnault  and  Reiset's  respiration  apparatus, 

617 
Reissner's  membrane,  516 
Eemak's  ganglion,  940,  942 
Renal  excretion,  1110-1160 
mechanism,  1149-1151 
Rennin,  688 

Reproduction,  1199-1245 
in  man,  1217-1245 
in  metazoa,  1202 
in  protozoa,  1200 
Reproductive  organs,  development  of,  1217 
female,  1221 


Reproductive  organs,  male,  1219 
Residual  air,  1047 
Resonants,  527 
Resonators,  507 
Respiration,  1039-1109 

apparatus,  Benedict's,  617 
Haldane's,  616 
Pettenlcofer's,  618 
Regnault  and  Reisef,  617 
Ztintz  and  Geppert,  618 
chemistry  of,  1051-1075 
effects  of  changes  in  air  on,  1098-1 104 
effect  on  circulation,  937 
of  deglutition  on,  681 
of  division  of  vagi,  1089 
movements,  co-ordination  of,  1076 
rate  of,  1041 

reflex  regulation  of,  1089-1097 
'  Respiration  of  swallowing,'  677 
Respiratory  centre,  1077 

automaticity  of,  1078 
chemical  excitants   of, 

1079-1081,  1087 
inhibitory  action  of  vagus 

on,  1092 
spinal,  1078 

stimulation  of,   by  acids, 
1087 
by  oxygen  lack, 
1083 
exchange,  total,  616 
movements,     chemical     regulation     of, 
1079-1089 
Head's  method,  1089 
mechanics  of,  1039-1050 
regulation  of,  1076-1097 
muscles,  1043 
quotient,  640,  1051 

effect  of  foods  on,  641 
in  diabetes,  809 
in  hibernation,  794 
in  muscular  work,  217 
sounds,  1045 
Restiform  body,  368,  402 
Rete  mucosum,  1161 
Reticulin,  107 

Retina,  chemical  changes  in,  564 
development  of,  558 
physical  changes  in,  564 
structure  of,  559 
Retinal  changes  in  vision,  558-567 
image,  path  of  rays,  534 
induction,  582 
Retractor  lentis,  548 

penis  muscle,  247.  1229 
Retrograde  degeneration,  320 
Reverser,  PohVs,  188 
Reversibility  of  ferment  action,  166,  168 
Revertose,  167,  168 
Rheocord,  192 
Rheonome,  270 
Rheoscopic  frog,  233 
Rheotaxis,  1228 
Rhinccephalon,  421 
Rhodopsin,  559,  565 
Rhombencephalon,  362 
Ribs,  movements  of,  1042 
Ricin,  1031 
Rigor  mortis,  208,  214 
Rima  glottidis,  521 
Ringer's  fluid,  963 


INDEX 


1267 


RUter-  Valli  law,  274 

Kods  of  Corti,  51(j 

Rolandic  fissure,  419 

Roof  nuclei  of  cerebellum,  383,  402 

Rubro-spinal  tract,  353,  389 

Buffird's  organs,  497 

Saccharic  acid,  62 

Saccharose,  07 

Saccule,  515 

Saccus  endol3'mpliaticus,  004 

Sacral  autonomic  fibres,  473 

Salicylic  acid,  50 

Saliva,  comjiosition  of,  601 

energy  involved  in  secretion,  074 
secretion  of,  003 

effect  of  nerves  on,  GOO 
Salivary      secretion,      energy    changes     in. 
074 
effect  of  metabolites,  075 
histological  changes  in,  070 
pressure,  6158 
theories  of,  608 
Salivary  digestion,  062 

in  stomach,  603 
glands,  innervation  of.  005 

changes   accompanying  secre- 
tion, 008-073 
double  ncrve-suppl}'.  073 
electrical    changes    in,    during 
secretion,  072 
Salmin,  composition  of,  91 
Salt  hunger,  047 

solutions,  absorbability  of.  738 
Salts,  absorption  of,  753 
Saponification,  40,  50 

number,  50 
Sarcolactic  acid,  215 
Sarcolcmma,  179 
Sarcomere,  179 
Sarcoplasm,  179 
Sarcosine,  84 
Sarcostyles.  179.  181 
Sai'cous  elements,  181 
Sartorius  of  frog,  1 83 
Scala  media,  515 
Scatol,  fate  of,  770 

Schafers  theory  of  contraction,  182,  236 
Schciner's  experiment,  589 
Schematic  eye,  532 
Schlcnim,  canal  of,  543 

functions,  596 
Schivann's  sheath,  251 
Scleroproteins.  106 
Sclerotic  coat  of  eye,  542 
Scratch  reflex,  332,  343 
Sebaceous  glands,  1162 
Sebum.  1162 
Second  wind,  1008 
Secondary'  contraction,  233 
Secretin,  TO9.  1179 

action  on  intestinal  secretion,  720 
liver,  716 
Secretion,  energy  changes  in.  674 
Semicircular  canals,  399,  515 

destruction  of,  606 
functions,  605 
Semilunar  ganglion,  400 

valves,  structure  of,  893 
Semi-permeable  cell,  125 

membranes,  125,  132 


Sensation,  extent  of  stimulus,  4S2 
locali.sation  of,  481 
modality  of,  479 
physiology  of,  478-009 
projection  of,  481 
quantitative  study  of.  482—485 
relation  to  stimulus.  478-485 
Sensations,  organic.  598-009 
Sensori-motor  areas.  444 
Sensory  adaptation,  482 
aphasia,  454 
areas  of  cortex,  444 
association.  451 
paralysis,  .340 
path,  357 
Septo-marginal  bundle,  354 
Serine,  81.  91 

Serous  salivary  glands,  663 
Sertoli,  cells  of,  1221 
Serum-albumin,  98.  865 

composition  of,  91 
crystal! i.^ation  of,  73 
Serum-globulin,  98,  860 
Serum-proteins,  osmotic  pressure  of,  143 
Seventh  nerve,  nucleus  of,  379,  381,  413 

visceral  fibres.  472 
Sex^al  organs,  relation  to  ductless  glands,  1219 
process,  essential  features  of,  1199-1211 
Sham  feeding,  090 
Shock,  300 

spinal,  330 
Short  ciliary  nerves.  552 

sight,  535 
Sibilant  consonants.  .527 
Side-chain  theorj',  1034 
Side  wire,  Hehnhol/z,  189 
Simultaneous  contrast,  583 
Sino-auricular  node,  951 
Sixth  nerve,  nucleus  of.  379,  411 
Size,  illusions  of.  591 
judgment  of,  590 
Skin,  absorption  by.  1165 
functions  of,  1101-1 10() 
gaseous  exchanges  in,  1105 
structure  of,  1101 
Small  intestine,  absorption  from,  733 
innervation  of.  728 
lymph  production  in.  735 
movements  in,  725-729 
Smell,  sense  of,  501 

sensations,  498,  502 
Smooth  muscle,  see  Plain  muscle 
Soaps,  40,  55 

in  digestion,  742 
Sodium,  43 
Solar  plexus.  408 
Soliditv.  judgment  of.  593 
Sols.  139 

Solubilitv  of  gas,  effect  of  pressure  on,  1057 
Solute,  131 

Somatic  nervous  S3'stem,  406 
Sorbite,  62 
Sound,  natvne  of.  505 
jiitch  of.  500 
timbre.  506 
Spaces  of  Fonlaiia.  543 
Spastic  gait,  335.  4.50 

paraplegia,  335,  450 
Specific   dvnamic   action   of   proteins,   630, 
764!  803 
irritability,  law  of,  255 


1268 


INDEX 


Speech,  453,  520-527 

intellectual  basis  of,  455 
mechanism  of,  525 

Spermaceti,  56 

Spermatids,  1208 

Spermatocytes,  1208 

Spermatozoa,  development  of,  1208 

Spherical  aberration,  537 

Sphincter  puiDillse,  550 
trigoni,  1153 
urogenitalis,  1153 

Sphingomyeline,  57 

Sphygmographs,  922 

Spinal  animal,  329,  393 

Spinal  cord,  aiJerent  path,  328 

anterior  cerebellar  tract,  354 

columns,  356 
ascending  tracts,  352,  354 
Biirdach's  column,  324 
cells  in,  318 

of  columns,  318 
central  canal,  300 
Clarke's  column,  318 
collaterals  in,  324,  351,  357 
comma  tract,  353 
commissural  cells,  318 
conduction  in,  351-360  ^ 

crossed  pyramidal  tract,  353 
descending  tracts,  352 
development,  299 
direct  cerebellar  tract,  354 

pyramidal  tract,  352 
dorsal  cerebellar  tract,  354 
effect  of  poisons,  347 
efferent  path,  327 
endogenous  fibres,  352 
Golgi  cells,  318 
Galls''  column,  324 
Gower's  tract,  356 
Helweg's  bundle,  353 
hemisection,  359 
lateral  basis  bundle,  371 
lateral  columns,  354 
Lissauer's  tract,  324,  352,  357 
Mane's  tract,  354 
MonaJcow's  bundle,  353 
motor-cells,  318 
olivo-spinal  tract,  353 
pain  impulses,  359 
path  of  impulses,  357 
posterior  columns,  354 
postero-external  column,  324 
jjre-pyramidal  tract,  353 
pyramidal  tracts,  352 
as  reflex  centre,  322 
rubro-spinal  tract,  353 
sensori-motor  path,  357 
septo-marginal  bundle,  354 
structure,  315 
thalamico-spinal  tract,  353 
tracts,  methods  of  tracing,  319 
trophic  functions,  349 
ventral  cerebellar  tract,  354 
vestibulo-spinal  tract,  353 
Wallerian  degeneration'  352 
white  matter,  arrangement,  351 
Spinal  dog,  331 
shock,  330 

Spino-tectal  tract,  356 
Spino-thalamic  tract,  356 
Spiral  ganglion,  517 


Spiral  lamina,  517 
Splanchnic  nerve,  996 
Spleen,  function  of,  1195 

rhythmic  contractions  of,  1195 
structure  of,  1194 
Spongin,  108 
Spongioblasts,  252,  298 
Spongioplasm,  18 
Staircase  phenomenon,  245 

in  heart  muscle,  956 
Stannius'  ligature,  940 
Stapedius  muscle,  514 
Stapes,  513 
Starches,  68 
Starch,  digestion  by  saliva,  662 

hydrolysis  of,  68,  99 

molecular  weight,  68 

soluble,  68 

structure  of,  69 
Starvation,     carbohydrate    metabolism    in, 
628 

fat  metabolism  in,  630 

loss  in  various  organs,  625 

metabolism  in,  624-030 

protein  metabolism  in,  630,  633 
Static  ataxy,  346 
Stearic  acid,  54 
Stearyl-lecithin,  57 
Stellate  ganglion,  466 
Stepping  reflex,  332 
Stercobilin,  origin  of,  715 
Stereoisomerism,  52,  60,  78 
Stereosomers,  action  of  ferments  on,  167 
Stereoscope,  593 
Stereoscopic  vision,  593 
Sternzellen,  816 
Stimulation,  electrical,  nature  of,  270 

of  human  nerve,  268 
Stimuli,  summation  of,  245 
Stimulus,  intensity  of,  482 

liminal,  482 

locus  of,  339 

maximal,  193,  205 

minimal,  193,  205 

threshold,  483 
Stokes -Adams  disease,  955 
Stomach,  digestion  in,  683-696 

innervation,  700 

movements  of,  697 

secretory  nerves  of,  691 

sphincters,  701 
Stratum  granulosum,  1161 
Stratum  lueidum,  1161 
Stria  terminalis,  377 
Striae  acousticse,  379,  380 
Striated  muscle,  structure  of,  179 

of  invertebrates,  248 
String  galvanometer,  228 
Siromuhr,  Ludwig's,  888 

Starling's,  888 
Structural  basis  of  body,  13 
Strychnine,  effect  on  cord,  347 

spasm,  electrical  variation,  242 
Sturin,  composition  of,  91 
Sublingual  gland,  663 
Submaxillary  ganglion,  473,  666 

gland,  663 
Substantia  gelatinosa  of  Rolando,  316 

nigra,  374,  377,  383 
Substrate,  164 

effect  of  ferments  on,  167 


m 


INDEX 


1269 


Subthalamic  region,  377 
Successive  contrast,  5815 

spinal  induction,  344 
iSuccus  entcricus,  .see  Intestinal  juici 
Sugar  in  urine.  11 22 

formation  of,  from  fat,  794 

from  protein.  112^ 

in  plants.  Ill 

utilisation  of.  in  body,  790 
Sugars,  chemistry  of.  (KMiS 

oxidisability  of.  in  body.  I  KXi 
Sulphocyanate  in  saliva.  (W\ 
Sulphur,  42 

excretion  of.  7H9 

test  for  jjrotcins,  Sfi.  94 
Summation.  245 

of  muscular  conti'actions.  20(> 

of  sensation,  482 

of  stimuli.  245.  272 

in  heart  muscle.  95() 

tones,  510 
•Supplemental  air.  1046 
Suprarenal  bodies.  J181-llS(i 
Surface  tension.  21.  24 

in  colloids.  141 
Suspensory  ligament.  543 
Swallowing — -sfi'  1  )egliitition 
Sweat,  amount  and  pro])erties.  Il(i3 

glands.  1 103 

loss  of  heat  by.  1 1 7<i 

secretion.  1 1<)4 
Swira-bladder  of  lish.  1074 

tension  of  oxygen  in.  135 
Sylvian  aqueduct.  .363.  373 

fissure.  419 
Symbiosis,  1021 
SymiMthetic  ganglia.  4()(> 
functions.  474 
svstem.  969.  975 


T.\CHYl'N(E.\,   1080 
Tactile  localisation.  489 

sensations.  489 

sense  area.  444 
paths.  444 
Tiilbot'"  law.  572 
Tartaric  acid.  52 
Taste,  498 

area,  448 

buds.  499 

nerves  of.  500 

sensation,  classification.  499 
Tears,  comi)osition  of,  594 
Tecto-spinal  tract.  391 
Tenon,  capsule  of,  585 
Tension,  efieet  of  on  bliidder.  1 1  ~Ai 
on  lii^art.  958 
on  muscle.  201 
'I'ensions  of  gases  in  liquids.  1059 
Tensor  tymi)ani  muscle.  514 
Tenth  nerve,  nucleus  of.  414 
Testis,  structure  of,  1219 
Tetanus.  207 

toxin,  action  on  cord,  348 
Tetrachromic  vision.  580 
Tetrapeptidcs.  89 
Tegmentum  of  jions.  372 

of  mid-brain.  374 
Tcichnidnn'-i  crystals.  825 
Telencephalon,  363 


Telophase  of  mitosis,  1206 
T(Mnperature.  action  of,  on  heart,  962 
on  muscle,  207 
effect  of,  on  metabolism,  1168,  1172 

on     electrical     variations     in 
mu.scle,  230 
limits  of,  for  life,  6 
sense,  486 

adaptation  of,  488 
Temi)oral  lobe.  417 
Temporo-iJontine  fibres,  424 
Tendon  phenomena,  333 

use  of,  336 
reflexes.  333 
Thalamenccphalon.  392,  395 
Thalamico-spinal  tract,  353 
Thalamo-cortical  tract,  422 
Thalamo-frontal  fibres,  423 
Thalamo-spinal  tract,  391 
Theobromine,  103,  775 
Thermo-electric  couple,  220 
Thermogenic  centres.  1177 
Thermopile,  219 
Thermotaxic  system,  1 1 77 
Thigmotaxis,  27 
Thiophenc  test.  215 
Third  nei-ve.  functions  of,  552 

nucleus  of.  379.  382.  4(i.S.  41u 
visceral  fibres  in.  472 
Tltiii/-  Valid  fistula,  718 
Threshold  .stimulus,  483 
Thrombin.  842 
Thrombogen.  844 
Thrombokinasc.  844 
Thymine.  104.  776 

Thymus,  structure  and  functions  of.  1193 
Thyroid  gland.  1186 

extirpation  of.  1 187 
extract,  efifectsof.  1188 
structure  of,  1186 
Tidal  air,  1046 
Tissue-fibrinogen.  102.  846 
Tissue-nroteins.  642 
Tone  in  muscle.  333 

in  heart,  958 
Tonus,  postural,  449 
Tortoise  heart.  *^10 
Touch  discrmination.  491 
impulses  in  cord,  359 
projection  of.  493 
sense.  489 
spots.  489 
Toxins,  adsor])tion  of,  1(*34 
bacterial.  10.30 
mode  of  action.  10.30 
Toxoids.  1034 
To.xones.  1032 
Toxophore  group.  1034 
Tmnbc-Hnlnii  curves.  988 
Trapezium  of  pons.  371.  381.  3S7 
Triclu'omats,  anomalous.  581 
Trichromatic  vision.  57s 
'i'ricuspid  valve.  893 
Trigeminal  nerve,  nucleus  of.  38(t 
Trigemino-thalamic  tract.  387 
Trimcthylamine.  49 
Tripeptides.  89 
Trii>l«-  phosphate.  1114.  1125 
Tritocerebrom.  294 
I'rwnvirr'-t  test,  (i2 
Trophoblast,  1231 


1270  INDEX 

Trypsin,  703 

action  on  polypeptides,  704 
on  proteins.  703 

velocity  of  action,  166.  705 
Trypsinogen.  703 
Tryptophane.  85.  91.  94 

fate  of,  772 
Tuber  cinereiim.  363.  375 
Tympanic  membrane,  512 

movements  of.  513 
Tympanum,  512 
Tyrosinase.  1108 
Tyrosine,  50,  84,  91 

in  urine.  1125 


Uffehnan7Vs  reagent,  215 
Ultra-microscope,  145 
Umbilical  cord,  1232 
Uncinate  fasciculus,  426 
Uncus,  419 

Unipolar  excitation,  269 
law  of,  269 
Unstriated  muscle,  243 

propagation  of  wave  in,  246 
Uracil,  104,  776 
Urate  deposit,  1124 
Urates,  1118 
Urea,  1115 

estimation,  1126 

Folin's  method,  1127 
hypobromite  method,  1126 
fermentation  of,  1115 
origin  of,  759 
output  in  starvation,  630 

on  protein  diet,  758 
preparation  from  urine,  1117 
Ureter,  contractions  of.  1152 
Uric  acid,  103,  1117 
crystals,  1125 
daily  amount,  1119 
endogenous,  780 
estimation,  1128 
excretion,  779 
in  gout,  781 
origin  of.  777 
preparation,  1117 
production  in  birds,  760 
structure  of,  775 
synthesis,  103 
tests,  1118 
Uricolytic  ferment,  779 

Urinary  constituents,  estimation  of,   1126-- 
1130 
deposits,  1124 
Urine,  abnormal  constituents  in,  1121-1125 
acetone  in,  1123 
ammonia  in,  1115 
average  composition.  1112 
bases  of,  1114 
chlorides  of,  1112 
composition  of,  1110-1130,  1142 

on  various  diets,  780 
conditions  of  glomerular  filtration,  1138 
freezing-point.  1111 
inorganic  constituents  of,  1112 
lactose  in,  1123 
neutral  sulphur  in,  1113 
organic  constituents  of,(1115 
oxyacids  in,  11231 
phosphates  of,  1113 


Urine,  pigments  of,  1120 

pressure  of,  in  ureter,  1137 

reaction  of,  1111 

secretion  of,  1131-1151 
in  glomerulus,  1135 
influence  of  colloids,  1137 

kidney  volume,  1139 

specific  gravity  of,  1111 

sugar  in,  1122 

sulphates  of,  1113 
Uriniferous  tubule,  course  of,  1131 

tubule,  functions  of,  1134 
Urobilin,  1121 
Urochrome,  1120 
Uroerythrin,  1121 
Urorosein,  1121 
Urotropine,  1127 
Uterus,  changes  in,  during  pregnancy,  1 230 

nerve-supply,  1228 
Utricle,  515 

primordial,  14,  127 
Uvea,  561 

Vacuole,  contractile,  15 
Vago-glossopharyngeal  nucleus,   379,   414 
Vagus,  473 

action  on  auricles,  972 
on  heart,  971 
on  intestines,  729 
on  oesophagus,  682 
on  respiration,  1089 
on  stomach,  701 
distribution  in  abdomen,  700 
nucleus  of,  414 

proof  of  inspiratory  fibres  in,  1092 
tonic  action  on  heart,  975 
Valerianic  acid,  54 
Valine,  81 

Valve  of  Vieussens,  362,  371 
Valves  of  heart,  see  Heart 
Variation,  monophasic,  230 
Vasa  afferentia.  1133 
efferentia,  1133 
recta,  1133 
Vascular  area  of  chick,  831 

system,    influence    of    capacity    of,    on 

circulation,  880 
tone,  effect  of  central  nervous  svstom 

on.  982 
peripheral,  990 
Vaso-constrictor  fibres,  course  of,  994 
Vaso-dilatation,  criteria  of,  991 
Vaso-dilatation  by  metabolites,  1002 
Vaso-dilator  fibres  in  nerve-trunks,  997 

nerves,  996 
Vaso-motor  centre,  action  of  acids  on,  989 
location  of.  983 
variations  in  activity  of.  983 
centres  in  cord,  989 
impulses,  path  of,  in  cord,  300 
nerves,  course  of,  990 
reflexes,  1000 
Vegetable  food,  utilisation  of,  649 
Veins,  blood-flow  in,  932-934 
capacity  of,  883 
distensibility  of,  871 
structure  oi\  870 
valves  in,  933 
Velocity  of  reaction,  162,  103 

in  vascular  system,  879 
Venous  pressure  in  man,  877 


INDEX 


1271 


Venous  outflow,  determination  of,  994 

pulse,  933 

iu  heart  block,  955 
Ventilation,  1104 
Ventral  cerebellar  tract,  354 
Ventricles,  capacity  of,  891 

pressure  in,  890 
Veratrine,  action  of,  on  muscle,  2\  1 
Vesicular  murmur,  1045 
Vestibular  nerve.  Inciters'  nucleus,  381,  402 
functions  of,  398 
nucleus  of,  380,  413 
Vestibule,  515,  604 
Vestibulo-cerelx'llar  fibres,  370,  389 
Vestibulo-apinal  tract,  353,  391 
Vibrative  consonants,  527 
Vtcq  (VAzyr's  bundle,  388,  421 
Villus,  changes  in,  during  protein  absorption, 

745 
Villus,  structure  of,  734 
Viscera,  innervation  of.  473 

sensibility  of,  494 
Visceral  nervous  system,  400—477 
Vision,  528-597 
Visual  adaptation.  572 

angle,  534.  589 

axis,  561 

centre,  447 

fatigue,  572 

judgments,  589-593 

localisation,  589 

path,  387,  406,  447 

purple,  559,  565 

reflexes,  406-409 

sensation,  Weber's  law,  570 

sensations,  568-584 

stimuli,  time  relations,  571 
Visuo-psj'chic  area,  lamination,  431 
Visuo-sensory  area,  lamination,  431 
Vital  capacity,  1046 
Vitalism,  8 
Vitamines,  652 
Vitellins,  100 
Vitreous  humour,  532 
Vocal  cords,  521 
Voice,  520-527 
VolhanVs  method  for  chlorides,  1129 


Voluntary  contraction,  239 

electrical  changes  in,  242 
muscle,  177 
Vowel  sounda,  525 

Wallerian"  degeneration.  36i- 

method,  320  i 
Warm  points,  486 
Water,  absorption  of,  733 

estimation  in  food,  014 

neces.sity  for,  6 

and  dissolved  substances,  passage  across 
membranes,  131-138 

rigor,  231,  945 
Weber's  law,  485,  491 

in  vision,  570 
Wernicke's  aphasia,  454 
WeyVs  test,  1117 
White  rami.  468 

sensation  of,  576 
Word- blindness,  455 
Work,  relation  to  stimulus,  26 

Xanthine,  103,  778 
Xanthoproteic  reaction,  93 
Xylose,  61,  104 

Yeasts,  action  on  amines,  77 

on  carbohydrates,  64,  65,  67 
Yellow  spot,  561 
Young-Helmholtz  theory,  577 

Zein,  98 

food-value  of,  646 
Zincative,  229 
Zollner's  lines,  592 
Zona  fascicidata,  1181 

glomerulosa,  1181 

pellucida,  1222 

reticulata,  1181 
Zonula  ciliaris,  543 
Zonule  of  Zinn,  543 
Zooid,  818 
Zymins,  671 
Zymogen  granules,  671 


HALr-AxrvxK,  HA^•^!0^'  &>  co    ltd. 

LONDON    AND    EDINBURGH 


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